3-[(1H-pyrazole-4-yl)oxy]pyrazine-2-amine compounds as HPK1 inhibitors and their use

Abstract

Disclosed herein are 3-[(1H-pyrazol-4-yl)oxy]pyrazin-2-amine compounds of Formula (I), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same. Also disclosed are methods for modulating, e.g., inhibiting or treating, HPK1-related disorders or diseases, including cancer, by using the compounds disclosed herein. [Formula 1] JPEG2023543212000422.jpg63165

Description

[Technical Field]

[0001] This specification provides 3-[(1H-pyrazole-4-yl)oxy]pyrazine-2-amine compounds, as well as their compositions and methods of use. The compounds disclosed herein modulate, for example, inhibit hematopoietic progenitor cell kinase 1 (HPK1) activity and are useful in the treatment of various diseases, including cancer. [Background technology]

[0002] HPK1 is a member of the MAP4K family, which includes MAP4K1 / HPK1, MAP4K2 / GCK, MAP4K3 / GLK, MAP4K4 / HGK, MAP4K5 / KHS, and MAP4K6 / MINK [Hu, MC, et al., Genes Dev, 1996.10: pp.2251-64]. HPK1 regulates the diverse functions of various immune cells, and its kinase activity is linked to the T cell receptor (TCR) [Liou J., et al., Immunity, 2000.12(4):pp.399-408], the B cell receptor (BCR) [Liou J., et al., Immunity, 2000.12(4):pp.399-408], the transforming growth factor receptor (TGF-βR) [Wang, W., et al., J Biol Chem, 1997.272(36):pp.22771-5, Zhou, G., et al., J Biol Chem, 1999.274(19):pp.13133-8], and the Gs-coupled PGE2 receptor (EP2 and EP4) [Ikegami, R., et al., J It has been shown that this is induced by the activation of [Immunol, 2001.166(7):pp.4689-96]. Overexpression of HPK1 suppresses TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that HPK1 is necessary to inhibit the Erk MAPK pathway [Liou J., et al., Immunity, 2000.12(4):pp.399-408], and that this blockade is thought to be the inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription [S. Sawasdikosol., et al., Immunol Res, 2012.54:pp.262-265].

[0003] In vitro HPK1- / - T cells have a lower TCR activation threshold, proliferate robustly, produce enhanced amounts of Th1 cytokines, and HPK1- / - mice experience more severe autoimmune symptoms [S. Sawasdikosol., et al., Immunol Res, 2012.54:pp.262-265]. In humans, HPK1 is downregulated in peripheral blood mononuclear cells of psoriatic arthritis patients or T cells of systemic lupus erythematosus (SLE) patients [Batliwalla FM, et al., Mol Med, 2005.11(1-12):pp.21-9], suggesting that attenuation of HPK1 activity may contribute to autoimmunity in patients. Furthermore, HPK1 may regulate antitumor immunity via T cell-dependent mechanisms. In a PGE2-producing Lewis lung cancer tumor model, tumors developed more slowly in HPK1 knockout mice compared to wild-type mice [US Patent Application No. 2007 / 0087988]. HPK1-deficient T cells were more effective than wild-type T cells in controlling tumor growth and metastasis [Alzabin, S., et al., Cancer Immunol Immunother, 2010.59(3):pp.419-29]. Similarly, BMDCs from HPK1 knockout mice were more efficient than wild-type BMDCs in initiating a T cell response to eradicate Lewis lung cancer [Alzabin, S., et al., J Immunol, 2009.182(10):pp.6187-94]. Overall, HPK1 may be a good target for enhancing anti-tumor immunity.

[0004] As HPK1 modifiers, WO2016 / 205942 discloses benzimidazole, WO2018 / 049152A1 discloses pyrazolopyrimidine, WO2018 / 049191A1 discloses pyrazolopyridone, and WO2008 / 124849, WO2018 / 049200A1, and WO2018 / 049214A1 disclose pyrazine. WO2019 / 238067 and WO2020 / 103896 disclose pyrrolopyridine. [Overview of the Initiative] Problems to be solved by the invention

[0005] However, there is a need to provide new HPK1 kinase inhibitors useful in the treatment of cancer.

Means for Solving the Problems

[0006] In a first aspect, what is disclosed herein are aminopyrazine compounds of formula (I) and methods of use. The first embodiment includes the following aspects: Aspect 1: A compound of formula (I)

Chemical formula

[0007] In some embodiments, R a and R b These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered carbon ring selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62 ) together with the atoms to which they are bonded form a 7-12 membered bridged heterocycline, and the bridge contains 1-6, 1-4, or 1-2 carbon atoms. In some embodiments, (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62 These, together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, where the cross-linking comprises 1-6, 1-4, or 1-2 atoms selected from carbon, oxygen, or nitrogen.

[0008] In some embodiments, R4 is deuterated C 1-8 It is an alkyl group.

[0009] In some embodiments, the compound of formula (I) is disclosed herein. [ka] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, During the ceremony, X is N or CR2, and R2 is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkynyl, halogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NR c R d , -OR d ,-(CR a R b ) n -R d ,-(CR a R b ) n -NR c R d ,-(CR a R b ) n -CONR c R d ,-CONR c -(CR a R b ) n -R d ,-(CR a R b ) n -NR c COR d , -NR c -CO-(CR a R b ) n -R d ,-(CR a R b ) n -SO2-NR c R d ,-(CR a R b ) n -NR c -SO2-R d -SO2-NR c -(CR a R b ) n -R d ,-(CR a R b ) n -NR c-CS-NR d R e , or -(CR a R b ) n -NR c -CO-NR d R e Selected from, the -C 1-8 Each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups optionally contains at least one R f Replaced by, R1 and R3 each independently produce hydrogen and -C 1-8 Alkyl, halogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NR c R d , -OR d ,-(CR a R b ) n -R d ,-(CR a R b ) n -NR c R d ,-(CR a R b ) n -CONR c R d ,-CONR c -(CR a R b ) n -R d ,-(CR a R b ) n -NR c COR d , -NR c -CO-(CR a R b ) n -R d ,-(CR a R b ) n -SO2-NR c R d ,-(CR a R b ) n -NR c -SO2-R d -SO2-NR c -(CRa R b ) n -R d , or -(CR a R b ) n -NR c -CO-NR d R e Selected from, the -C 1-8 Each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups optionally contains at least one R f Replaced by, R4 is hydrogen, -C 1-8 Alkyl, cycloalkyl, independently selected from heterocyclyls (such as monocyclic heterocyclyls) containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur as ring members, and said -C 1-8 Each of alkyl, cycloalkyl, or heterocyclyl is optionally R f Replaced by, Each R f However, independently, oxo, halogen, -C 1-8 Alkyl, hydroxy, -C 1-8 Selected from alkoxy or heterocyclyl, the heterocyclyl or -C 1-8 The alkyl group optionally has at least one R g Replaced by, R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , R 82 , and R9 are independently hydrogen, halogen, and -C. 1-8 Alkyl, or -C 1-8 Selected from alkoxy, or (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62) together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, where the cross-linking contains 1-6 atoms selected from carbon, oxygen, nitrogen, or sulfur. R a and R b However, each independently, hydrogen, -C 1-8 It is alkyl, or heterocycline, or R a and R b Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. R c , R d , and R e However, each independently, hydrogen, -C 1-8 Alkyl, aryl, CN, hydroxyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, or -NR 1c R 1d and -C 1-8 Each of the alkyl, cycloalkyl, aryl, or heterocyclyl groups optionally contains at least one R g Replaced with R 1c and R 1d However, each independently, hydrogen or -C 1-8 It is alkyl, Each R g However, independently, oxo, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Selected from alkoxy or heterocyclyl, n is a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, where n is independently 0, 1, 2, 3, or 4.

[0010] In some embodiments, R a and R b These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered carbon ring selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, (R 51 and R61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62 ) together with the atoms to which they are bonded form a 7-12 membered bridged heterocycline, and the bridge contains 1-6, 1-4, or 1-2 carbon atoms. In some embodiments, (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62 These, together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, where the cross-linking comprises 1-6, 1-4, or 1-2 atoms selected from carbon, oxygen, or nitrogen.

[0011] Embodiment 2: X is N or CR2, and R2 is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkinyl, C 3-7 Cycloalkyl, aryl, 5-6 membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, 3-7 membered heterocyclyls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, -NR c R d ,-(CR a R b ) n -R d ,-(CR a R b ) n -NR c R d ,-(CR a R b ) n -CONR c R d ,-CONR c -(CR a R b )n -R d ,-(CR a R b ) n -NR c COR d ,-(CR a R b ) n -SO2-NR c R d ,-(CR a R b ) n -NR c -CO-NR d R e ,-(CR a R b ) n -NR c -CS-NR d R e ,-(CR a R b ) n -NR c -SO2-R d , or -(CR a R b ) n -NR c -CO-NR d R e Selected from, the -C 1-8 Alkyl, C 3-7 Each of the cycloalkyl, aryl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl optionally contains at least one R f Replaced by, R1 is hydrogen, -C 1-8 Alkyl, halogen, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl containing independently 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidizable sulfur as ring members, -NR c R d , or -OR d Selected from, the -C 1-8 Alkyl, C 3-7 Each of the cycloalkyl, 5-6 member heteroaryl, or 3-7 member heterocyclyl optionally contains at least one R f Replaced by, R3 is hydrogen, -C 1-8 Alkyl, C 3-7 Cycloalkyls, independently, 3- to 7-membered heterocyclines containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, silicon, or optionally oxidized sulfur as ring members, -(CR a R b ) n -NR c R d ,-(CR a R b ) n -CONR c R d , -SiR a R b R c ,-(CR a R b ) n -NR c COR d ,-CONR c -(CR a R b ) n -R d ,-(CR a R b ) n -SO2-NR c R d -SO2-NR c -(CR a R b ) n -R d ,-(CR a R b ) n -NR c -SO2-R d ,-(CR a R b ) n -NR c -CO-NR d R e , or -(CR a R b ) n -NR c R d Selected from, the -C 1-8 Alkyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, optionally with at least one R f Replaced by, R4 is hydrogen, -C 1-8 Alkyl, C 3-7 Cycloalkyls are independently selected from 3- to 7-membered heterocyclines containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, each of the -C 1-8 Alkyl, C 3-7 Cycloalkyl or 3- to 7-membered heterocyclyl, optionally, R f Replaced by, Each R f However, independently, oxo, halogen, hydroxy, -NR 1c R 1d , -C 1-8 Alkyl, -C 1-8 Selected from alkoxys and 3- to 7-membered heterocyclines, the heterocycline or -C 1-8 The alkyl group optionally has at least one R g Replaced with R 1c and R 1d However, each independently, hydrogen or -C 1-8 It is alkyl, R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , and R 82 However, each is independent of hydrogen, halogen, and -C. 1-8 Alkyl, or -C 1-8 Selected from alkoxy, or (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62 ) together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, where the cross-linking contains 1-6 atoms selected from carbon, oxygen, nitrogen, or sulfur. R a and R b However, each independently, hydrogen, -C 1-8It is alkyl, or heterocycline, or R a and R b Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. R c , R d , and R e However, each independently, hydrogen, -C 1-8 Alkyl, 5-6 member heteroaryl, aryl, CN, hydroxyl, -C 1-8 Alkoxy, C 3-7 Cycloalkyls are 3- to 7-membered heterocyclines containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur, or -NR. 1c R 1d And each of the -C 1-8 Alkyl, 5-6 member heteroaryl, C 3-7 A cycloalkyl, aryl, or 3- to 7-membered heterocycline may optionally contain at least one R g Replaced with R 1c and R 1d However, each independently, hydrogen or -C 1-8 It is alkyl, and each R g However, independently, oxo, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Selected from alkoxy or 3- to 7-membered heterocyclyl, The compound according to embodiment 1, wherein n is independently 0, 1, 2, 3, or 4.

[0012] In some embodiments, R4 is a 3- to 7-membered monocyclic heterocycline. In some embodiments, (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62These, together with the atoms to which they are bonded, form a 7-12 membered bridged heterocycline, where the bridge contains 1-6, 1-4, or 1-2 atoms selected from carbon or oxygen.

