Pyrimidines for degrading Bruton's tyrosine kinase

Abstract

To provide compounds that induce proteolysis of Btk via a ubiquitin proteolysis pathway.SOLUTION: The present invention provides compounds of formula (I), where R1, R2, R3, R4A, R4b and R5 are as defined herein, and pharmaceutically acceptable salts thereof, which are useful as agents in treatment of CLL.SELECTED DRAWING: Figure 1

Description

[Background Technology]

[0001] Bruton's tyrosine kinase (Btk) is a key signaling enzyme expressed in hematopoietic cell types. Btk plays an essential role in the B cell signaling pathway, which links stimulation of the cell surface B cell receptor (BCR) to downstream intracellular responses. Btk is a key 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). In addition, Btk plays a role in other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR)- and cytokine receptor-mediated TNF-α production 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. See, for example, CA Jeffries et al. (2003), Journal of Biological Chemistry 278:26258-26264; NJ Horwood et al. (2003), The Journal of Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3):1646-1656, and Quek et al. (1998), Current Biology 8(20):1137-1140. Btk inhibitors are currently under investigation. As an alternative to inhibition, proteolysis of Btk may affect B cell function not only by blocking BCR signaling, but also by reducing the presence of Btk protein from the cell itself, which should reduce Btk kinase activity as well as any protein interaction or scaffolding function of Btk.Therefore, there is a medical need to develop agents that degrade Btk. [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] CA Jeffries et al. (2003) Journal of Biological Chemistry 278:26258-26264 [Non-patent document 4] NJ Horwood et al. (2003) The Journal of Experimental Medicine 197:1603-1611 [Non-Patent Document 5] Iwaki et al. (2005), Journal of Biological Chemistry, Vol. 280(48): 40261-40270 [Non-patent document 6] Vassilev et al. (1999) Journal of Biological Chemistry 274(3):1646-1656 [Non-Patent Document 7] Quek et al. (1998) Current Biology 8(20):1137-1140 Summary of the Invention [Means for solving the problem]

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

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

[0005] [ka] [In the formula, 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 CHOCH; R 5 is selected from the group consisting of hydrogen, halo, and C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, R 1 is selected from the group consisting of hydrogen, C1-C3 alkyl, CN (cyano), C1-C3 haloalkyl, halo, CHOCH; CHOH; and CHCN or a pharmaceutically acceptable salt thereof. 1 is C1-C3 alkyl or a pharmaceutically acceptable salt thereof. 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 CF or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is halo or a pharmaceutically acceptable salt thereof. In some embodiments, R1 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 CHOH or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is CHCN or a pharmaceutically acceptable salt thereof.

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

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

[0009] In some embodiments, R 4a and R 4b are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, and CHOCH, or a pharmaceutically acceptable salt thereof. 4a is hydrogen and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a is hydrogen and R 4bis methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a 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 is ethyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a 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 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 is CH2OCH3 and R 4b is hydrogen or a pharmaceutically acceptable salt thereof.

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

[0011] In some embodiments, R 1 is methyl and R 2 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is methyl and R 2 is hydrogen and R 3 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 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 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 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 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 is methyl and R 3 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is hydrogen and R 4a is hydrogen and R4b 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 the 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 the 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, R 5 is the halo and R 4ais hydrogen and R 4b is ethyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is F and R 4a is hydrogen and R 4b is ethyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is the halo and R 4a is ethyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is F and R 4a is ethyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof.

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

[0016] In some embodiments, a therapeutically effective amount of

[0017] [ka] 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] is.

[0022] In some embodiments, the compound is

[0023] [ka] is a pharmaceutically acceptable salt of

[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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2,2-dimethylpiperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-(trifluoromethyl)phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; and 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-fluorophenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

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

[0029] It should be noted that as used in this specification and the intended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a 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 moiety is indicated by the prefix "C x ~C y」 where x is the minimum value and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C3 alkyl" means an alkyl substituent containing from 1 to 3 carbon atoms.

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

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

[0033] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halo group. 1~ "C3 haloalkyl" refers to a haloalkyl having 1, 2, or 3 carbon atoms. In some embodiments, 1, 2, or 3 hydrogen atoms can be replaced by fluoro groups, respectively. An example of a haloalkyl is trifluoromethyl or CF3. [Brief explanation of the drawings]

[0034] [Figure 1] FIG. 1 shows the in vivo activity of Compound 1 (Example 1) in TCL1-driven CLL harboring the BtkC481S mutation in C57BL / 6 mice. DETAILED DESCRIPTION OF THE INVENTION

[0035] In some embodiments, the compounds disclosed herein comprise two ligands connected 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 and / or includes 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, including 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 are capable of binding to Btk and reducing the amount of Btk in a cell by degradation.

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

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

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

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

[0040] The phrase "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

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

[0042] As used herein, the terms "treat," "treating," and "treatment" refer to a method of alleviating or arresting diseases and / or their attendant symptoms.

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

[0044] General Synthesis The compounds of the present disclosure can be better understood in connection with the following synthetic schemes and methods that illustrate the means by which the compounds can be prepared. Representative procedures are shown in, but not limited to, Schemes 1-5. In Schemes 1-5, the variable group R 1 , R 2 , R 3 , R 4 and R 5may be as described herein. Final compounds of the present invention were 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. Intermediates were named using CHEMDRAW® Professional v.20.1.1.125.

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

[0046] [ka]

[0047] A method for preparing substituted 1-phenyldihydropyrimidine-2,4(1H,3H)-dione building blocks 1-6 is illustrated in Scheme 1. The substituent R in compound 1-1 5 can be halo, hydrogen, or C1-C3 alkyl, as described herein. Reaction of compound 1-1 with tert-butyldimethylsilyl chloride in the presence of imidazole can provide compound 1-2. 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 aqueous HCl to produce intermediate 1-5. Intermediate 1-5 can be treated with iodine followed by Ph3P in the presence of imidazole to produce iodo compound 1-6, or intermediate 1-5 can be treated with CBr4 followed by Ph3P to produce bromo compound 1-6.

[0048] [ka]

[0049] A method for preparing the substituted unit 2-7 is illustrated in Scheme 2. Substituted benzaldehyde 2-1 [wherein R 1 , R 2 and R 3 Reaction of (S)-2-methylpropane-2-sulfinamide 2-2 with (S)-2-methylpropane-2-sulfinamide 2-3 can produce compound 2-3. Reaction of compound 2-3 with CHMgBr under Grignard reaction conditions can produce intermediate 2-4. Intermediate 2-5 can be synthesized from intermediate 2-4 using bis(pinacolato)diboron and a palladium catalyst. Amine 2-6 can be prepared from intermediate 2-5 by removing the t-butylsulfinyl group using strong acid or iodine. Heteroarylcarboxamide building block 2-7 can be synthesized directly from amine 2-6 with methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate.

[0050] [ka]

[0051] As shown in Scheme 3, base unit 3-4 [wherein R 4a and R 4b

[0047] can be prepared from compound 3-3 by hydrogenation or nitro reduction. N It can be prepared from 2-nitro-5-halopyridine compound 3-1 and substituted piperazine compound 3-2 by Ar reaction or Buchwald-Hartwig cross-coupling reaction.

[0052] [ka]

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

[0054] [ka]

[0055] A general synthesis for target compounds of formula 5-4 is shown in Scheme 5, where R 1 , R 2 , R 3 , R 4a , R 4b and R 5 can be as described herein. Iodo or bromo building blocks 1-6 can be reacted with intermediate 4-5 via an alkylation reaction using sodium iodide and a base, such as N,N-diisopropylethylamine, to generate target compounds 5-4.

[0056] The scope of the present disclosure is defined in the appended claims, and it can be understood that the synthetic schemes and certain specific examples illustrated in the Examples section are illustrative and should not be read as limiting the scope of the present disclosure. All alternatives, modifications, and equivalents of the synthetic methods and certain specific examples are included within the scope of the claims.

[0057] The following examples may be used for illustrative purposes and should not be construed as narrowing the scope of the present disclosure.

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

[0059] [Table 1] TIFF0007805983000012.tif216169TIFF0007805983000013.tif218169TIFF0007805983000014.tif202169 [Example]

[0060] [Table 2] TIFF0007805983000016.tif89169

[0061] Final compounds obtained via preparative HPLC may be concentrated via lyophilization. Final examples were typically purified to ≥ 95% purity as determined by HPLC and LCMS at 254 nm. 1 H NMR spectra were recorded on a Bruker Avance™ III 400 MHz NMR spectrometer or a Bruker Ascend™ 500 MHz NMR spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual non-deuterated solvent 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 charged 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) at ambient temperature. 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 batches of combined reaction mixture, and 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 triturated in petroleum ether (5.0 L) for 2 hours and filtered. The filter 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 charged with dichloromethane (20.0 L) and Example 1A (1.00 kg, 3.31 mol). The mixture was cooled to -20 °C. CHMgBr (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 aqueous NHCl (5.0 L) was added to it. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (3.0 L x 2). The combined organic phases were washed with brine (5.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was triturated 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. 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)propane-2-sulfinamide A 5 L reactor was charged with Example 1B (600 g, 1.89 mol), dioxane (3.6 L), bis(pinacolato)diboron (600 g, 2.36 mol), potassium acetate (370 g, 3.77 mol), and Pd(dppf)Cl ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 23.0 g, 0.07 mol) at ambient temperature. The mixture was degassed with nitrogen and stirred under nitrogen at 85° C. for 8 hours. The same reaction was repeated four times on the same scale. The combined reaction mixture of five batches was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (0.5 L × 3). The filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography on silica 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)ethanamine A 3 L reactor was charged with Example 1C (250 g, 680 mmol) and ethyl acetate (750 mL) at 20° C. The mixture was cooled to 0° C. To the mixture was added hydrogen chloride in ethyl acetate (4 M, 750 mL) at 0° C. The reaction mixture was stirred at 20° C. for 2 hours. The mixture was filtered, and the solid product was triturated in ethyl acetate, filtered, and dried under reduced pressure to yield the crude title compound as the hydrochloride salt. 1 H 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) was added triethylamine (64.0 mL, 459 mmol) at 20° C. The mixture was stirred at 65° C. for 16 hours and then concentrated under reduced pressure to remove 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 solution (once) and brine (once), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the crude material. The crude material was purified by column chromatography on silica gel, eluting with petroleum ether and ethyl acetate to yield 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 charged with 2-(4-aminophenyl)ethan-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) at ambient temperature. 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, and concentrated under reduced pressure, and the residue was subjected to flash column chromatography (eluting 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 charged to a 3 L reactor. To the mixture was added toluene (1.4 L) and acrylic acid (67.4 g, 0.94 mol). The reaction mixture was stirred at 110° C. under nitrogen for 12 hours. The mixture was concentrated to dryness under reduced pressure to yield the crude title compound. MS (ESI) m / z 324.2 (M+H) + .

[0070] Example 1H 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl acetate To crude Example 1G (252 g, 0.78 mol) was added acetic acid (1.8 L) and urea (46.8 g, 0.78 mol). The reaction mixture was stirred under nitrogen at 110° C. for 12 hours and cooled to ambient temperature. To the mixture was added water (600 mL) and ethyl acetate (600 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (600 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to provide 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 To crude Example 1H (176 g, 0.63 mol) was added 6N aqueous HCl (1.23 L, 7.39 mol) and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was triturated with ethanol / ethyl acetate (250 mL / 250 mL) for 30 minutes. This material was isolated by filtration and dried under vacuum to yield the crude title compound. MS (ESI) m / z 235.1 (M+H) + .

[0072] [Example 1J] 1-(4-(2-iodoethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A 250 mL flask was charged 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 portionwise, followed by Ph3P (16.8 g, 0.06 mol) portionwise, followed by 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. Eight batches of the reaction mixture 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. The filtrate was concentrated under reduced pressure to produce the title compound. 1 H 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-nitropyridin-3-yl)piperazine-1-carboxylate To a solution of 5-chloro-2-nitropyridine (30 g, 189 mmol) in toluene (600 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (37.9 g, 189 mmol), potassium phosphate (60.2 g, 284 mmol), and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5.89 g, 9.46 mmol) at 20° C. The reaction vessel was evacuated and backfilled with argon three times, and palladium(II) acetate (2.124 g, 9.46 mmol) was added in one portion at 20° C. The vessel was then evacuated and backfilled with argon three times. The reaction mixture was warmed to 90° C. and stirred at 90° C. under an argon atmosphere for 24 hours. The reaction mixture was cooled and filtered through a pad of diatomaceous earth, washing with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash column silica (eluted with tetrahydrofuran in petroleum ether from 0% to 50%) to give 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-aminopyridin-3-yl)-3-methylpiperazine-1-carboxylate To a suspension of Pd / C (10 wt%, 46.2 g, 43.4 mmol) in tetrahydrofuran (700 mL) was added Example 1K (70 g, 217 mmol), and the reaction mixture was stirred under hydrogen (15 psi) at ambient temperature for 24 hours. The same reaction was repeated on the same scale. The combined reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product. This material was triturated with petroleum ether and ethyl acetate, the resulting solid was filtered, and the filter cake was dried under vacuum to give 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-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To 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 a solution of potassium phosphate (10.27 g, 48.4 mmol) in water (100 mL) at 20° C. The mixture was degassed at ambient temperature using a stream of nitrogen, and to the mixture was added [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.885 g, 1.210 mmol) under N 2 . 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 produce 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-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 1L (25 g, 86 mmol) in 1,4-dioxane (500 mL) was added Example 1M (34.2 g, 86 mmol), CsCO (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 and backfilled 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 and backfilled 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 and filtered through a pad of diatomaceous earth, washing with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with tetrahydrofuran in petroleum ether to give 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-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 1N (32 g, 48.8 mmol) in dioxane (300 mL) was added hydrochloride (4N in dioxane, 300 mL) dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered to isolate the crude material, which was dried under vacuum. The crude material was diluted with water (300 mL), and saturated aqueous sodium bicarbonate solution was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (twice), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 1J (18.36 g, 53.3 mmol), N,N-diisopropylethylamine (46.6 mL, 267 mmol), and sodium iodide (19.99 g, 133 mmol) 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 filter cake was triturated with ethyl acetate / tetrahydrofuran (twice). This material was dried under reduced pressure to provide 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0080] Example 2A tert-Butyl (R)-3-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 1K, substituting (R)-tert-butyl 3-methylpiperazine-1-carboxylate for (S)-tert-butyl 3-methylpiperazine-1-carboxylate. 1 H 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 / z 323.2 (M+H). + .