[0013] In some embodiments, X is N or CR2, and R2 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkinyl, C 3-7 Cycloalkyl, aryl, 5-6 membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, 3-7 membered heterocyclyls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, -NR c R d ,-(CR a R b ) n -R d ,-(CR a R b ) n -NR c R d ,-(CR a R b ) n -CONR c R d ,-CONR c -(CR a R b ) n -R d ,-(CR a R b ) n -NR c COR d ,-(CR a R b ) n -SO2-NR c R d ,-(CR a R b ) n -NR c -CO-NR d R e ,-(CR a R b ) n -NRc -CS-NR d R e , or -(CR a R b ) n -NR c -SO2-R d Selected from, the -C 1-8 Alkyl, C 3-7 Each of the cycloalkyl, aryl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl optionally contains at least one R f Replaced by, R1 is hydrogen, -C 1-8 Alkyl, halogen, C 3-7 Cycloalkyls, independently, 3- to 7-membered heterocyclines containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, -NR c R d , or -OR d Selected from, the -C 1-8 Alkyl, C 3-7 Each of the cycloalkyl, 5-6 member heteroaryl, or 3-7 member heterocyclyl optionally contains at least one R f Replaced by, R3 is hydrogen, -C 1-8 Alkyl, -(CR a R b ) n -CONR c R d ,-(CR a R b ) n -NR c COR d ,-CONR c -(CR a R b ) n -R d ,-(CR a R b ) n -SO2-NR c R d -SO2-NR c -(CR a R b ) n -R d ,-(CR aR b ) n -NR c -SO2-R d ,-(CR a R b ) n -NR c -CO-NR d R e , or -(CR a R b ) n -NR c R d Selected from, the -C 1-8 The alkyl group optionally has at least one R f Replaced by, R4 is hydrogen, -C 1-8 Alkyl, C 3-7 Cycloalkyls are independently selected from 3- to 7-membered heterocyclines containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, each of the -C 1-8 Alkyl, C 3-7 Cycloalkyl or 3- to 7-membered heterocyclyl, optionally, R f Replaced by, Each R f However, independently, oxo, halogen, hydroxy, -C 1-8 Alkyl, -C 1-8 Selected from alkoxys and 3- to 7-membered heterocyclines, the heterocycline or -C 1-8 The alkyl group optionally has at least one R g Replaced by, R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , and R 82 However, each is independent of hydrogen, halogen, and -C. 1-8 Alkyl, or -C 1-8 Selected from alkoxy, or (R 51 and R 61 ), (R 51 and R 62 ), (R 52 and R61 ), or (R 52 and R 62 ) together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, where the cross-linking contains 1-6 atoms selected from carbon, oxygen, nitrogen, or sulfur. R a and R b However, each independently, hydrogen, -C 1-8 It is alkyl, or heterocycline, or R a and R b Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. R c , R d , and R e However, each independently, hydrogen, -C 1-8 Alkyl, aryl, CN, hydroxyl, -C 1-8 Alkoxy, C 3-7 Cycloalkyls are 3- to 7-membered heterocyclines containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur, or -NR. 1c R 1d And each of the -C 1-8 Alkyl, C 3-7 A cycloalkyl, aryl, or 3- to 7-membered heterocycline may optionally contain at least one R g Replaced with R 1c and R 1d However, each independently, hydrogen or -C 1-8 It is alkyl, and each R g However, independently, oxo, hydroxy, halogen, -C 1-8 Alkyl, -C 1-8 Selected from alkoxy or 3- to 7-membered heterocyclyl, n is independently 0, 1, 2, 3, or 4.

[0014] In some embodiments, R4 is a 3- to 7-membered monocyclic heterocycline. In some embodiments, (R 51and R 61 ), (R 51 and R 62 ), (R 52 and R 61 ), or (R 52 and R 62 These, together with the atoms to which they are bonded, form a 7-12 membered bridged heterocycline, where the bridge contains 1-6, 1-4, or 1-2 atoms selected from carbon or oxygen.

[0015] Embodiment 3: R1 is halogen, -NR c R d , or -OR c , -C 1-4 Alkyl, C 3-6 Selected from cycloalkyl, nitrogen, oxygen, silicon, or sulfur, 4-6 member C-linked heterocyclines containing 1-3 heteroatoms selected from cycloalkyl, nitrogen, oxygen, silicon, or sulfur, 4-6 member Si-linked heterocyclines containing 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, or sulfur, 5, 6, or 7 member N-linked heterocyclines containing 0, 1, or 2 additional heteroatoms selected as ring members (may be multiple) from nitrogen, oxygen, or optionally oxidized sulfur, or 5-6 member heteroaryls, C 1-4 Alkyl, C 3-6 Each of the cycloalkyl, 4-6 member C-linked heterocyclyl, 4-6 member Si-linked heterocyclyl, or 5, 6, or 7 member N-linked heterocyclyl, or 5-6 member heteroaryl may optionally contain a halogen, hydroxyl, oxo, or -NH(C) 1-4 Alkyl), or -C 1-4 Substituted with at least one substituent selected from alkyl groups, R c and R d However, each independently, hydrogen or -C 1-4 The compound according to embodiment 1 or 2, wherein it is alkyl.

[0016] In some embodiments, the -C 1-4 Alkyl or C 3-6The cycloalkyl group is optionally substituted with at least one halogen or hydroxyl group, and / or the 4-6 member C-linked heterocyclyl or 4-6 member Si-linked heterocyclyl, the heterocyclyl is optionally substituted with at least one halogen, hydroxyl group, -NH(CH3), or oxo group, and / or the 5, 6, or 7 member N-linked heterocyclyl is optionally substituted with -C 1-4 Substituted with alkyl (preferably methyl), and / or a 5-6 member heteroaryl, optionally, -C 1-4 It is substituted with an alkyl group (preferably methyl). Preferably, the 5-6 membered N-linked heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or morpholinyl, each of which is optionally halogen, hydroxyl, or -C 1-4 Substituted with alkyl. Preferably, the 4-6 membered C-linked heterocyclyl is tetrahydrofuranyl, pyrrolidine-2-yl, or pyrrolidine-3-yl, oxetanyl, or tetrahydropyranyl, each of which is optionally halogen, hydroxyl, oxo, -NH(C) 1-4 Alkyl), or -C 1-4 It is substituted with an alkyl group. Preferably, the 4-6 member Si-linked heterocyclyl is siletanyl or siloranyl, each of which is optionally substituted with a hydroxyl group.

[0017] In some embodiments, R1 is a halogen, -NR c R d , or -OR c , -C 1-4 Alkyl, C 3-6 Selected from cycloalkyls, or 5, 6, or 7-membered N-linked heterocyclines containing 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, C 1-4 Alkyl, C 3-6 Each of the cycloalkyl or 5, 6, or 7-membered N-linked heterocyclyl may optionally contain a halogen or -C 1-4 Substituted with at least one substituent selected from alkyl groups, R c and Rd However, each independently, hydrogen or -C 1-4 It is alkyl.

[0018] In some embodiments, the -C 1-4 The alkyl group is optionally substituted with at least one halogen, and / or the 5-6 member N-linked heterocycline is optionally -C 1-4 Substituted with alkyl (preferably methyl). Preferably, the 5-6 membered N-linked heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or morpholinyl, each of which is optionally a halogen or -C 1-4 It is substituted with an alkyl group.

[0019] Embodiment 4: R1 is hydrogen, methyl, tert-butyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-methylpropyl, butyl, pentyl, hexyl, chloro, fluoro, methoxy, -CHF2, -NHCH3, -N(C2H5)2, -OCH(CH3)2, -S(O)2-NHCH3, -Si(CH3)2OH, -Si(C2H5)2OH, -CH(CH3)2OH, -CH2OCH3, [ka] A compound according to any one of embodiments 1 to 3, selected from the above.

[0020] In some embodiments, R1 is hydrogen, methyl, tert-butyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, butyl, pentyl, hexyl, chloro, fluoro, methoxy, -CHF2, -NHCH3, -N(C2H5)2, -OCH(CH3)2, [ka] Selected from.

[0021] Embodiment 5: X is -CR2, R2 is hydrogen, -C 1-4Alkyl, aryl, 5-6 membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur, 3-7 membered heterocyclyls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur, -(CH2) n -CON editing d , -CONH-(CH2) n -R d -CONH-R d ,-(CH2) n -NHR d ,-(CH2) n -NHCOR d ,-(CH2) n -R d -SO2-NH-(CH2) n -R d ,-(CH2) n -SO2-NHR d ,-(CH2) n -NH-CO-NR d R e ,-(CH2) n -NH-CS-NR d R e , or -(CH2) n -NH-SO2-R d Selected from the following, each of the aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclyl is optionally -C 1-4 Substituted with at least one selected from alkyl or oxo, where n is 1 or 2, R d and R e However, each is independent of hydrogen, hydroxyl, and -C. 1-4 Alkyl, phenyl, -C 1-4 Alkoxy, C 3-6 Cycloalkyl, aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, or -NR 1c R 1d Selected from, the -C 1-4 Alkyl, C 3-6 Each of the cycloalkyl, aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl optionally contains at least one halogen, CF3, or -C1-4 Substituted with alkyl or oxo, R 1c and R 1d However, each independently, hydrogen or -C 1-4 A compound according to any one of embodiments 1 to 4, which is alkyl.

[0022] In some embodiments, R d However, it is a 5-6 membered monocyclic heterocycline containing one or two heteroatoms selected from oxygen, nitrogen, silicon, or optionally oxidized sulfur, and optionally halogen or -C 1-4 It is substituted with alkyl. In further embodiments, R d These are pyrrolidinil, piperidinil, piperazinil, morpholino, morpholinil, or tetrahydropyranil.

[0023] In some embodiments, R d However, it is a 5-6 member heteroaryl compound containing one, two, or three heteroatoms selected from oxygen, nitrogen, or sulfur, and optionally, at least one halogen and / or -C 1-4 It is substituted with alkyl. In further embodiments, R d but, [ka] That is the case.

[0024] Embodiment 6: R2 is hydrogen, hydroxyl, methyl, halogen, [ka] [ka] A compound selected from the compound according to embodiment 5.

[0025] In some embodiments, R2 is hydrogen, hydroxyl, methyl, -CONHCH3, -CONHOCH3, [ka] Selected from.

[0026] Embodiment 7: R3 is hydrogen, -C 1-4 Alkyl, C 3-6 4-6 membered heterocyclyl containing 1-3 heteroatoms selected from cycloalkyl, nitrogen, oxygen, silicon, or sulfur, -(CH2) n -CON editing d , -CONH-(CH2) n -R d -CONH-R d ,-(CH2) n -NHCOR d -SO2-NH-(CH2) n -R d ,-(CH2) n -SO2-NHR d ,-(CH2) n -NH-CO-NR d R e ,-(CH2) n -NH-SO2-R d , -SiR a R b R c , [ka] , or selected from 5-6 member heteroaryls, the -C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, optionally, -C 1-4 Substituted with alkyl, halogen, oxo, or hydroxy, n is 0, 1, or 2, R d and R e However, each independently, hydrogen, -C 1-4 Alkyl, phenyl, -C 1-4 Alkoxy, CN, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, or -NR 1c R 1d Selected from, each of the -C 1-4 Alkyl, C 3-6 Cycloalkyl, aryl, or 5-6 membered heterocyclyl, optionally, -C1-4 Substituted with at least one of alkyl, halogen, or oxo, R 1c and R 1d However, each independently, hydrogen or -C 1-4 A compound according to any one of embodiments 1 to 6, which is alkyl.

[0027] In some embodiments, C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0028] In some embodiments, the 4- to 6-membered heterocyclil is selected from oxetanil, tetrahydrofuranil, tetrahydropyranil, siletanil, pyrrolidinil, piperidinil, azetidinil, siloranil, morpholinil, or oxazolidinil.

[0029] In some embodiments, R3 is hydrogen, -C 1-4 Alkyl, -(CH2) n -CON editing d , -CONH-(CH2) n -R d -CONH-R d ,-(CH2) n -NHCOR d -SO2-NH-(CH2) n -R d ,-(CH2) n -SO2-NHR d ,-(CH2) n -NH-CO-NR d R e ,-(CH2) n -NH-SO2-R d ,or [ka] Selected from, the -C 1-4 The alkyl group is optionally substituted with a halogen or hydroxyl group. n is 0, 1, or 2, R d and R eHowever, each independently, hydrogen, -C 1-4 Alkyl, phenyl, -C 1-4 Alkoxy, CN, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, or -NR 1c R 1d Selected from, each of the -C 1-4 Alkyl, C 3-6 Cycloalkyl, aryl, or 5-6 membered heterocyclyl, optionally, -C 1-4 Substituted with at least one of alkyl, halogen, or oxo, R 1c and R 1d However, each independently, hydrogen or -C 1-4 It is alkyl.