[0081] Example 2B tert-Butyl (R)-4-(6-aminopyridin-3-yl)-3-methylpiperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 1L, substituting Example 2A for Example 1K. 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-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 1N, substituting Example 2B for Example 1L. 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-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared according to the procedure used in Example 1O, substituting Example 2C for Example 1N. 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide The title compound was prepared following the procedure used in Example 1P, substituting Example 2D for Example 1O. 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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide

[0086] Example 3A tert-Butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 1K, substituting tert-butyl piperazine-1-carboxylate for (S)-tert-butyl 3-methylpiperazine-1-carboxylate. MS (ESI) m / z 309.2 (M+H). + .

[0087] Example 3B tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 1L, substituting Example 3A for Example 1K. 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-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 1N, substituting Example 3B for Example 1L. 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)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared according to the procedure used in Example 1O, substituting Example 3C for Example 1N. 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-diazinan-1-yl)phenyl]ethyl}piperazin-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 1P, substituting Example 3D for Example 1O. 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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0092] Example 4A (E)-2-(3-fluoro-4-nitrophenyl)-N,N-dimethylethen-1-amine A mixture of 2-fluoro-4-methyl-1-nitrobenzene (1.50 kg, 9.63 mol) and N,N-dimethylformamide dimethyl acetal (1.72 kg, 14.5 mol, 1.92 L) in N,N-dimethylformamide (2.4 L) was degassed and purged with nitrogen three times, 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 material was triturated with petroleum ether / tert-butyl methyl ether (1:1, 10.0 L) and filtered. The filter cake was washed with petroleum ether / tert-butyl methyl 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)ethan-1-ol To aqueous hydrochloric acid (4 M, 7.50 L) was added Example 4A (1.00 kg, 4.76 mol) in portions 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. To the mixture was added sodium borohydride (214 g, 5.68 mol) in portions 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) was added tert-butyldimethylsilyl chloride (804 g, 5.34 mol, 654 mL) in portions at ambient temperature. The mixture was stirred at ambient temperature for 12 hours, quenched by the addition of 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 flash column chromatography on silica (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) was added Example 4C (5.5 g, 18.37 mmol) 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 give 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) was added acrylic acid (0.802 g, 11.13 mmol). 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 give the crude title compound. MS (ESI) m / z 342.1 (M+H).+ .

[0097] Example 4F 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenethyl acetate To a solution of Example 4E (3 g, 8.78 mmol) in acetic acid (30 mL) was added urea (1.583 g, 26.4 mmol). 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 material was purified by preparative HPLC (Phenomenex Luna® C18 column, 50*250 mm, 10 μm, using 0.1% formic acid in water and acetonitrile as the mobile phase) to produce 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) at 20° C. was added concentrated hydrochloric acid (37%, 1 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. MS (ESI) m / z 253.1 (M+H). + .

[0099] Example 4H 1-(4-(2-bromoethyl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of Example 4G (0.3 g, 1.189 mmol) in dichloromethane (20 mL) was added CBr (0.789 g, 2.379 mmol), followed by PhP (0.624 g, 2.379 mmol) 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 flash column chromatography on silica (ethyl acetate in petroleum ether, 0-100%) to give 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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 10 (80 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) was added Example 4H (54 mg, 0.17 mmol), sodium iodide (65 mg, 0.43 mmol), and N,N-diisopropylethylamine (56 mg, 0.43 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was directly subjected to reverse-phase preparative HPLC to produce the title compound (Gilson GX-281 system, Waters™ Xbridge C18 column, 30×100 mm×10 μm, 10 mM ammonium bicarbonate in water and acetonitrile as the mobile phase). 1H 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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 4H (68 mg, 0.22 mmol), sodium iodide (81 mg, 0.54 mmol), and N,N-diisopropylethylamine (70 mg, 0.54 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was directly subjected to reverse-phase preparative HPLC to isolate the title compound (Gilson GX-281 system, Phenomenex Luna® C18 column, 30×75 mm×3 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 1 H 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 / z 790.2 (M+H) + .

[0102] [Example 6] 3-tert-Butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0103] Example 6A (S)-tert-Butyl 3-ethyl-4-(6-nitropyridin-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 / z 337.0 (M+H) + .

[0104] Example 6B (S)-tert-butyl 4-(6-aminopyridin-3-yl)-3-ethylpiperazine-1-carboxylate Example 6A (2.0 g, 5.95 mmol) was dissolved in methanol (200 mL). To the mixture was added Pd / C (10 wt%, 0.32 g, 3.0 mmol). 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 / z 307.2 (M+H) + .