[0030] In some embodiments, a 5-6 member heteroaryl is [ka] Selected from.

[0031] Embodiment 8: R3 is methyl, ethyl, propyl, cyclopropyl, -CH(OH)CH3, -C(OH)(CH3)2, -SO2NHCH3, -SO2NH2, -SO2NHC2H5, -CH(OH)CF3, -C(OH)(CF3)2, -C(OH)(CH3)2, Si(CH3)2OH, -Si(C2H5)2OH, -CH2NHCH3, [ka] A compound according to embodiment 7, selected from the above.

[0032] In some embodiments, R3 is methyl, CH(OH)CH3, -SO2NHCH3, -SO2NH2, -SO2NHC2H5, -CH(OH)CF3, -C(OH)(CF3)2, C(OH)(CH3)2 [ka] Selected from.

[0033] Appearance 9: R4 is C3-6 -C is substituted with a cycloalkyl group or optionally with a 4- to 6-membered monocyclic heterocycline. 1-4 A compound according to any one of embodiments 1 to 8, selected from alkyl groups.

[0034] In some embodiments, R4 is deuterated C 1-4 It is an alkyl group.

[0035] Embodiment 10: R4 is methyl, ethyl, isopropyl, cyclopropyl, or [ka] A compound selected from (oxetane-3-ylmethyl) according to any one of embodiments 1 to 9.

[0036] In some embodiments, R4 is CD3 or -CD2CD3.

[0037] Appearance 11: R 51 , R 52 , R 61 , and R 62 The compound according to any one of embodiments 1 to 10, wherein the compound is hydrogen.

[0038] Appearance 12: R 51 and R 61 Together with the atoms to which they are bonded, they form an 8-membered bridged heterocycline, and the bridge contains two carbon atoms (i.e., -CH2-CH2-), R 52 and R 62 The compound according to any one of embodiments 1 to 11, wherein the compound is hydrogen.

[0039] Appearance 13: R 71 , R 72 , R 81 , R 82 The compound according to any one of embodiments 1 to 12, wherein R9 is hydrogen.

[0040] Appearance 14: Equation (II), [ka] A compound according to any one of embodiments 1 to 13, wherein R1, R2, R3, and R4 are as defined in embodiments 1 to 13 of this specification.

[0041] In some embodiments, R1 is a 3- to 7-membered heterocycline containing, independently, one, two, or three heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members.

[0042] In some embodiments, R1 is pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxyranyl, aziridin-1-yl, azi Lysine-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thyranil, azetidine-1-yl, azetidine-2-yl, azetidine-3-yl, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinil, thioxanil, piperazinil, homopiperazinil, homopiperidinil, azepan-1-yl, azepan-2-yl , azepan-3-yl, azepan-4-yl, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepanil, 1,4-thiazepanil, and 1,4-diazepanil, 1,4-dithianil, 1,4-azathanil, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranil, dihydrofuranil, tetrahydrofuranil, tetrahydrothienyl, tetrahydro A 3, 4, 5, 6, or 7-membered heterocyclyl selected from dropyranil, tetrahydrothiopyranil, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinil, 2H-pyranil, 4H-pyranil, 1,4-dioxanil, 1,3-dioxolanil, pyrazolinil, pyrazolidinil, dithianil, dithiolanil, pyrazolidinil, imidazolinil, pyrimidinol, 1,1-dioxo-thiomorpholinil, oxazolidinil, or oxazolidine-4-yl, A 3, 4, 5, 6, or 7-membered heterocycline can optionally contain a halogen, hydroxyl, oxo, or -NH(C) 1-4 Alkyl), or -C 1-4It is substituted with at least one (preferably one, two, three, or four) substituents selected from alkyl groups.

[0043] Preferably, the 3- to 7-membered heterocyclil is a 5, 6, or 7-membered N-linked heterocyclil containing 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members.

[0044] In some embodiments, R1 is hydrogen, methyl, tert-butyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-methylpropyl, butyl, pentyl, hexyl, chloro, fluoro, methoxy, -CHF2, -NHCH3, -N(C2H5)2, -OCH(CH3)2, -S(O)2-NHCH3, -Si(CH3)2OH, -Si(C2H5)2OH, -CH(CH3)2OH, -CH2OCH3, [ka] Selected from.

[0045] In some embodiments, R2 is hydrogen, hydroxyl, methyl, halogen, [ka] [ka] Selected from.

[0046] In some embodiments, R3 is hydrogen, -C 1-4 Alkyl, C 3-6 Selected from 4-6 membered heterocyclines containing 1-3 heteroatoms selected from cycloalkyl, nitrogen, oxygen, silicon, or sulfur, wherein the 4-6 membered heterocycline optionally contains -C 1-4 It is substituted with one, two, three, or four substituents selected from alkyl, halogen, oxo, or hydroxyl.

[0047] In some embodiments, R3 is methyl, ethyl, propyl, cyclopropyl, -CH(OH)CH3, -C(OH)(CH3)2, -SO2NHCH3, -SO2NH2, -SO2NHC2H5, -CH(OH)CF3, -C(OH)(CF3)2, -C(OH)(CH3)2, -Si(CH3)2OH, -Si(C2H5)2OH, -CH2NHCH3, [ka] Selected from.

[0048] In some embodiments, R4 is C 3-6 -C is substituted with a cycloalkyl group or optionally with a 4- to 6-membered monocyclic heterocycline. 1-4 Selected from alkyl groups.

[0049] Embodiment 15: Compounds selected from the following, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0050] In a second aspect, disclosed herein are pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0051] In a third aspect, a method for inhibiting HPK1 activity is disclosed herein, which comprises administering to an individual a compound disclosed herein, including a compound of formula (I) or a specific compound exemplified herein, or a pharmaceutically acceptable salt thereof.

[0052] In a fourth aspect, the foregoing discloses a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, as an HPK1 kinase inhibitor, wherein the compound disclosed herein includes the compound of formula (I) or certain compounds exemplified herein. In some embodiments, the disease or disorder is associated with the inhibition of HPK1 interaction. Preferably, the disease or disorder is cancer. [Modes for carrying out the invention]

[0053] The following terms have the meanings set forth throughout this specification: Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which the present invention pertains.

[0054] The following terms have the meanings set forth throughout this specification: As used herein, including in the attached claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly indicates otherwise.

[0055] The term "or" means "and / or" and is used interchangeably unless the context explicitly indicates otherwise.

[0056] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, even 1 to 10, even 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0057] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0058] The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu").

[0059] The term "pentyl" refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.

[0060] The term "hexyl" refers to 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0061] The term "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0062] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodine. An example of a haloalkyl is halo C. 1-8 Alkyl, Halo C 1-6 Alkyl or Halo C 1-4 While alkyl groups are included, they are not limited to -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, etc.

[0063] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 carbon atoms, for example, 2 to 8 or even 2 to 6. 2-6 Examples of alkenyls include, but are not limited to, ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylprop-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl groups.

[0064] The term "alkynyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 carbon atoms, such as, for example, 2 to 8 carbon atoms, and further, for example, 2 to 6 carbon atoms. An alkynyl group, for example, C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0065] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.

[0066] For example, a cycloalkyl group can contain 3 to 12 carbon atoms, such as, for example, 3 to 10 carbon atoms, further 3 to 8 carbon atoms, further 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Further, for example, a cycloalkyl group can be selected from monocyclic groups containing 3 to 12 carbon atoms, such as, for example, 3 to 10 carbon atoms, further 3 to 8 carbon atoms, 3 to 6 carbon atoms. Monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups, such as, for example, C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, 3 to 6 carbon atoms (C 3-6A monocyclic ring containing a cycloalkyl group. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as fused bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems.

[0067] The term "condensed cycloalkyl" refers to a bicyclic cycloalkyl group as defined herein, which is saturated and formed by two or more rings sharing two adjacent atoms.

[0068] The term "crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-12 membered crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two non-adjacent atoms.

[0069] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a monocyclic or polycyclic structure and at least one double bond, preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopento-1-enyl, 1-cyclopento-2-enyl, 1-cyclopento-3-enyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, preferably cyclohexenyl.

[0070] The term "condensed cycloalkenyl" refers to a bicyclic cycloalkyl group as defined herein, which is formed by two or more rings sharing two adjacent atoms and containing at least one double bond.

[0071] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group consisting of 5 to 10 carbon atoms, having a single or multiple rings and at least one triple bond.

[0072] The term "condensed cycloalkylnyl" refers to a bicyclic cycloalkyl group as defined herein, which is formed by two or more rings sharing two adjacent atoms and containing at least one triple bond.

[0073] Examples of condensed cycloalkyls, condensed cycloalkenyls, or condensed cycloalkynyls include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo3- to 8-membered cycloalkyls, benzoC 4-6 This includes, but is not limited to, cycloalkenyls, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, and 1,4-dihydronaphthyl. Preferred embodiments are 8-9 membered fused rings, which refer to cyclic structures containing 8-9 ring atoms in the examples above.

[0074] When used alone or in combination with other terms, the term “aryl” refers to a base selected from the following: a) Five-membered and six-membered carbocyclic aromatic rings, for example, phenyl, b) Bicyclic ring systems, for example, 7-12 membered bicyclic ring systems, in which at least one ring is a carbon ring and an aromatic ring, for example, naphthyl and indanyl, and c) A bicyclic ring system, for example, a 10-15 member tricyclic ring system, wherein at least one ring is a carbon ring and an aromatic ring, for example, fluorenyl.

[0075] The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10It has an aryl group. Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphtho-1-yl, naphtho-2-yl, anthracenyl, and phenantrenyl. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphtho-1-yl or naphtho-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0076] Specifically, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0077] The term "heteroaryl" refers to a group selected from the following: a) A 5, 6, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon. b) A 7-12 membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or 1-3 heteroatoms in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring, and c) An 11-14 membered tricyclic ring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or 1-3 heteroatoms in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom located within the aromatic ring.

[0078] If the total number of S and O atoms in a heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heteroring is not greater than 1. If a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form N-oxides.

[0079] More specifically, the term “bicyclic condensed heteroaryl” refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed bicyclic heteroaryl ring as defined herein. Typically, bicyclic condensed heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The groups can be bonded to the rest of the molecule via any of the rings.

[0080] Representative examples of bicyclic condensed heteroaryl groups include the following groups: benzoisoxazolyl, benzodiazolyl, benzofuranil, benzoflazanil, benzofuryl, benzimidazolyl, benzoisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzooxadiazolyl, benzoxazolyl, phlopyridinyl, phlopyrolyl, imidazopyridinyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolidinyl, indolyl, isobenzofuryl, i This includes, but is not limited to, soindolyl, isoquinolinyl (or isoquinolyl), naphthilidinyl, phthalazinyl, pteridinyl, purinyl, pyrazinopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridyl, pyrazolotriazinyl, pyridazolopyridyl, pyrrolopyridinyl, quinazolinyl, quinolinyl (or quinolyl), quinoxalinyl, thiazolopyridyl, thienopyrazinyl, thienopyrazolyl, thienopyroryl, thienotienyl, or triazolopyridyl.

[0081] The term "benzo-condensed heteroaryl" refers to a bicyclic condensed heteroaryl in which a monocyclic heteroaryl ring with 5 to 7 members (preferably 5 or 6 members) is condensed to a benzene ring, as defined herein.

[0082] The terms “aromatic heterocycle” and “heteroaryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring-forming members, each independently comprising 1, 2, 3, or 4 heteroatom ring members selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5-6 member heteroaryl ring that is monocyclic and independently comprises 1 or 2 heteroatom ring members selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic 8- to 10-membered heteroaryl ring having one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0083] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include (counting from the bond position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), synnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thia) Diazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridadinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1 ,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl-5-yl), benzoxazolyl (e.g., benzo[d]oxazole-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3- This includes, but is not limited to, diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, flazanyl (e.g., flazan-2-yl, flazan-3-yl), benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, phlopyridinil, benzothiazolyl (e.g., benzo[d]thiazole-6-yl), and indazolyl (e.g., 1H-indazole-5-yl).

[0084] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, silicon, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic and fused rings, i.e., monocyclic heterocyclyls and fused heterocyclic groups, bridging heterocyclic groups, or spiroheterocyclic groups.