[0105] Example 6C tert-Butyl (S)-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 To a solution of Example 1E (300 mg, 0.75 mmol) in 1,4-dioxane (6 mL) was added 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). The mixture was degassed using a stream of argon and stirred at 100 °C for 16 h. 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 provide 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-ethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-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) was added hydrochloride (4N in dioxane, 3 mL) dropwise at ambient temperature. The mixture was stirred for 2 hours, concentrated under reduced pressure, diluted with water (5 mL), and treated with saturated aqueous sodium carbonate to adjust the pH to 8. The mixture was extracted with ethyl acetate (15 mL, 3 times), and 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-diazinan-1-yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Gemini® AXA C18 column, 30×250 mm×5 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)-3-fluorophenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Luna® C18 column, 30×75 mm×3 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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, substituting (R)-tert-butyl 3-ethylpiperazine-1-carboxylate for (S)-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, substituting Example 8A for Example 6A. 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, substituting Example 8B for Example 6B. 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, substituting Example 8C for Example 6C. 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-diazinan-1-yl)phenyl]ethyl}-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 following the procedure used in Example 6E, substituting Example 8D for Example 6D. 1 H 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-diazinan-1-yl)phenyl]ethyl}-2,2-dimethylpiperazin-1-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide

[0116] Example 9A tert-Butyl 3,3-dimethyl-4-(6-nitropyridin-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 was added cesium carbonate (9.12 g, 28.0 mmol), BINAP ((R / S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 0.872 g, 1.40 mmol), and tris(dibenzylideneacetone)dipalladium(0) (1.282 g, 1.40 mmol). The reaction mixture was stirred at 120° C. under a nitrogen atmosphere for 15 hours. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified using silica chromatography (ethyl acetate and hexanes) to produce the title compound. LC / MS(ESI+)m / z336.9(M+H) + .

[0117] Example 9B tert-Butyl 4-(6-aminopyridin-3-yl)-3,3-dimethylpiperazine-1-carboxylate Example 9A (1.1 g, 3.27 mmol) was dissolved in methanol (100 mL). To the mixture was added Pd / C (10 wt%, 0.17 g, 1.64 mmol). 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 give 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-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3,3-dimethylpiperazine-1-carboxylate A stirred mixture of Example 9B (400 mg, 1.30 mmol), Example 1E (522 mg, 1.30 mmol), racemic BINAP-Pd-G3 (CAS 2151915-22-7, 130 mg, 0.13 mmol), and cesium carbonate (1276 mg, 3.92 mmol) in 1,4-dioxane (6.5 mL) 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 using silica chromatography with ethyl acetate and hexanes 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-dimethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-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 to the mixture was added hydrochloride (4N in 1,4-dioxane, 1.6 mL). The mixture was stirred at ambient temperature for 2 hours and concentrated under reduced pressure to yield 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-diazinan-1-yl)phenyl]ethyl}-2,2-dimethylpiperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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 directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Gemini® AXA C18 column, 30×250 mm×5 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 charged with 1-bromo-2-fluoro-4-iodobenzene (288 g, 0.96 mol) in anhydrous tetrahydrofuran (2.0 L). The mixture was cooled to -60 °C, and lithium diisopropylamide (2 M in tetrahydrofuran, 526 mL, 1.05 mol) was added. 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 (1.0 L) and extracted with methyl tert-butyl ether (1.0 L × 3). The same reaction was repeated three times on the same scale. The combined organic layers of the 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 charged 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 h. To the mixture, morpholine-4-carbaldehyde (158 g, 1.37 mol) was added at -60 °C. The mixture was stirred at 0-5 °C for 4 h. The reaction mixture was diluted with saturated aqueous NH4Cl (0.8 L) and extracted with methyl tert-butyl ether (1.7 L × 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 give 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-methylpropane-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-methylpropane-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 produce 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, 3 H), 1.28 (s, 9H) ppm.MS(ESI)m / z320.0, 322.0(M+H) + .

[0125] Example 10D (S)-N-((R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-2-methylpropane-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. CHMgBr (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 NHCl 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 produce the title compound. 1H 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) was added bis(pinacolato)diboron (9.13 g, 36.0 mmol) and potassium acetate (5.88 g, 60.0 mmol) at 20° C. The reaction vessel was evacuated and backfilled 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 backfilled 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 pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting 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)ethan-1-amine To a solution of Example 10E (20.0 g, 52.2 mmol) in methyl tert-butyl ether (400 mL) was added hydrochloride (4N in methyl tert-butyl ether, 400 mL) dropwise at ambient temperature. The mixture was stirred for 3 hours, concentrated under reduced pressure, and triturated in methyl tert-butyl ether (50 mL). The solid was isolated by filtration and dried under vacuum to produce the crude title compound. 1 H 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 / z 280.0 (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) was added triethylamine (23.5 mL, 169 mmol) at 20° C. The mixture was stirred at 60° C. for 12 hours and then concentrated under reduced pressure to remove ethanol. The crude material was purified by column chromatography on silica gel eluting with petroleum ether and ethyl acetate to produce the title compound. 1H 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 / z 432.2(M+H) + .

[0129] Example 10H (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To 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 a solution of potassium phosphate (2.76 g, 12.98 mmol) in water (30 mL) at 20 °C. The mixture was degassed at ambient temperature using a stream of nitrogen, and to the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (265 mg, 0.33 mmol) 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 produce 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-carboxamido)ethyl)-2-fluoro-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 10H (500 mg, 1.20 mmol) in 1,4-dioxane (10 mL) was added Example 1L (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). The mixture was degassed using a stream of nitrogen and stirred at 100° C. under a nitrogen atmosphere for 16 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. 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-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-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) was added dropwise hydrochloride (4N in methyl tert-butyl ether, 2 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 1J (54 mg, 0.17 mmol), potassium iodide (145 mg, 0.87 mmol), and potassium carbonate (48 mg, 0.35 mmol). The mixture was stirred at 80° C. for 2 hours. The mixture was cooled to ambient temperature, filtered, and directly subjected to reverse-phase preparative HPLC to isolate the title compound (Gilson GX-281 system, Phenomenex Gemini® NX C18 column, 30×75 mm×3 μm, 10 mM ammonium bicarbonate in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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-carboxamido)ethyl)-2-fluoro-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazine-1-carboxylate To a solution of Example 10H (2.40 g, 5.46 mmol) in 1,4-dioxane (80 mL) was added Example 3B (1.67 g, 6.00 mmol), Pd(dba) (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). The mixture was degassed using a stream of nitrogen and stirred at 100° C. under a nitrogen atmosphere for 16 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 10.15 (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)pyridin-2-yl)amino)pyrimidin-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) was added dropwise hydrochloride (4N in 1,4-dioxane, 40 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield the title compound as the hydrochloride salt. 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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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) was added Example 1J (86 mg, 0.25 mmol), sodium bromide (129 mg, 1.25 mmol), and sodium bicarbonate (70 mg, 0.84 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was cooled to ambient temperature, filtered, and directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Gemini® NX C18 column, 40×80 mm×3 μm, 10 mM ammonium bicarbonate in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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 charged with 1-bromo-2-fluoro-4-iodo-5-methylbenzene (25 g, 79 mmol) and anhydrous tetrahydrofuran (400 mL) and cooled to -25 °C. iPrMgCl (isopropylmagnesium chloride, 1.3 M in tetrahydrofuran, 67.2 mL, 87 mmol) was added, and the mixture was stirred at -25 °C for 30 minutes. To the mixture was added anhydrous N,N-dimethylformamide (7.38 mL, 96 mmol) at -25 °C. The mixture was allowed to warm 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 phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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 charged with Example 12A (17.00 g, 78.0 mmol) and dichloromethane (340 mL). To this stirred solution at ambient temperature was added (S)-2-methylpropane-2-sulfinamide (10.44 g, 86.0 mmol) and titanium(IV) ethoxide (35.7 g, 157 mmol). The mixture was stirred for 16 hours and then quenched with water (36 mL) at 0° C. The mixture was filtered, and the filter cake was washed with dichloromethane (3×300 mL). The filtrate was concentrated under reduced pressure, and the crude material was triturated in hexane (50 mL) for 30 minutes. The solid was isolated by filtration, washed with hexane, and dried under high vacuum to provide 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 charged with anhydrous dichloromethane (400 mL) and Example 12B (21.6 g, 67.5 mmol). The mixture was cooled to 0° C. CHMgBr (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 aqueous NHCl (500 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL × 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) was added bis(pinacolato)diboron (13.19 g, 51.9 mmol) and potassium acetate (8.49 g, 87.0 mmol) at 20° C. The reaction vessel was evacuated and backfilled 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 backfilled 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 pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting 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)ethan-1-amine To a solution of Example 12D (3.00 g, 7.83 mmol) in dichloromethane (10 mL) was added hydrochloride (4N in 1,4-dioxane, 30 mL) 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) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (6.16 mL, 40.80 mmol) at ambient temperature. The reaction mixture was stirred at 85 °C for 16 hours, cooled, concentrated under reduced pressure, and purified by column chromatography on silica gel, eluting with hexane and ethyl acetate, to give the title compound. MS (ESI) m / z 432.2 (M+H). + .