[0085] As used herein, the term “optionally oxidizable sulfur” refers to S, SO, or SO2.

[0086] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member (e.g., 1 to 3 heteroatoms, 1 or 2 heteroatoms (or more)) is a heteroatom selected from nitrogen, oxygen, silicon, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated (i.e., it does not form a fully conjugated pi-electron system).

[0087] Examples of monocyclic 4- to 9-membered heterocyclyl groups include pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxylanil, and aziridine. -1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thyranil, azetidine-1-yl, azetidine-2-yl, azetidine-3-yl, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, dihydropyridinil, tetrahydropyridinil, thiomorpholinil, thioxanil, piperazinil, homopiperazinil, homopiperidinil, azepan-1-yl , azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepanil, 1,4-thiazepanil, and 1,4-diazepanil, 1,4-dithianil, 1,4-azathanil, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranil, dihydrofuranil, tetrahydrofuranil, tetrahydro This includes, but is not limited to, dorothienyl, tetrahydropyranil, tetrahydrothiopyranil, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinyl, 2H-pyranil, 4H-pyranil, 1,4-dioxanil, 1,3-dioxolanil, pyrazolinil, pyrazolidinil, dithianil, dithiolanil, pyrazolidinil, imidazolinil, pyrimidinol, 1,1-dioxo-thiomorpholinil, oxazolidinil, or oxazolidine-4-yl.

[0088] The term "condensed heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group, where each ring in the system contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and shares adjacent atom pairs (carbon and carbon, or carbon and nitrogen atoms) with another ring whose remaining ring members are carbon. One or more rings of the condensed heterocyclyl group may contain one or more double bonds, but the condensed heterocyclyl group does not have a fully conjugated pi electron system. Preferably, condensed heterocyclyls are 6- to 14 members, more preferably 7- to 12 members, or 7- to 10 members. Depending on the number of member rings, condensed heterocyclyls are divided into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyls. The group can bond to the rest of the molecule via any of the rings.

[0089] More specifically, the term “bicyclic condensed heterocyclyl” refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed heterocyclyl as defined herein, comprising two condensed rings and containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. Typically, bicyclic condensed heterocyclyls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic condensed heterocyclyls. Representative examples of (bicyclic) condensed heterocycles include the following groups: octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindlinyl, octahydro-benzo[b][1,4]dioxin, indlinyl, isoindlinyl, benzopyranil, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolinyl), dihydrobenzofuranil, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzof This includes, but is not limited to, lanyl, benzodioxolyl, benzodioxonyl, chromanyl, clomenyl, octahydroclomenyl, dihydrobenzodioxynyl, dihydrobenzoxedinyl, dihydrobenzodioxypinyl, dihydrothienodiooxynyl, dihydrobenzoxazepinyl, tetrahydrobenzoxazepinyl, dihydrobenzoazepinyl, tetrahydrobenzoazepinyl, isochromanyl, chromanyl, or tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl).

[0090] The term "benzo-condensed heterocyclyl" refers to a bicyclic condensed heterocyclyl obtained by condensing a monocyclic 4- to 9-membered heterocyclyl (preferably 5 or 6-membered) with a benzene ring, as defined herein.

[0091] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, where each of the two rings in the system shares two cleaved atoms, with one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members being carbon. More specifically, a bridge with two bridgeheads contains 1 to 6 atoms selected from carbon, oxygen, nitrogen, and sulfur, where two heteroatoms (oxygen, nitrogen, and sulfur) are not bonded to each other. One or more rings of the bridged heterocyclyl group may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably, bridged heterocyclyls are 6- to 14-membered, or 7- to 12-membered, more preferably 7- to 10-membered. Depending on the number of member rings, cross-linked heterocyclils are divided into bicyclic, tricyclic, tetracyclic, or polycyclic cross-linked heterocyclils, preferably bicyclic, tricyclic, or tetracyclic cross-linked heterocyclils, and more preferably bicyclic or tricyclic cross-linked heterocyclils. Representative examples of cross-linked heterocyclils include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0092] A “spiroheterocyclyl” refers to a 5- to 20-membered polycyclic heterocyclyl having a ring bonded via one common carbon atom (referred to as a spiro atom), wherein the ring has one or more heteroatoms selected from the group consisting of N, O, S, SO, or SO2 heteroatoms as ring atoms, and the remaining ring atoms are C. Preferably, spiroheterocyclyls are 6- to 14 members, more preferably 7- to 10 members. Depending on the typical number of spiro atoms, spiroheterocyclyls are divided into monospiroheterocyclyls, dispiroheterocyclyls, or polyspiroheterocyclyls, preferably monospiroheterocyclyls or dispiroheterocyclyls, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyls. Representative examples of spiroheterocyclyls include, but are not limited to, the following groups: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl, and 2-oxa-6-azaspiro[3.3]heptyl.

[0093] As disclosed herein, “N-linked heterocyclyl” refers to a heterocyclyl group that is linked to the rest of the molecule by a bond from the nitrogen atom of the heterocyclyl ring. “N-linked heterocyclyl containing 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members” refers to a heterocyclyl group that is linked to the rest of the molecule by a bond from the nitrogen atom of the heterocyclyl ring, and contains 0, 1, or 2 additional heteroatoms in addition to the nitrogen atom linked to the rest of the molecule.

[0094] As disclosed herein, “C-linked heterocyclyl” refers to a heterocyclyl group that is bonded to the rest of the molecule by a bond from the carbon atoms of the heterocyclyl ring. As disclosed herein, “Si-linked heterocyclyl” refers to a heterocyclyl group that is bonded to the rest of the molecule by a bond from the silicon atoms of the heterocyclyl ring.

[0095] The term “at least one substituent” as disclosed herein includes, for example, 1 to 3 substituents, or 1 to 4 substituents, as long as the theory of valence is satisfied. For example, “at least one substituent R” as disclosed herein d " refers to the R disclosed herein. d It includes 1 to 3 substituents selected from the list, and 1 to 4 substituents, such as 1 or 2.

[0096] The compounds disclosed herein may contain chiral centers and therefore may exist as enantiomers. “Enantiomer” refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. If a compound disclosed herein has two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially pure decomposed enantiomers, their racemic mixtures, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomer composition is not specified, all possible isomers are included.

[0097] The compounds disclosed herein also include deuterated compounds. The term “deuterated compound” refers to a compound in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms. Similarly, the term “deuterated” is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms, such as “deuterated alkyl,” “deuterated cycloalkyl,” “deuterated heterocycloalkyl,” “deuterated aryl,” “deuterated morpholinyl,” etc. For example, the term “deuterated alkyl” as defined above refers to an alkyl group as defined herein, in which at least one hydrogen atom bonded to carbon is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium, and it is possible for one or more carbon atoms in the alkyl group to be bonded to deuterium.

[0098] As used herein, the term “substantially pure” means that the target stereoisomer contains any other stereoisomer(s) in an amount of 35% by weight or less, e.g., 30% by weight or less, further e.g., 25% by weight or less, e.g., even further 20% by weight or less. In some embodiments, the term “substantially pure” means that the target stereoisomer contains any other stereoisomer(s) in an amount of 10% by weight or less, e.g., 5% by weight or less, e.g., 1% by weight or less.

[0099] Where a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0100] Where a compound disclosed herein includes a disubstituted cyclic ring system, the substituents found in such a ring system may adopt cis and trans configurations. Cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on the carbon, while trans configuration means they are on opposite sides. For example, a disubstituted cyclic ring system may be a cyclohexyl or cyclobutyl ring.

[0101] It may be advantageous to separate reaction products from each other and / or from the starting materials. The desired products from each step or series of steps are separated and / or purified to a desired degree of homogeneity (hereinafter, separated) by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, for example, reversed-phase and normal-phase, size exclusion, ion exchange, high, medium, and low-pressure liquid chromatography methods and apparatus, small-scale analysis, simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash techniques. Those skilled in the art will apply the technique that is most likely to achieve the desired separation.

[0102] A "diastereomer" refers to a stereoisomer of a compound that has two or more chiral centers but is not a mirror image of one another. A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moscher acid chloride), separating the diastereomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0103] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer with an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. “Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): pp.283-302). The racemic mixture of the chiral compound of the present invention can be separated and isolated by any preferred method, including: (1) formation of an ionic diastereomer salt by the chiral compound and separation by fractional crystallization or other methods; (2) formation of a diastereomer compound by a chiral derivatizing reagent, separation of the diastereomer and conversion to a pure stereoisomer; and (3) direct separation of substantially pure or concentrated stereoisomers under chiral conditions. Reference: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0104] The arrangement of diastereomers or enantiomer isomers can be determined by techniques including, but not limited to, the following: 1D- or 2D-NMR spectroscopy of the compound or its derivatives (e.g., Moscher esters), optical rotation and dispersion, circular dichroism spectroscopy, X-ray diffraction, and in silico calculations (e.g., QM or MMGBSA).

[0105] A "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that corresponds to a reasonable benefit / risk ratio. Pharmacologically acceptable salts can be prepared separately at Insights during the final isolation and purification of the compounds disclosed herein, or by reacting free base functional groups with suitable organic acids, or by reacting acidic groups with suitable bases.

[0106] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid acid. Conversely, when the product is a free base, addition salts such as pharmaceutically acceptable addition salts can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without excessive experimentation to prepare non-toxic, pharmaceutically acceptable addition salts.

[0107] As defined herein, “a pharmaceutically acceptable salt of the compound” includes salts of at least one compound of formula (I), and salts of stereoisomers of the compound of formula (I), such as salts of enantiomers and / or salts of diastereomers.

[0108] In this specification, the terms “administer,” “to administer,” “to treat,” and “to treat” mean, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment includes the contact of a reagent with cells, as well as the contact of a reagent with a fluid, where the fluid comes into contact with the cells. The terms “administer” and “treat” also mean in vitro and ex vivo treatment, for example, with cells, reagents, diagnostics, conjugate compounds, or with another cell. In this specification, the term “subject” includes any living organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), most preferably a human.

[0109] The terms “effective dose” or “therapeutic dose” refer to the amount of an active ingredient, such as a compound, that is sufficient to influence such treatment for a disease, disorder, or symptom when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder. “Therapeutic dose” may vary with the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given case may be obvious to those skilled in the art or can be determined by customary experiment. In some embodiments, “therapeutic dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, which is effective for “treatment” of a disease or disorder in a subject as defined herein. In the case of combination therapy, “therapeutic dose” refers to the total amount of the combination subject for effective treatment of a disease, disorder, or condition.

[0110] Pharmaceutical compositions containing the compounds disclosed herein can be administered to subjects requiring them via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation such as tablets, powders, granules, or capsules; a liquid formulation such as water or oil suspension; or another liquid formulation such as syrup, solution, or suspension. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, or lyophilized powder. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be a single dose in a precise dosage. In addition, the pharmaceutical composition may further contain additional active ingredients.

[0111] All formulations of the pharmaceutical compositions disclosed herein can be manufactured by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to produce the desired formulation. "Pharmacologically acceptable excipients" means conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles, such as water and various organic solvents; excipients, such as starch and sucrose; binders, such as cellulose derivatives, arginates, gelatin, and polyvinylpyrrolidone (PVP); wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecanol; absorption carriers, such as kaolin and soap clay; and lubricants, such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. In addition, the pharmaceutical composition further includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, permeability enhancers, polymers, fragrances, sweeteners, and dyes.

[0112] The term “disease” refers to any illness, discomfort, disorder, symptom, or adaptation, and may be interchangeable with the terms “disorder” or “condition.”

[0113] Throughout this specification and the following claims, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", are intended to specify the presence of the stated feature without excluding the presence or addition of one or more other features. As used herein, the term "comprising" may be replaced by the terms "containing", "including", or in some cases, "having".

[0114] Throughout this specification and the following claims, the term "C n-m " denotes a range that includes the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 and C 1-6 and the like.

[0115] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains.

[0116] General synthesis The compounds and their salts disclosed herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0117] The reactions for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, a temperature that can vary from the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of solvents.

[0118] The selection of appropriate protecting groups can be readily determined by one of ordinary skill in the art.

[0119] The reaction can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compound can be purified by various methods, including HPLC and normal-phase silica chromatography.