[0144] Example 12G (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared according to the procedure used for Example 10H, substituting Example 12F for Example 10G. 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-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazine-1-carboxylate A stirred mixture of Example 3B (406 mg, 1.46 mmol), Example 12G (435 mg, 1.04 mmol), racemic BINAP-Pd-G3 (CAS 2151915-22-7, 99 mg, 0.1 mmol), and cesium carbonate (746 mg, 2.29 mmol) in 1,4-dioxane (6.5 mL) was heated at 110° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled, filtered, and concentrated under reduced pressure, and the residue was purified using silica chromatography with ethyl acetate and hexanes 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)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared according to the procedure used in Example 11B, substituting Example 12H for Example 11A. 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-diazinan-1-yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-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) was added Example 1J (81 mg, 0.24 mmol), potassium iodide (139 mg, 0.84 mmol), and N,N-diisopropylethylamine (205 μL, 1.17 mmol). The mixture was stirred at 80° C. for 2 hours. The mixture was cooled to ambient temperature, filtered, and directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Gemini® AXA C18 column, 30×250 mm×5 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0149] Example 13A tert-Butyl (S)-3-isopropyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate To a mixture of 5-fluoro-2-nitropyridine (467 mg, 3.28 mmol) in dimethyl sulfoxide (10 mL) was added (S)-tert-butyl 3-isopropylpiperazine-1-carboxylate (500 mg, 2.190 mmol) and N,N-diisopropylethylamine (1.147 mL, 6.57 mmol) under N 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 material in the mixture was collected by filtration. This material was triturated in a mixture of ethyl acetate and petroleum ether to form a slurry. The slurry was filtered, and the filter 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-aminopyridin-3-yl)-3-isopropylpiperazine-1-carboxylate To a mixture of Pd / C (10 wt%, 121 mg, 0.114 mmol) in ethyl acetate (12 mL) was added Example 13A (400 mg, 1.142 mmol) at ambient temperature. The mixture was hydrogenated using a hydrogen balloon for 2 hours. The mixture was filtered through a pad of diatomaceous earth, 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-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-isopropylpiperazine-1-carboxylate To a solution of Example 1M (200 mg, 0.49 mmol) in 1,4-dioxane (5 mL) was added 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). The mixture was degassed using a stream of nitrogen and stirred at 100 °C for 12 h. 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-isopropylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-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) was added hydrochloride (4N in dioxane, 3 mL) 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-diazinan-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 1J (175 mg, 0.51 mmol), sodium iodide (153 mg, 1.02 mmol), and N,N-diisopropylethylamine (296 μL, 1.70 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was cooled to ambient temperature, filtered, and directly subjected to reverse-phase preparative HPLC to isolate the title compound (Waters™ Xbridge C18 column, 30×100 mm×10 μm, 10 mM ammonium bicarbonate in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 charged 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) at ambient temperature. The mixture was stirred at 70 °C for 12 h. 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 material from all four batches was combined to yield 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 charged 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 aqueous NH4Cl 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 × 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 triturated 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) was added bis(pinacolato)diboron (10.1 g, 40.0 mmol) and potassium acetate (7.82 g, 80.0 mmol) at 20° C. The reaction vessel was evacuated and backfilled 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 backfilled 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 pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with petroleum ether and ethyl acetate to produce the title compound. MS(ESI) m / z 386.2(M+H) + .