[0120] Chiral analysis HPLC was used to analyze the retention time of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used. [ka]

[0121] For example, the compound of formula (I) can be formed as shown in scheme I. Compound (I) can be deprotonated and reacted with 2-amino-3,5-dihalopyrazine (ii) to obtain compound (iii), which can then be coupled with compound (iv) using a transition metal catalyst to obtain compound (v) [i.e., formula (I)]. [ka]

[0122] For example, the compound of formula (I) can be formed as shown in scheme II. Compound (i) can be coupled with 2-amino-3,5-dihalopyrazine (ii) to obtain compound (iii), which is then reacted with the deprotonated compound (iv) to obtain compound (v) [i.e., formula (I)]. [ka]

[0123] For example, the compound of formula (I) can be formed as shown in scheme III. Compound (i) can be deprotonated and reacted with 2-amino-3,5-dihalopyrazine (ii) to obtain compound (iii), and compound (iii) can be borated to obtain compound (iv), which can then be coupled with compound (v) using a transition metal catalyst to obtain compound (vi) [i.e., formula (I)]. [Table 1-1] [Table 1-2]

[0124] Example A1 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-(dimethylamino)ethyl)-2,6-dimethylbenzamide [ka] Step 1: tert-butyl 4-(4-hydroxy-1H-pyrazole-1-yl)piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (23.5 g, 62.3 mmol) and NaOH (4.98 g, 124.5 mmol) in THF (400 mL) and water (80 mL), 30% H2O2 (14.2 g, 124.5 mmol) was added dropwise at 0°C, and the mixture was then warmed to room temperature and stirred for 1 hour. Saturated Na2S2O3 (50 mL) was added, and the mixture was extracted with ELISA (300 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (14.5 g, 87%). LCMS(M+H)+ =268.

[0125] Step 2: tert-butyl4-(4-((3-amino-6-bromopyrazine-2-yl)oxy)-1H-pyrazole-1-yl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-hydroxy-1H-pyrazole-1-yl)piperidine-1-carboxylate (14.5 g, 54.2 mmol), Cs2CO3 (35.2 g, 108.4 mmol), and 3,5-dibromopyrazine-2-amine (13.7 g, 54.2 mmol) in DMF (250 mL) was stirred at 90°C for 2 hours and then cooled to room temperature. Water (600 mL) was added, and the mixture was extracted with HCl (500 mL x 2). The combined organic layer was successively washed with water (300 mL x 3) and brine (300 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / HCl = 5 / 1 to 1 / 1) to obtain the title compound (18.5 g, 78%). LC-MS (M+H) + =439,441.

[0126] Step 3: 5-Bromo-3-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine hydrochloride [ka] To a solution of tert-butyl 4-(4-((3-amino-6-bromopyrazine-2-yl)oxy)-1H-pyrazole-1-yl)piperidine-1-carboxylate (18.5 g, 42.1 mmol) in dioxane (100 mL), HCl (42.1 mL, 4 M, 168.4 mmol) in dioxane was added. The mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration to obtain the title compound (15.8 g, 100%). LC-MS(M+H) + =339,341.

[0127] Step 4: 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] To a solution of 5-bromo-3-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine hydrochloride (13 g, 34.6 mmol) in MeOH (200 mL), 37% HCHO solution (11 mL, 138.5 mmol) and NaBH(OAc)3 (14.6 g, 69.2 mmol) were added at room temperature, and the mixture was stirred for 16 hours. The mixture was concentrated under vacuum, diluted with saturated NaHCO3 solution (200 mL), and extracted with DCM (400 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (12.0 g, 89%). LCMS(M+H) + =353,355.

[0128] Step 5: 4-Bromo-N-(2-(dimethylamino)ethyl)-2,6-dimethylbenzamide [ka] A solution of 4-bromo-2,6-dimethylbenzoic acid (4.2 g, 18.3 mmol) in SOCl2 (30 mL) was stirred under reflux for 1 hour and then cooled to room temperature. The solvent was concentrated under reduced pressure. The residue was dissolved in dry DCM (50 mL), and then N1,N1-dimethylethane-1,2-diamine (2.42 g, 27.5 mmol) and triethylamine (2.8 g, 27.5 mmol) were added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours, then quenched with saturated NaHCO3 solution (50 mL), and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (5.4 g, 98%). LCMS(M+H) + = 299, 301.

[0129] Step 6: N-(2-(dimethylamino)ethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] A mixture of 4-bromo-N-(2-(dimethylamino)ethyl)-2,6-dimethylbenzamide (5.4 g, 18 mmol), BPD (6.0 g, 23 mmol), Pd(dppf)Cl2 (659 mg, 0.9 mmol), and AcOK (3.53 g, 36 mmol) in dioxane (70 mL) was heated under reflux overnight under nitrogen. The solution was cooled to room temperature, diluted with siRNA (50 mL), and washed with brine (30 mL). The aqueous layer was extracted with siRNA (100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM / MeOH = 30 / 1 to 20 / 1) to obtain the title compound (4.5 g, 72%). LC-MS (M+H) + =347.1.

[0130] Step 7: 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-(dimethylamino)ethyl)-2,6-dimethylbenzamide To a solution of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (1.6 g, 4.5 mmol) and N-(2-(dimethylamino)ethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.87 g, 5.4 mmol) in dioxane (50 mL) and water (10 mL), K2CO3 (1.24 g, 9.0 mmol) and Pd(dppf)Cl2 (0.2 g, 0.27 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 90 °C for 15 hours and then cooled to room temperature. The mixture was extracted with ELISA (50 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 40 / 1 to 20 / 1) to obtain Example A1 (1.05 g, 47%). 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.2-8.14 (m, 1H), 8.11 (s, 1H), 7.58 (s, 1H), 7.49 (s, 2H), 6.72 (s, 2H), 4.18-4.06 (m, 1H), 3.25-3.32 (m, 2H), 2.90-2.80 (m, 2H), 2.42-2.34 (m, 2H), 2.23 (s, 6H), 2.20 (s, 3H), 2.18 (s, 6H), 2.12 - 1.93 (m, 6H).LCMS(M+H) + =493.5.

[0131] Example A2 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide [ka] Step 1: 3-Bromo-5-methylbenzenesulfonyl chloride [ka] SOCl2 (35.2 g, 295.6 mmol) was added dropwise to water (200 mL) at 0°C and stirred overnight at room temperature. The solution was cooled to 0°C, then CuCl (5.32 g, 53.8 mmol) was added, and the mixture was stirred at room temperature for 30 minutes to obtain mixture A. In a separate vessel, 3-bromo-5-methylaniline (10.0 g, 53.8 mmol) was dissolved in concentrated HCl (150 mL), then a solution of NaNO2 (5.2 g, 75.3 mmol) in water (10 mL) was added dropwise at 0°C, and the mixture was stirred at room temperature for 30 minutes to obtain mixture B. Mixture B was added dropwise to mixture A at 0°C, and the final mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (11.9 g, 82%).

[0132] Step 2: 3-Bromo-N,5-dimethylbenzenesulfonamide [ka] To a solution of 3-bromo-5-methylbenzenesulfonyl chloride (500 mg, 1.86 mmol) in pyridine (5 mL), MeNH2 (2.09 mL, 2 M, 4.18 mmol) in THF was added at room temperature. The mixture was stirred at room temperature for 2 hours, then quenched with water (10 mL). The mixture was extracted with ₹ (20 mL × 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (238 mg, 49%). LC-MS (M+H) + =266.0.

[0133] Step 3: N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (101 mg, 42%) was prepared from 3-bromo-N,5-dimethylbenzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS (M+H) + = 312.1.

[0134] Step 4: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide Example A2 (16 mg, 4%) was prepared from N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 5-bromo-3-(1-(1-methylpiperidine-4-yl))-1H-pyrazole-4-yloxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.45-7.37 (m, 1H), 6.89 (s, 2H), 4.17-4.05 (m, 1H), 2.90-2.82 (m, 2H), 2.45-2.40 (m, 6H), 2.21 (s, 3H), 2.10-1.90 (m, 6H).LC-MS (M+H) + = 458.2.

[0135] Example A3 4-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-N,2,6-trimethylbenzamide [ka] Step 1: 4-Bromo-N,2,6-trimethylbenzamide [ka] A solution of 4-bromo-2,6-dimethylbenzoic acid (5.0 g, 20.7 mmol), DIPEA (11.4 mL, 88.3 mmol), HATU (9.13 g, 22.8 mmol), and methylamine hydrochloride (2.95 g, 41.5 mmol) in DMF (20 mL) was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by silica gel chromatography (PE / SiO₂ = 2 / 3) to obtain the title compound (4.5 g, 85%). LC-MS(M+1)+=242.1.

[0136] Step 2: N,2,6-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] The title compound (206 mg, 45%) was prepared from 4-bromo-N,2,6-trimethylbenzamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =290.2.

[0137] Step 3: 4-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-N,2,6-trimethylbenzamide Example A3 (18 mg, 32%) was prepared from 5-bromo-3-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-amine and N,2,6-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.15-8.07 (m, 2 H), 7.57 (s, 1 H), 7.48 (s, 2 H), 6.70 (s, 1 H), 4.19-4.03 (m, 1 H), 2.88-2.79 (m, 2 H), 2.74 (d, J = 4.5 Hz, 3 H), 2.23-2.16 (m, 9 H), 2.12-1.86 (m, 6 H).LC-MS(M+H) + =436.3.

[0138] Example A4 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethyl-N-(2-(pyrrolidine-1-yl)ethyl)benzamide [ka] Step 1: 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzoic acid [ka] To a solution of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (5.3 g, 15 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (5.0 g, 18 mmol) in dioxane (100 mL) and water (30 mL), K2CO3 (4.14 g, 30 mmol) and Pd(dppf)Cl2 (0.73 g, 0.9 mmol) were added under nitrogen. After stirring at 90 °C for 15 hours, the reaction mixture was cooled to room temperature and washed with HCl (50 mL). The aqueous phase was acidified to pH=2-3 with HCl (4 M). The precipitate was collected by filtration to obtain the title compound (3.2 g, 50.7%). LCMS (M+H) + = 423.1.

[0139] Step 2: 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethyl-N-(2-(pyrrolidine-1-yl)ethyl)benzamide To a solution of 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzoic acid (60 mg, 0.14 mmol) in DMF (2.0 mL), DIPEA (57 mg, 0.42 mmol), HATU (84 mg, 0.21 mmol), and 1-(2-aminoethyl)pyrrolidine (20 mg, 0.17 mmol) were added at room temperature. After 2 hours, the mixture was extracted with DCM (4 mL x 2). The combined organic layer was washed with brine (8 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain Example A4 (17 mg, 23%). 1 H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 8.07 (s, 1 H), 7.70 (s, 1 H), 7.56-7.51 (m, 2 H), 4.28-4.18 (m, 1 H), 3.60-3.52 (m, 2 H), 3.09-3.00 (m, 2 H), 2.79-2.72 (m, 2 H), 2.70-2.62 (m, 4 H), 2.41-2.35 (m, 9 H), 2.34-2.08 (m, 4 H), 1.91-1.82 (m, 4 H).LC-MS(M+H) + =519.4.

[0140] Example A5 4-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-2,6-dimethyl-N-(2-(piperidine-1-yl)ethyl)benzamide [ka] Example A5 (23 mg, 41%) was prepared from 4-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-2,6-dimethylbenzoic acid and 2-(piperidine-1-yl)ethanamine in the same manner as in step 2 of Example A4. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1 H), 8.15-8.06 (m, 2 H), 7.58 (s, 1 H), 7.50 (s, 2 H), 6.72 (s, 2 H), 4.19-4.07 (m, 1 H), 3.37-3.33 (m, 2 H), 2.89-2.80 (m, 2 H), 2.44-2.33 (m, 6 H), 2.25 (s, 6 H), 2.20 (s, 3 H), 2.12-1.92 (m, 6 H), 1.54-1.44 (m, 4 H), 1.43-1.34 (m, 2 H).LC-MS (M+H) + = 533.4.

[0141] Example A6 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylbenzenesulfonamide [ka] Step 1: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (90 mg, 69%) was prepared from 3-bromo-5-methylbenzenesulfonamide and BPD in the same manner as in step 6 of Example A1.

[0142] Step 2: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylbenzenesulfonamide Example A6 (29 mg, 24%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.32 (s, 2H), 6.89 (s, 2H), 4.19 - 4.07 (m, 1H), 2.89-2.82 (m, 2H), 2.41 (s, 3H), 2.20 (s, 3H), 2.10-1.90 (m, 6H).LC-MS(M+H) + =444.2.