[0158] [Example 14D] (R)-1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-amine To a solution of Example 14C (8.00 g, 20.7 mmol) in 1,4-dioxane (100 mL) was added hydrochloride (4N in 1,4-dioxane, 100 mL) dropwise at ambient temperature. The mixture was stirred for 2 hours and concentrated under reduced pressure to yield 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) was added triethylamine (17.4 mL, 125 mmol) at 20° C. The mixture was stirred at 80° C. for 12 hours and then concentrated under reduced pressure to remove ethanol. The crude material was purified by column chromatography on silica gel eluting 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-chloropyrimidin-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) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (1.13 g, 1.38 mmol) and potassium phosphate (5.87 g, 27.7 mmol). The mixture was degassed at ambient temperature using a stream of nitrogen and stirred at 80°C under a nitrogen atmosphere for 1 hour. 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 produce 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-carboxamido)ethyl)-3-chlorophenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 14H (288 mg, 0.69 mmol) in 1,4-dioxane (6.4 mL) was added Example 1L (240 mg, 0.82 mmol), Pd(dba) (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). The mixture was degassed using a stream of nitrogen and stirred at 100° C. under a nitrogen atmosphere for 16 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 provide 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-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 14G (258 mg, 0.38 mmol) in 1,4-dioxane (3 mL) was added hydrochloride (4N in 1,4-dioxane, 3 mL) dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in water (10 mL), and basified with saturated aqueous sodium bicarbonate to adjust the pH to 8. The mixture was extracted with dichloromethane (10 mL, 3 times), and the combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 1J (102 mg, 0.30 mmol), sodium iodide (66 mg, 0.44 mmol), and N,N-diisopropylethylamine (129 μL, 0.74 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was cooled to ambient temperature, filtered, and directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Luna® C18 column, 30×75 mm×3 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added a solution of sodium carbonate (2.205 g, 20.81 mmol) in water (6.00 mL) 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 column chromatography on silica gel 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. To the mixture was added 1,8-bis(dimethylamino)naphthalene (4.89 g, 22.83 mmol) in one portion, 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, allowed to warm 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 produce 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) was added Example 15B (1.3 g, 3.57 mmol). The reaction mixture was hydrogenated using a hydrogen balloon at ambient temperature for 16 hours. The mixture was filtered through a pad of diatomaceous earth, 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-nitropyridin-3-yl)piperazine-1-carboxylate To a mixture of 5-fluoro-2-nitropyridine (740 mg, 5.21 mmol) in dimethyl sulfoxide (16 mL) was added Example 15C (800 mg, 3.47 mmol) and N,N-diisopropylethylamine (1.820 mL, 10.42 mmol) at ambient temperature. The reaction mixture was heated to 120° C. and stirred for 12 hours. The reaction mixture was cooled and poured into water, and the mixture was extracted with ethyl acetate (twice). 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 produce 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-butyl 4-(6-aminopyridin-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) was added Example 15D (1.2 g, 3.41 mmol). The reaction mixture was hydrogenated using a hydrogen balloon at ambient temperature for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.62 (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-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-(methoxymethyl)piperazine-1-carboxylate To a solution of Example 1E (300 mg, 0.75 mmol) in 1,4-dioxane (5 mL) was added Example 15E (363 mg, 1.13 mmol), Pd(dba) (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). The mixture was degassed using a stream of argon 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 provide 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)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-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) was added hydrochloride (4N in dioxane, 3 mL) 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-diazinan-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Luna® C18 column, 30×75 mm×3 μm, 0.1% formic acid in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 charged with 4-bromo-2-(trifluoromethyl)benzaldehyde (10.00 g, 39.5 mmol) and dichloromethane (100 mL). To the stirred mixture was added (S)-2-methylpropane-2-sulfinamide (6.23 g, 51.4 mmol), 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 and the organic phase separated. 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 provide 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 charged with anhydrous toluene (60 mL) and Example 16A (5.40 g, 15.16 mmol). The mixture was cooled to -5 °C. CHMgBr (3.0 M in tetrahydrofuran, 10.1 mL, 30.3 mmol) was added dropwise. The mixture was then stirred at 0 °C for 3 h, and the reaction was quenched by the addition of saturated aqueous NHCl (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. 1H 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 (quintet, 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) was added bis(pinacolato)diboron (853 mg, 3.36 mmol) and potassium acetate (527 mg, 5.37 mmol) at 20° C. The reaction vessel was evacuated and backfilled 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 backfilled 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 pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting 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)ethan-1-amine To a solution of Example 16C (900 mg, 2.15 mmol) in 1,4-dioxane (5 mL) was added hydrochloride (4N in 1,4-dioxane, 10 mL) dropwise at ambient temperature. The mixture was stirred for 1 hour and then concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. 1 H 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 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) was added triethylamine (622 mg, 6.14 mmol) at 20° C. The mixture was stirred at 60° C. for 16 hours and then concentrated under reduced pressure to remove ethanol. The crude material was purified by column chromatography on silica gel eluting with petroleum ether and ethyl acetate to produce the title compound. 1 H 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 (quintet, 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 / z 468.2(M+H) + .

[0179] [Example 16F] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To 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 a solution of potassium phosphate (209 mg, 0.98 mmol) in water (2.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (22 mg, 0.03 mmol). The mixture was degassed at ambient temperature using a stream of nitrogen and stirred at 80°C under a nitrogen atmosphere 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 ethyl acetate in hexane to produce 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-carboxamido)ethyl)-3-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 16F (170 mg, 0.38 mmol) in 1,4-dioxane (4 mL) was added Example 1L (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). The mixture was degassed using a stream of nitrogen and stirred at 100 °C under a nitrogen atmosphere 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 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-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 16G (100 mg, 0.14 mmol) in methanol (20 mL) was added dropwise hydrochloride (4N in methanol, 20 mL). 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 1J (56 mg, 0.16 mmol), sodium iodide (65 mg, 0.43 mmol), and N,N-diisopropylethylamine (56 μL, 0.32 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was cooled to ambient temperature, filtered, and directly subjected to reverse-phase preparative HPLC to isolate the title compound (Waters™ Xbridge C18 column, 30×100 mm×10 μm, 10 mM ammonium bicarbonate in water and acetonitrile as the mobile phase). 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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 charged 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) at ambient temperature. 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 × 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 charged with anhydrous dichloromethane (3.0 L) and Example 16A (150 g, 0.49 mol). The mixture was cooled to 0° C. CHMgBr (3.0 M in tetrahydrofuran, 245 mL, 0.73 mol) was added dropwise. The mixture was allowed to warm to ambient temperature and stirred for 12 hours, after which the reaction was quenched by the addition of saturated aqueous NHCl (1.0 L). 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 provide 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)ethan-1-amine A 1 L reactor was charged with Example 17B (87.0 g, 0.27 mol) and methanol (870 mL). To the stirred solution at 0° C. was added hydrochloride (4N in methanol, 435 mL, 1.74 mol). The reaction mixture was stirred at 0° C. for 2 hours and concentrated to dryness under reduced pressure to yield the crude title compound as the hydrochloride salt. 1 H 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 charged with Example 17C (65.0 g, 0.30 mol), tetrahydrofuran (650 mL), and water (650 mL). To the stirred solution at 0° C. was added sodium hydroxide (35.8 g, 0.89 mol) and di-tert-butyl decarbonate (78.1 g, 0.36 mol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was diluted with water (1.0 L), and the mixture was 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) was added bis(pinacolato)diboron (72.8 g, 0.29 mol) and potassium acetate (46.9 g, 0.48 mol) at 20° C. The reaction vessel was evacuated and backfilled 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 backfilled 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 pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting 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)ethan-1-amine To a solution of Example 17E (1030 mg, 2.15 mmol) in dichloromethane (20 mL) was added hydrochloride (4N in 1,4-dioxane, 14 mL) dropwise at ambient temperature. The mixture was stirred for 3 hours and concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. 1 H 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) at ambient temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.28 mL, 8.46 mmol). 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 phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate to produce the title compound. 1 H 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-chloropyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To 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 a solution of potassium phosphate (775 mg, 3.65 mmol) in water (2 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (149 mg, 0.18 mmol). The mixture was degassed at ambient temperature using a stream of nitrogen and stirred at 85°C under a nitrogen atmosphere for 20 minutes. 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 produce the crude title compound. MS (ESI) m / z 404.1 (M+H) + .