[0143] Example A7 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methoxy-N-methylbenzenesulfonamide [ka] Step 1: 3-Bromo-5-methoxy-N-methylbenzenesulfonamide [ka] A solution of 3-bromo-5-methoxybenzenesulfonyl chloride (7.1 g, 25 mmol), methylamine hydrochloride (3.35 g, 50 mmol), and triethylamine (7.57 g, 75 mmol) in DCM (50 mL) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (PE / Â=20 / 1~5 / 1) to obtain the title compound (3.0 g, 40%). LCMS(M+H) + =280.1.

[0144] Step 2: 3-Methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] Dioxane (15 mL) contains 3-bromo-5-methoxy-N-methylbenzenesulfonamide (0.53 g, 1.9 mmol), BPD (0.53 g, 2.1 mmol), and Pd(dppf)Cl2 . A mixture of DCM (77.7 mg, 0.095 mmol) and AcOK (0.56 g, 5.7 mmol) was heated under reflux and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.60 g, 94%). LC-MS (M+H) + =328.2.

[0145] Step 3: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methoxy-N-methylbenzenesulfonamide Example A7 (16 mg, 20%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.69(s, 1H), 7.67(s, 1H), 7.47-7.39 (m, 1H), 7.18 (s, 1H), 6.91(s, 2H), 4.17-4.03 (m, 1H), 3.87(s,3H), 2.89-2.82 (m, 2H), 2.46-2.41 (d, J = 4.2 Hz, 3H), 2.21 (s, 3H), 2.09 - 1.94 (m, 6H).LCMS (M+H) + =474.4.

[0146] Example A8 5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,2,3-trimethylbenzenesulfonamide [ka] Step 1: 5-Bromo-2,3-dimethylaniline [ka] Iron powder (2.43 g, 41.3 mmol) was added to a solution of 5-bromo-1,2-dimethyl-3-nitrobenzene (2.0 g, 8.26 mmol) and NH4Cl (2.33 g, 41.3 mmol) in EtOH (12 mL) and H2O (24 mL). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The filtration cake was rinsed with DCM (10 mL x 3), and the filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (siRNA / PE 0:1~1:9) to obtain the title compound (1.4 g, 85%). LC-MS (M+H) + =199.8.

[0147] Step 2: 5-Bromo-2,3-dimethylbenzenesulfonyl chloride [ka] To a solution of 5-bromo-2,3-dimethylaniline (700 mg, 3.16 mmol) in concentrated HCl (4.0 mL) and AcOH (8.0 mL), NaNO2 (275 mg, 3.79 mmol) in water (2 mL) was added dropwise at -15 °C, and the mixture was stirred for 30 minutes to prepare the diazonium salt. Meanwhile, AcOH (8.0 mL) was bubbling with SO2 (g) for 15 minutes, and then CuCl (99 mg, 0.95 mmol) was added. Bubbling with SO2 was continued until a fine suspension was obtained. The suspension was cooled to 5 °C, and then the aforementioned diazonium solution was partially added. The mixture was heated to room temperature, stirred for 2 hours, and then cooled to 0 °C. The reaction was quenched with ice water (8 mL) and extracted with SiO2 (8 mL × 2). The combined organic layers were washed with saturated NaHCO3 (10 mL x 2) and water (20 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure, and the crude product (600 mg) was used in step 3 without further purification.

[0148] Step 3: 5-Bromo-N,2,3-trimethylbenzenesulfonamide [ka] To a solution of 5-bromo-2,3-dimethylbenzenesulfonyl chloride (600 mg, 1,056 mmol) in pyridine (4.0 mL), methylamine in THF solution (2 M, 0.63 mL, 1.26 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and ground with water (5 mL). The mixture was filtered, and the filtrate was discarded. The filter cake was rinsed with DCM (5 mL x 2), and the filtrate was concentrated under reduced pressure to obtain the title compound (300 mg, 34%) in 2 steps. LC-MS (M+H) + =278.0.

[0149] Step 4: N,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (227 mg, 68%) was prepared from 5-bromo-N,2,3-trimethylbenzenesulfonamide and BPD in the same manner as in step 2 of Example A7. LC-MS(M+H) + =326.1.

[0150] Step 5: 5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,2,3-trimethylbenzenesulfonamide Example A8 (7.3 mg, 9%) was prepared from N,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 5-bromo-3-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H),7.91 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 6.80 (s, 2H), 4.17-4.05 (m, 1H), 2.90-2.76 (m, 2H), 2.49-2.41 (m, 6H), 2.35 (s, 3H), 2.20 (s, 3H), 2.11-1.91 (m, 6H).LC-MS (M+H) + = 472.3.

[0151] Example A9 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methyl-N-(2-(piperidine-1-yl)ethyl)benzenesulfonamide [ka] Step 1: 3-Bromo-5-methyl-N-(2-(piperidine-1-yl)ethyl)benzenesulfonamide [ka] The title compound (209 mg, 55%) was prepared from 3-bromo-5-methylbenzenesulfonyl chloride and 2-(piperidine-1-yl)ethane-1-amine in the same manner as in step 2 of Example A2. LC-MS(M+H) + =361.1.

[0152] Step 2: 3-Methyl-N-(2-(piperidine-1-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (117 mg, 49%) was prepared from 3-bromo-5-methyl-N-(2-(piperidine-1-yl)ethyl)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS (M+H) + = 409.2.

[0153] Step 3: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methyl-N-(2-(piperidine-1-yl)ethyl)benzenesulfonamide Example A9 (22 mg, 17%) was prepared from 5-bromo-3-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-amine and 3-methyl-N-(2-(piperidine-1-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 6.90 (s, 2H), 4.17-4.07 (m, 1H), 2.91-2.82 (m, 4H), 2.42 (s, 3H), 2.29-2.12 (m, 9H), 2.12-1.92 (m, 6H), 1.43-1.34 (m, 4H), 1.34-1.25 (m, 2H).LC-MS(M+H) + =555.2.

[0154] Example A10 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-cyanoethyl)-5-methylbenzenesulfonamide [ka] Step 1: 3-Bromo-N-(2-cyanoethyl)-5-methylbenzenesulfonamide [ka] A solution of 3-bromo-5-methylbenzenesulfonyl chloride (0.50 g, 1.85 mmol), 3-aminopropanenitrile (0.13 g, 1.85 mmol), and triethylamine (0.37 g, 3.7 mmol) in DCM (50 mL) was stirred overnight at room temperature. The mixture was removed under reduced pressure, and the residue was purified by silica gel chromatography (PE / ₹=5 / 1~1 / 1) to obtain the title compound (0.38 g, 59%). LCMS(M+H) + =303,305.

[0155] Step 2: N-(2-cyanoethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] A mixture of 3-bromo-N-(2-cyanoethyl)-5-methylbenzenesulfonamide (0.37 g, 1.22 mmol), BPD (0.37 g, 1.46 mmol), Pd(dppf)Cl2 (53.5 mg, 0.073 mmol), and AcOK (0.24 g, 2.43 mmol) in dioxane (15 mL) was heated overnight under reflux under nitrogen. The mixture was cooled to room temperature and diluted with SiO2 (20 mL). The mixture was washed with brine (30 mL), and the aqueous layer was extracted with SiO2 (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the title compound (0.40 g, 93.6%). LC-MS(M+H) + =351.1.

[0156] Step 3: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-cyanoethyl)-5-methylbenzenesulfonamide Example A10 (70 mg, 25%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2-cyanoethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.12 (s, 1H), 8.08-7.99 (m, 2H), 7.94 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 6.89 (s, 2H), 4.18-4.16 (m, 1H), 3.05-2.95 (m, 2H), 2.92-2.83 (m, 2H), 2.67-2.60 (m, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 2.13 - 1.95 (m, 6H).LCMS(M+H) + =497.4.

[0157] Example A11 N-(1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)methanesulfonamide [ka] Step 1: 1-(3-bromo-5-methylphenyl)cyclopropan-1-amine [ka] To a solution of 3-bromo-5-methylbenzonitrile (9.50 g, 48.5 mmol) and Ti(Oi-Pr)4 (16.1 g, 56.6 mmol) in Et2O (200 mL), ethylmagnesium bromide (3 M, 35.7 mL, 107 mmol) in Et2O was added at -70°C, and the mixture was stirred for 10 minutes. The mixture was warmed to room temperature within 1 hour, and then BF3 was added. . Et2O (12.3 mL, 86.5 mmol) was added. After 1 hour, HCl (30 mL, 1 N) and Et2O (100 mL) were added. Then, NaOH aqueous solution (40 mL, 10%) was added, and the mixture was extracted with ether (100 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH in DCM, 0%~10%) to obtain the title compound (5.1 g, 44%). 1 H NMR (300 MHz, DMSO-d6) δ 7.41 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 2.28 (s, 2H), 1.31 - 1.08 (m, 4H).

[0158] Step 2: N-(1-(3-bromo-5-methylphenyl)cyclopropyl)methanesulfonamide [ka] A stirred solution of 1-(3-bromo-5-methylphenyl)cyclopropan-1-amine (1.0 g, 4.2 mmol) and triethylamine (1275 mg, 12.6 mmol) in acetonitrile (20 mL) was mixed with MsCl (722 mg, 6.302 mmol) at 0°C. The mixture was stirred overnight at room temperature, and then stirred at 80°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 15:1) to obtain the title compound (1.2 g, 89%). 1 H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.09 (s, 1H), 2.59 (s, 3H), 2.30 (s, 3H), 1.42 - 1.30 (m, 2H), 1.17 - 1.09 (m, 2H).

[0159] Step 3: N-(1-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methanesulfonamide [ka] The title compound (450 mg, 46%) was prepared from N-(1-(3-bromo-5-methylphenyl)cyclopropyl)methanesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+NH4) + =369.0.

[0160] Step 4: N-(1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)methanesulfonamide Example A11 (23 mg, 17%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(1-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methanesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 2H), 8.14 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.15 (s, 1H), 6.72 (s, 2H), 4.19-4.07 (m, 1H), 2.91-2.81 (m, 2H), 2.51 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H), 2.10-1.91 (m, 6H), 1.29-1.20 (m, 2H), 1.21-1.06 (m, 2H).LC-MS(M+H) + =498.3.

[0161] Example A12 N-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenethyl)methanesulfonamide [ka] Step 1: 2-(3-bromo-5-methylphenyl)ethanamine hydrochloride [ka] To a stirred solution of 2-(3-bromo-5-methylphenyl)acetonitrile (378 mg, 1.81 mmol) in MeOH (5 mL), Boc₂O (218 mg, 0.948 mmol), NiCl₂₆H₂O (118 mg, 0.470 mmol), and NaBH₄ (1109 mg, 27.8 mmol) were added under nitrogen at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under vacuum. The crude product was dissolved in dioxane (10 mL), and HCl (10 mL, 40 mmol, 4 M) from the dioxane was added. The resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum. The residue was ground in ethyl acetate (3 mL). The precipitate was collected by filtration and rinsed with ethyl acetate (1 mL x 3) to obtain the title compound (444 mg, 98%). LC-MS(M+H) + =214.0.

[0162] Step 2: N-(3-bromo-5-methylphenethyl)methanesulfonamide [ka] The title compound (334 mg, 64%) was prepared from 2-(3-bromo-5-methylphenyl)ethaneamine hydrochloride and MsCl in the same manner as in step 2 of Example A11. LC-MS(M+H) + =292.0.

[0163] Step 3: N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)methanesulfonamide [ka] Compound 3 (214 mg, 55%) was prepared from N-(3-bromo-5-methylphenethyl)methanesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =340.2.

[0164] Step 4: N-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenethyl)methanesulfonamide Example A12 (4.2 mg, 1%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)methanesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.51 (s, 2H), 7.14 (t, J = 5.8 Hz, 1H), 6.98 (s, 1H), 6.70 (s, 2H), 4.19 - 4.07 (m, 1H), 3.23-3.14 (m, 2H), 2.90-2.86 (m, 2H), 2.85 (s, 3H), 2.75 (t, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.21 (s, 3H), 2.10-1.90 (m, 6H).LC-MS(M+H) + =486.3.

[0165] Example A13 3-(5-amino-6-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide [ka] Example A13 (27 mg, 19%) was prepared from 5-bromo-3-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine hydrochloride and N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.58 (s, 1H), 7.49 (m, 2H), 6.90 (s, 2H), 4.27-4.12 (m, 1H), 3.11-3.00 (m, 2H), 2.70-2.54 (m, 3H), 2.43 (s, 6H), 2.07-1.95 (m, 2H), 1.90-1.73 (m, 2H).LC-MS(M+H) + =444.3.