[0192] [Example 17I] tert-Butyl (S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-fluorophenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 17G (268 mg, 0.66 mmol) in 1,4-dioxane (10 mL) was added Example 1L (349 mg, 1.20 mmol), racemic BINAP-Pd-G3 (CAS 2151915-22-7, 66 mg, 0.066 mmol), and cesium carbonate (649 mg, 1.99 mmol). The mixture was heated at 75° C. under a nitrogen atmosphere for 40 minutes. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica chromatography with 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-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-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) was added hydrochloride salt (4N in 1,4-dioxane, 6.6 mL). 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 (7N ammonia in methanol was added) 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-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-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) was added Example 1J (56 mg, 0.16 mmol), potassium iodide (119 mg, 0.72 mmol), and N,N-diisopropylethylamine (50 μL, 0.29 mmol). The mixture was stirred at 80° C. for 2 hours. It was cooled to ambient temperature, 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, 0.1% ammonium hydroxide in water and acetonitrile as the mobile phase). 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 assay (MSA). The ability of Btk to phosphorylate a fluorescent peptide substrate (FAM-GEEPLYWSFPAKKK-NH2) was measured. Kinase reactions were assembled in a total volume of 25 μL per well in a 384-well plate. To each well was added: compound buffer (or control); enzyme buffer; and substrate buffer, as further described below.

[0196] Specifically, the following were added: (1) compound buffer or control: 5 μL of 5× compound buffer [5× compound buffer consisting of (1× main buffer, X μM test compound in 5% dimethyl sulfoxide; 2× 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 MgCl, 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 preincubated for 15 minutes. Additionally, 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 to each well 45 μL of 1.55× stop buffer (1× main buffer and 31 mM EDTA). 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 terminated reactions were analyzed using a 12-channel LABCHIP® 3000 microfluidic detection device (available from Caliper Life Sciences, Waltham, MA). Enzymatic phosphorylation of the peptide changed the net charge, allowing electrophoretic separation of the product from the substrate peptide. As the substrate and product peptides separated, two peaks of fluorescence were observed. The change in relative fluorescence intensity of the substrate and product peaks was the measured parameter reflecting enzyme activity. In the presence of active compound, the ratio between product and substrate was altered. The product signal decreased and the substrate signal increased. Capillary electropherograms (RDA acquisition files) were analyzed using HTS Well Analyzer software (available from Caliper Life Sciences, Waltham, MA).

[0198] Activity in each sample was determined as the product-to-total ratio (PSR): P / (S+P), where P was the peak height of the product peptide and S was the peak height of the substrate peptide. For each compound, enzyme activity was measured at various concentrations (12 concentrations of compound spaced by 3× dilution intervals). Negative control samples (0% inhibition in the absence of active compound) and positive control samples (100% inhibition in the presence of 20 mM EDTA) were assembled in quadruplicate and used to calculate the % inhibition value for each active compound at each concentration. Percent inhibition (Pinh) was determined using the following equation: Pinh = (PSR0% - PSRinh) / (PSR0% - PSR100%) * 100, where PSRinh is the product sum ratio in the presence of inhibitor, PSR0% is the average product sum ratio in the absence of active compound, and PSR100% is the average product sum ratio in the 100%-inhibited control sample.

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

[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 an amplified luminescent proximity homogeneous assay). In this assay, donor and acceptor beads are brought into close proximity by ligand binding to the CRBN protein. Excitation of the donor bead stimulates the release of a singlet oxygen, which triggers a cascade of energy transfer reactions to the acceptor bead, resulting in a sharp peak in light emission at 615 nm.

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

[0202] Antagonism experiments: Test compounds in 100% dimethyl sulfoxide were seeded into white, low-volume 384-well plates (PerkinElmer Proxiplate 384 plus #6008289) using a Labcyte Echo acoustic dispenser in an 11-point dose curve and 3-fold dilution scheme. This resulted in a 10 μM top dose (starting concentration) and 0.1% DMSO final concentration after the addition of 10 μL of assay mixture containing His-tagged cereblon / DDB1 complex and 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). The plates were incubated at room temperature for 30 minutes.

[0203] Detection: 10 μL detection reagent containing nickel chelate acceptor beads and streptavidin donor beads (Perkin Elmer 6760002) was added under low light conditions resulting in a final concentration of 20 μg / ml. Plates were incubated for 1 hour and read on a PerkinElmer™ Envision™ plate reader (680 nm excitation and 570 nM emission settings). The IC of each compound was 50 was determined by calculating the percent inhibition from no drug and no protein controls, and the K i was calculated using the Chen-Pull soft transformation. i From IC 50 The IC value was determined. 50 The value is CRBN IC 50 Reported in Table 2 in the (nM) column.

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

[0205] Specifically, approximately 80 μL of fresh human whole blood obtained from healthy donors was transferred to each well of a 96-well V-bottom plate (Costar, Cat. No. 3894). Using a TECAN™ D300e Digital Dispenser (Tecan), 1:4 serial dilutions of compounds (in DMSO solution (final 0.2%) starting at a highest concentration of 3 μM (8-point assay)) were added in duplicate. The plate was then placed in a 37°C incubator and incubated for 6 hours.

[0206] At the end of the incubation, 80 μL of 2× CST lysis buffer (Cell Signaling Technology, Cat. No. 9803), prepared from a 10× stock solution, was added per well to lyse the blood. The plate was then sealed with a plate sealer, and the samples were frozen at −80° C. overnight.

[0207] The total amount of Btk protein remaining in the blood samples after compound treatment was measured using an MSD ELISA. After thawing the frozen plate, the blood lysate was thoroughly mixed and transferred to a small, spotted, high-binding MSD plate (Mesoscale Discovery, catalog no. L45XB-3) and coated with a capture antibody, rabbit anti-human BTK (D3H5) (Cell Signaling Technology, catalog no. 8547CF). The primary detection antibody, mouse anti-human BTK monoclonal antibody (BD Biosciences, catalog no. 611117), and the secondary detection antibody, anti-mouse SULFO-TAG (Mesoscale Discovery, catalog no. R32AC-1), were then added. The assay plate was read on an MSD S600 plate reader by adding 2x MSD read buffer (Mesoscale Discovery, catalog no. R92TC-1). All reagent transfers, including blood lysis, were performed using a Biomed i7 liquid handler. From the dose-response curve, the DC 50 Values ​​were calculated by averaging data from duplicate experiments and curve fitting was performed by nonlinear regression using GraphPad Prism. 50 Values ​​are hWB BTK DC 50 (nM) column in Table 2. max Values ​​represent the maximum amount of BTK degradation observed in compound-treated samples compared to samples treated with DMSO alone. dMax (%) values ​​are 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 / control were prepared in EtOH; PEG-400; Phosal 53 MCT (10:30:60, v / v). Four mice were tested per compound or vehicle / control. On day 1, mice received a single dose of dose A. On day 2 (24 hours later), tissue (bone marrow) was harvested from one hind limb per mouse.

[0209] An MSD (mesoscale discovery) ELISA (enzyme-linked immunosorbent assay)-based assay was used to determine BTK degradation in mouse bone marrow. The following materials and equipment were used: 10% NP40 solution (non-ionic 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® 2 mL lysis tubes with 2.8 mm beads (VWR, catalog number 10032-756); Bertin Precellys® 24 / Cryolys® cooling system; 96-well MSD streptavidin precoated plates (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, 4x (MSD, catalog number R92TC-1); recombinant Btk protein (ThermoFisher, catalog number PR5442A); MSD Tris wash buffer (10x) (MSD, catalog number R61TX-1); PBS (phosphate-buffered saline); deionized water (diH2O); lysis buffer [0.2% NP40 in PBS + protease inhibitor tablet (1 tablet / 10 mL) + PhosphoSTOP tablet (1 tablet / 10 mL)]; 3% MSD Blocker A [MSD Blocker A + 450 mL diH2O + 50 mL]; and 10x MSD Tris wash buffer.

[0210] procedure Sample Processing for PD Assays Mouse bone marrow lysate preparation Lysis buffer [(PBS + 0.2% NP40 + PI (protease inhibitor) + PhosphoSTOP)] was prepared and placed on ice until sufficiently chilled. Ice-cold lysis buffer (300 μL) was added to each Precellys® tube containing beads and bone marrow sample. Sample tubes were transferred to the Precellys® machine and homogenized using 5000 rpm - 2 x 20 seconds. After homogenization, the sample lysates were centrifuged at 14,000 rpm for 20 minutes at 4°C.

[0211] Protein Estimation (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 standard stock solution of 300 ng / ml of recombinant Btk protein in lysis buffer was prepared, and samples were serially diluted in 3-fold dilutions (10-point assay, highest concentration was 300 ng / ml, lowest concentration was 0.015 ng / ml).

[0213] Performing the MSD assay Day 1 MSD plate coating: Coating antibody (biotinylated-BTK mAb) stock solution was prepared at 1 μg / mL in PBS buffer. 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 1x 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 for an additional 1-2 hours at ambient temperature with gentle shaking. The plate was washed three times with 1x MSD wash buffer using a plate washer. Bone marrow lysate (30 μg) was added to the plate in a final volume of 50 μL per well. Serially diluted standard samples were added to the same plate in 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 with 1x MSD wash buffer (prepared from 10x concentration buffer) using a plate washer. 50 μL of primary detection antibody was added per well (BTK RpAb; 1:1000 dilution in 1% MSD Blocker A). The plate was incubated for 2 hours at ambient temperature with gentle shaking. The plate was washed three times with 1x MSD wash buffer using a plate washer. 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 for 1-2 hours at ambient temperature. The plate was washed three times with 1x MSD Tris wash buffer using a plate washer. MSD read buffer (150 μL) (1x) was added, and the plate was read on the MSD machine. A standard curve was generated, and the absolute BTK amounts were used to calculate the % BTK remaining in vehicle vs. treated samples. The % BTK remaining in the samples is reported in Table 2.

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

[0216] [Table 3]

[0217] Tumor cell development Eμ-TCL1 CLL transgenic mice (Crogen Pharmaceuticals LLC) were transfected with BTK. C481S By crossing with knock-in mice (AbbVie), BTK C481S We generated Eμ-TCL1 transgenic mice carrying the BTK mutation. C481S Leukemic splenocytes from Eμ-TCL1 transgenic mice (first passage cells) were intravenously transferred into C57BL / 6 mice, resulting in the development of CLL in the peripheral blood and spleen. When the circulating CLL burden (CD5+CD19+ cells, as described below) in recipient mice reached 90%, those splenocytes containing high CLL burden (second passage cells) were cryopreserved and used for CLL efficacy testing.

[0218] livestock Mouse tumor efficacy studies were conducted in accordance with AbbVie's Animal Care and Use Committee (AICC) and the National Institutes of Health's Guide for Care and Use of Laboratory Animals guidelines at the Vivarium in South San Francisco, California. 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 treatment Second-passage Eμ-TCL1 BTK containing high CLL burden C481S Splenocytes were thawed, washed, and filtered through a 70-μM strainer in cold Hank's Balanced Salt Solution (HBSS). 10 × 10 cells in 0.2 mL of HBSS were collected. 6 Splenocytes were injected intravenously into the tail vein of female 8- to 10-week-old C57BL / 6 mice per mouse to develop CLL.

[0220] To determine absolute / total white blood cell counts, complete blood counts were determined for each mouse using a Genesis™ animal hematology analyzer (Oxford Science Inc.).

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

[0222] Whole blood was collected weekly via submandibular cheek bleeding after tumor implantation. Circulating leukemia burden was assessed by absolute white blood cell count / total white blood cell count and immunophenotype CD19 + CD5 + was calculated by multiplying the percentage of leukocytes with

[0223] Starting 9 days after inoculation, mice were weighed, exsanguinated, and N=10 (mean circulating CD19 + CD5 + The subjects were randomized into five groups (CLL cell count: 1,525 / μL). Compound 1 (Example 1) was formulated at different concentrations in a vehicle containing 10% ethanol, 30% PEG-400, and 60% Phosal-50 MCT. The vehicle contained 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 19 days with: Group 1: vehicle; Group 2: Compound 1, dose 1; Group 3: Compound 1, dose 2; Group 4: Compound 1, dose 3; and Group 5: Compound 1, dose 4.

[0225] As shown in Figure 1, Compound 1 (Example 1) inhibited BTK in C57BL / 6 mice in a dose-dependent manner. C481S The circulating leukemia burden of TCL1-driven CLL with mutations was controlled. The y-axis shows the number of CLL cells (CD19+CD5+) per 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 mentioned herein are herein incorporated by reference in their entirety, to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0227] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be taken as limiting the scope of the present disclosure, which is defined by the appended claims and their equivalents.

Claims

【Request Item 1】 【Chemistry 1】 or a pharmaceutically acceptable salt thereof. 【Request Item 2】 【Chemistry 2】 A compound which is a pharmaceutically acceptable salt of 【Request Item 3】 【Chemistry 3】 A compound.

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