[0166] Example A14 3-(5-amino-6-((1-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide [ka] Step 1: tert-butyl(1R,3s,5S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.73 mmol), tert-butyl(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 9.27 mmol), DIAD (2.24 g, 11.6 mmol), and PPh3 (3.0 g, 11.6 mmol) in THF (30 mL) was stirred overnight at room temperature under nitrogen. After removing the solvent, the residue was purified by silica gel chromatography (PE / SiO=10 / 1~5 / 1) to obtain the title compound (3.0 g, 95%). LCMS(M+H) + =404.1.

[0167] Step 2: tert-butyl(1R,3s,5S)-3-(4-hydroxy-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] The title compound (1.5 g, 69%) was prepared from tert-butyl(1R,3s,5S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate by the same method as described in Step 1 of Example A1. LCMS(M+H) + =294.

[0168] Step 3: tert-butyl(1R,3s,5S)-3-(4-((3-amino-6-bromopyrazine-2-yl)oxy)-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] The title compound (0.35 g, 66%) was prepared from tert-butyl(1R,3s,5S)-3-(4-hydroxy-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate and 3,5-dibromopyrazine-2-amine in the same manner as described in step 2 of Example A1. LCMS(M+H) + =465,467.

[0169] Step 4: 3-((1-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole-4-yl)oxy)-5-bromopyrazine-2-amine hydrochloride [ka] The title compound (0.30 g, 100%) was prepared from tert-butyl(1R,3s,5S)-3-(4-((3-amino-6-bromopyrazine-2-yl)oxy)-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate by the same method as described in step 3 of Example A1. LCMS(M+H) + =365,367.

[0170] Step 5: 5-Bromo-3-((1-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] The title compound (0.30 g, 99%) was prepared from 3-((1-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole-4-yl)oxy)-5-bromopyrazine-2-amine hydrochloride by the same method as described in step 4 of Example A1. LCMS(M+H) + = 379, 381.

[0171] Step 6: 3-(5-amino-6-((1-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide Example A14 (33 mg, 25%) was prepared from 5-bromo-3-((1-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.61-7.53 (m, 2H), 7.50 (s, 1H), 6.90 (s, 2H), 4.55-4.40 (m, 1H), 3.21 (s, 2H), 2.43 (s, 6H), 2.25 (s, 3H), 2.16-2.05 (m, 2H), 2.05-1.95 (m, 2H), 1.89-1.81 (m, 2H), 1.74-1.65 (m, 2H).LCMS(M+H) + =484.4.

[0172] Example A15 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-ethyl-5-methylbenzenesulfonamide [ka] Step 1: 3-Bromo-N-ethyl-5-methylbenzenesulfonamide [ka] A solution of 3-bromo-5-methylbenzenesulfonyl chloride (2.67 g, 10 mmol), ethylamine hydrochloride (1.62 g, 20 mmol), and TEA (3.03 g, 30 mmol) in DCM (50 mL) was stirred overnight at room temperature. The mixture was concentrated, and the crude product was purified by silica gel chromatography (PE / siRNA = 20 / 1 to 5 / 1) to obtain the title compound (0.85 g, 31%). LC-MS (M+H) + =278,280.

[0173] Step 2: N-Ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] 3-Bromo-N-ethyl-5-methylbenzenesulfonamide (850 mg, 3.0 mmol), BPD (762 mg, 3.0 mmol), Pd(dppf)Cl2 . in dioxane (15 mL), DCM (123 mg, 0.15 mmol), and AcOK (882 mg, 9.0 mmol) were heated under reflux overnight under nitrogen. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the title compound (810 mg, 83%). LC-MS (M+H) + = 326.3.

[0174] Step 3: 3-(5-Amino-6-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyrazin-2-yl)-N-ethyl-5-methylbenzenesulfonamide Example A15 (48 mg, 34%) was prepared from N-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 5-bromo-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine in the same manner as in Step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) 8.31 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.60 (s, 1H), 7.50 (s, 2H), 6.90 (s, 2H), 4.20 - 4.05 (m, 1H), 2.92 - 2.85(m, 2H), 2.83 - 2.75 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 2.12 - 1.94 (m, 6H), 0.98 (t, J = 7.2 Hz, 3H). LCMS(M+H) + = 472.4.<0002x877>

[0175] Example A16 3-(5-Amino-6-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyrazin-2-yl)-5-isopropoxy-N-methylbenzenesulfonamide; Formic acid [ka] Step 1: 1-Bromo-3-isopropoxy-5-nitrobenzene [ka] A mixture of 3-bromo-5-nitrophenol (5.45 g, 25 mmol), 2-iodopropane (8.5 g, 50 mmol), and K2CO3 (6.9 g, 50 mmol) in DMF (50 mL) was stirred overnight at room temperature. Water (150 mL) was added, and the mixture was extracted with  (150 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to obtain the title compound (6.3 g, 97%).

[0176] Step 2: 3-bromo-5-isopropoxyaniline [ka] The title compound (4.8 g, 86%) was prepared from 1-bromo-3-isopropoxy-5-nitrobenzene in the same manner as in Step 1 of Example A8. LC-MS(M+H) + =230.2.

[0177] Step 3: 3-Bromo-5-isopropoxybenzenesulfonyl chloride [ka] The title compound (4.6 g, 71%) was prepared from 3-bromo-5-isopropoxyaniline in the same manner as in step 2 of Example A8.

[0178] Step 4: 3-Bromo-5-isopropoxy-N-methylbenzenesulfonamide [ka] The title compound (584 mg, 24%) was prepared from 3-bromo-5-isopropoxybenzenesulfonyl chloride in the same manner as in step 3 of Example A8. LCMS(M+H) + =308,310.

[0179] Step 5: 3-Isopropoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (600 mg, 96%) was prepared from 3-bromo-5-isopropoxy-N-methylbenzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =356.2.

[0180] Step 6: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-isopropoxy-N-methylbenzenesulfonamide; formic acid Example A16 (20 mg, 37%) was prepared from 3-isopropoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) 8.33 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.58 (d, J = 4.4 Hz, 2H), 7.45 (s, 1H), 7.14 (s, 1H), 6.92 (s, 2H), 4.78 - 4.64 (m, 1H), 4.15 - 4.05 (s, 1H), 2.95- 2.85 (m, 2H), 2.43 (d, J = 4.8 Hz, 3H), 2.23 (s, 3H), 2.13 - 1.96 (m, 6H), 1.31 (d, J = 6.0 Hz, 6H).LCMS(M+H) + =502.4.

[0181] Example A17 5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-(dimethylamino)ethyl)-2,3-dimethylbenzamide [ka] Step 1: 5-Bromo-N-(2-(dimethylamino)ethyl)-2,3-dimethylbenzamide [ka] The title compound (400 mg, 89%) was prepared from 5-bromo-2,3-dimethylbenzoic acid and (2-aminoethyl)dimethylamine in the same manner as in Step 1 of Example A3. LC-MS(M+H) + =301.2.

[0182] Step 2: N-(2-(dimethylamino)ethyl)-2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] The title compound (185 mg, 47%) was prepared from 5-bromo-N-(2-(dimethylamino)ethyl)-2,3-dimethylbenzamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =347.2.

[0183] Step 3: 5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-(dimethylamino)ethyl)-2,3-dimethylbenzamide Example A17 (26 mg, 21%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2-(dimethylamino)ethyl)-2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.27-8.19 (m, 2H), 8.09 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 6.70 (s, 2H), 4.19-4.07 (m, LC-MS(M+H) + =493.4.

[0184] Example A18 5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-fluoro-N,2-dimethylbenzenesulfonamide [ka] Step 1: 5-Bromo-3-fluoro-2-methylaniline [ka] 5-Bromo-1-fluoro-2-methyl-3-nitrobenzene (9.96 g, 42.6 mmol) and iron powder (11.9 g, 213 mmol) were added to a mixture of concentrated HCl (10 mL), ethanol (100 mL), and water (2 mL). The mixture was heated under reflux for 1 hour and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was partitioned between water (50 mL) and ethyl acetate (50 mL). Organic matter was separated, dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (PE / ethyl acetate = 10:1) to obtain the title compound (3.5 g, 40%). LC-MS (M+H) + =203.9,205.9.

[0185] Step 2: 5-bromo-3-fluoro-N,2-dimethylbenzenesulfonamide [ka] The title compound (1.0 g, 36%) was prepared from 5-bromo-3-fluoro-2-methylaniline in the same manner as in steps 1 and 2 of Example A2. LC-MS(M+H) + =281.9 283.9.

[0186] Step 3: 3-Fluoro-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (400 mg, 100%) was prepared from 5-bromo-3-fluoro-N,2-dimethylbenzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =330.1.

[0187] Step 4: 5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-fluoro-N,2-dimethylbenzenesulfonamide Example A18 (70 mg, 26%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-fluoro-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 10.9 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 6.96 (s, 2H), 4.10 (dd, J = 9.8, 4.8 Hz, 1H), 2.86 (d, J = 10.4 Hz, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 2.21 (s, 3H), 2.09 - 1.94 (m, 6H).LC-MS(M+H) + =476.1.

[0188] Example A19 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)methanesulfonamide [ka] Step 1: 1-(4-bromo-2,6-dimethylphenyl)methaneamine [ka] At 0°C, BH3-THF (1M, 20mL, 20 mmol) was added under nitrogen to a solution of 4-bromo-2,6-dimethylbenzonitrile (900 mg, 4.07 mmol) in THF (20 mL). The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. The mixture was cooled to 0°C and quenched with MeOH (5 mL) and ice water (5 mL). The mixture was then heated to 70°C and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH in DCM with a 0% to 13% gradient) to obtain the title compound (868 mg, 99%). LC-MS (M+H) + =214.

[0189] Step 2: N-(4-bromo-2,6-dimethylbenzyl)methanesulfonamide [ka] The title compound (504 mg, 85%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine in the same manner as in step 2 of Example A11. LC-MS(M+H) + =292.0.

[0190] Step 3: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide [ka] The title compound (418 mg, 80%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)methanesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+NH4) + =357.2.

[0191] Step 4: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)methanesulfonamide Example A19 (25 mg, 13%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.10 (s, 1H), 7.57 (s, 1H), 7.49 (s, 2H), 7.08-6.99 (m, 1H), 6.70 (s, 2H), 4.18-4.04 (m, 3H), 2.93 (s, 3H), 2.89-2.79 (m, 2H), 2.36 (s, 6H), 2.19 (s, 3H), 2.11-1.89 (m, 6H).LC-MS(M+H) + =486.1.

[0192] Example A20 N-(1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)benzenesulfonamide [ka] Step 1: tert-butyl(1-(3-bromo-5-methylphenyl)cyclopropyl)carbamate [ka] To a stirred solution of 1-(3-bromo-5-methylphenyl)cyclopropan-1-amine (1.50 g, 6.30 mmol) and triethylamine (2.77 mL, 27.3 mmol) in DCM (15 mL), Boc2O (1.85 mL, 8.45 mmol) was partially added at 0°C. The mixture was warmed to room temperature, stirred for 3 hours, and then diluted with water (60 mL). The mixture was extracted with DCM (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.53 g, 75%).

[0193] Step 2: tert-butyl(1-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate [ka] The title compound (1.55 g, 94%) was prepared from tert-butyl (1-(3-bromo-5-methylphenyl)cyclopropyl) carbamate and BPD in the same manner as in step 6 of Example A1. LC-MS (Mt-Bu) + =318.2.

[0194] Step 3: tert-butyl(1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)carbamate [ka] The title compound (688 mg, 81%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and tert-butyl(1-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate in the same manner as in step 7 of Example A1. LC-MS(M+H) + =520.3.

[0195] Step 4: 5-(3-(1-aminocyclopropyl)-5-methylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] To a stirred solution of tert-butyl(1-(3-(5-amino)-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)carbamate (688 mg, 1.33 mmol) in MeOH (20 mL), HCl (3 M, 4 mL, 12 mmol) in MeOH was added dropwise at room temperature. After 2 hours, the mixture was concentrated under vacuum. The residue was partitioned between saturated NaHCO3 (30 mL) and DCM (30 mL). The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH = 10:1) to obtain the title compound (450 mg, 81%). LC-MS (M+H) + =420.2.

[0196] Step 5: N-(1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)benzenesulfonamide To a solution of 5-(3-(1-aminocyclopropyl)-5-methylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (77 mg, 0.185 mmol) in pyridine (5 mL), benzenesulfonyl chloride (137 mg, 0.74 mmol) was added under nitrogen at room temperature. After 4 hours, the mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (7.0 mg, 7%) to obtain Example A20. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (br s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.59 (s, 1H), 7.57-7.51 (m, 2H), 7.43-7.27 (m, 5H), 6.84 (s, 1H), 6.70 (s, 2H), 4.22-4.09 (m, 1H), 2.90-2.83 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 2.10-1.94 (m, 6H), 1.17-1.11 (m, 2H), 1.06-1.00 (m, 2H).LC-MS(M+H) + =560.2.

[0197] Example A21 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methoxy-2,6-dimethylbenzamide [ka] A solution of 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzoic acid (240 mg, 0.568 mmol), O-methylhydroxylamine hydrochloride (71 mg, 0.852 mmol), HATU (324 mg, 0.852 mmol), and DIPEA (220 mg, 1.70 mmol) in DMF (10 mL) was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the crude product was purified by silica gel chromatography to obtain Example A21 (20 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.53 (s, 2H), 6.77 (s, 2H), 4.13 (s, 1H), 3.73 (s, 3H), 2.85 (d, J = 10.6 Hz, 2H), 2.26 (s, 6H), 2.20 (s, 3H), 2.09-1.96 (m, 6H).LC-MS(M+H) + =452.0.

[0198] Example A22 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(methylamino)benzenesulfonamide [ka] Step 1: 3-Bromo-N-methyl-5-nitroaniline [ka] A mixture of 1-bromo-3-fluoro-5-nitrobenzene (4.0 g, 17.3 mmol) and methylamine hydrochloride (2.33 g, 34.5 mmol) in DMAC (30 mL) was mixed with Cs2CO3 (6.0 g, 17.5 mmol) at room temperature. The mixture was heated to 80°C, stirred for 2 hours, and then cooled to room temperature. The mixture was extracted with HCl (100 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / HCl = 5:1) to obtain the title compound (3.72 g, 93%). LC-MS (M+H) + =231.0.

[0199] Step 2: 5-Bromo-N 1 -methylbenzene-1,3-diamine [ka] The title compound (3.0 g, 93%) was prepared from 3-bromo-N-methyl-5-nitroaniline in the same manner as in Step 1 of Example A8. LC-MS(M+H) + =201.1.

[0200] Step 3: 3-Bromo-5-(methylamino)benzenesulfonyl chloride [ka] The title compound (562 mg, 40%) was administered to 5-bromo-N 1 -Methylbenzene-1,3-diamine was prepared in the same manner as in Step 2 of Example A8. LC-MS(M+H) + =283.9.

[0201] Step 4: 3-Bromo-N-methyl-5-(methylamino)benzenesulfonamide [ka] The title compound (200 mg, 36%) was prepared from 3-bromo-5-(methylamino)benzenesulfonyl chloride in the same manner as in step 3 of Example A8. LC-MS(M+H) + =278.9.

[0202] Step 5: N-methyl-3-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (110 mg, 94%) was prepared from 3-bromo-N-methyl-5-(methylamino)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =327.2.

[0203] Step 6: 33-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(methylamino)benzenesulfonamide Example A22 (8 mg, 8%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-methyl-3-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.40-7.34 (m, 1H), 7.33-7.27 (m, 1H), 7.19-7.15 (m, 1H), 6.88-6.84 (m, 1H), 6.82 (s, 2H), 6.26-6.19 (m, 1H), 4.15-4.03 (m, 1H), 2.90-2.80 (m, 2H), 2.75 (d, J = 4.9 Hz, 3H), 2.42 (d, J = 4.9 Hz, 3H), 2.20 (s, 3H), 2.10-1.88 (m, 6H).LC-MS(M+H) + =473.0.

[0204] Example A23 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(pyrrolidine-1-yl)benzenesulfonamide [ka] Step 1: 1-(3-bromo-5-nitrophenyl)pyrrolidine [ka] The title compound (4.37 g, 93%) was prepared from 1-bromo-3-fluoro-5-nitrobenzene and pyrrolidine in the same manner as in Step 1 of Example A22. LC-MS(M+H) + =271.1.

[0205] Step 2: 3-Bromo-5-(pyrrolidine-1-yl)aniline [ka] The title compound (3.18 g, 82%) was prepared from 1-(3-bromo-5-nitrophenyl)pyrrolidine in the same manner as in Step 1 of Example A8. LC-MS(M+H) + =241.1.

[0206] Step 3: 3-Bromo-5-(pyrrolidine-1-yl)benzenesulfonyl chloride [ka] The title compound (208 mg, 24%) was prepared from 3-bromo-5-(pyrrolidine-1-yl)aniline in the same manner as in step 2 of Example A8. LC-MS(M+H) + =323.9.

[0207] Step 4: 3-Bromo-N-methyl-5-(pyrrolidine-1-yl)benzenesulfonamide [ka] The title compound (145 mg, 88%) was prepared from 3-bromo-5-(pyrrolidine-1-yl)benzenesulfonyl chloride in the same manner as in step 3 of Example A8. LC-MS(M+H) + =319.0.

[0208] Step 5: N-methyl-3-(pyrroridine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (149 mg, 89%) was prepared from 3-bromo-N-methyl-5-(pyrrolidine-1-yl)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =367.3.

[0209] Step 6: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(pyrrolidine-1-yl)benzenesulfonamide Example A23 (6 mg, 6%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-methyl-3-(pyrrolidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.35-7.30 (m, 1H), 7.21-7.16 (m, 1H), 6.84 (s, 2H), 6.80-6.77 (m, 1H), 4.15-4.03 (m, 1H), 3.33-3.27 (m, 4H), 2.91-2.83 (m, 2H), 2.42 (d, J = 5.0 Hz, 3H), 2.21 (s, 3H), 2.10-1.90 (m, 10H).LC-MS(M+H) + =513.3.

[0210] Example A24 3-(5-amino-6-((1-(1-cyclopropylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide [ka] Step 1: 5-Bromo-3-((1-(1-cyclopropylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] To a stirred solution of 5-bromo-3-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (100 mg, 0.286 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (105 mg, 0.572 mmol) in MeOH (2 mL) and THF (2.00 mL), AcOH (0.30 mL) and NaBH3CN (57 mg, 0.86 mmol) were added at room temperature, and the mixture was heated overnight to 60°C under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 6:1) to obtain the title compound (70 mg, 60%). LC-MS (M+H) + = 381.0.

[0211] Step 2: 3-(5-amino-6-((1-(1-cyclopropylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide Example A24 (27 mg, 26%) was prepared from 5-bromo-3-((1-(1-cyclopropylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.41-7.30 (m, 1H), 6.87 (s, 2H), 4.24-4.08 (m, 1H),3.10-2.95 (m, 2H), 2.46-2.26 (m, 8H), 2.10-1.99(m, 2H), 1.98-1.80 (m, 2H), 1.66 (s, 1H), 0.48-0.26 (m, 4H).LC-MS(M+H) + =484.2.

[0212] Example A25 N-(1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopropyl)-2,2,2-trifluoroethane-1-sulfonamide [ka] Example A25 (32 mg, 26%) was prepared from 5-(3-(1-aminocyclopropyl)-5-methylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 2,2,2-trifluoroethanesulfonyl chloride in the same manner as in step 5 of Example A20. 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.23 ​​(s, 1H), 8.16 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.15 (s, 1H), 6.75 (s, 2H), 4.23-4.07 (m, 1H), 4.07-3.89 (m, 2H), 2.95-2.81 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 2.15-1.94 (m, 6H), 1.39-1.29 (m, 2H), 1.28-1.13 (m, 2H).LC-MS(M+H)+ =566.3.

[0213] Example A26 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-methylurea [ka] Step 1: 1-(4-bromo-2,6-dimethylbenzyl)-3-methylurea [ka] To a stirred solution of 1-(4-bromo-2,6-dimethylphenyl)methaneamine (100 mg, 0.451 mmol) in DCM (20 mL), triethylamine (0.13 mL, 0.902 mmol) and triphosgene (45 mg, 0.144 mmol) were added at 0°C. After 3 hours, methylamine (2 M, 0.45 mL, 0.90 mmol) in THF was added. The mixture was warmed to room temperature and stirred overnight. The resulting mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH = 8:1) to obtain the title compound (55 mg, 45%). LC-MS (M+H) + =271.1.

[0214] Step 2: 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-methylurea [ka] The title compound (44 mg, 68%) was prepared from 1-(4-bromo-2,6-dimethylbenzyl)-3-methylurea and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =319.3.

[0215] Step 3: 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-methylurea Example A26 (11 mg, 20%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-methylurea in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.10 (s, 1H), 7.57 (s, 1H), 7.46 (s, 2H), 6.66 (s, 2H), 5.96-5.83 (m, 1H), 5.60-5.49 (m, 1H), 4.21-4.03 (m, 3H), 2.92-2.79 (m, 2H), 2.53 (d, J = 4.6 Hz, 3H), 2.32 (s, 6H), 2.19 (s, 3H), 2.12-1.97 (m, 6H).LC-MS(M+H) + =465.2.

[0216] Example A27 3-(5-amino-6-((1-(1-ethylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide [ka] Step 1: 3-(5-amino-6-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide The title compound (2.0 g, 99%) was prepared from N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 5-bromo-3-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. LC-MS(M+H) + =444.1.

[0217] Step 2: 3-(5-amino-6-((1-(1-ethylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide To a solution of 3-(5-amino-6-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide (400 mg, 0.898 mmol) and acetaldehyde (200 mg, 4.49 mmol) in DCM (3 mL), AcOH (55 mg, 0.898 mmol) was added at 0°C. The mixture was stirred under nitrogen at 0°C for 1.5 hours, and then NaBH3CN (114 mg, 1.80 mmol) was added. After 1 hour, the mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example A27 (53 mg, 12%). 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.46-7.40 (m, 1H), 6.90 (s, 2H), 4.18-4.08 (m, 1H), 3.01-2.90 (m, 2H), 2.45-2.40 (m, 6H), 2.39-2.30 (m, 2H), 2.10-1.92 (m, 6H), 1.02 (t, J = 7.2 Hz, 3H).LC-MS(M+H) + =472.1.

[0218] Example A28 3-(5-amino-6-((1-(1-(oxetan-3-ylmethyl)piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide [ka] Example A28 (14 mg, 20%) was prepared from 3-(5-amino-6-((1-(piperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N,5-dimethylbenzenesulfonamide and oxetane-3-carbaldehyde in the same manner as in step 2 of Example A27. 1 H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.10 (s, 1H), 8.01-7.98 (m, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.41-7.34 (m, 1H), 6.89 (s, 2H), 4.67-4.57 (m, 2H), 4.25 (t, J = 6.1 Hz, 2H), 4.18-4.02 (m, 1H), 3.23-3.08 (m, 1H), 2.91-2.78 (m, 2H), 2.68-2.60 (m, 2H), 2.44-2.37 (m, 6H), 2.15-1.81 (m, 6H).LC-MS(M+H) + =514.2.

[0219] Example A29 4-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylphenyl)oxazolidine-2-one [ka] Step 1: 2-amino-2-(4-bromo-2,6-dimethylphenyl)acetonitrile [ka] To a solution of 4-bromo-2,6-dimethylbenzaldehyde (5.0 g, 22.3 mmol) in MeOH (20 mL), MeOH (7 M, 26 mL, 178 mmol) and NH3 in Ti(Oi-Pr)4 (7.67 g, 25.6 mmol) were added under nitrogen at room temperature. After 2 hours, TMSCN (2.33 g, 22.3 mmol) was added dropwise. After 24 hours, ice water (100 mL) was added. The solid was filtered, and the filter cake was rinsed with siRNA (20 mL x 3). The filtrate was extracted with siRNA (300 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (siRNA:hexane = 3:2) to obtain the title compound (2.07 g, 39%).

[0220] Step 2: Amino(4-bromo-2,6-dimethylphenyl) acetate hydrochloride [ka] 2-amino-2-(4-bromo-2,6-dimethylphenyl)acetonitrile (1.71 g, 7.15 mmol) was mixed with HCl aqueous solution (6 M, 90 mL), and the mixture was then heated overnight to 105°C. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to approximately one-third of its original volume. The precipitate was collected by filtration and dried under vacuum to obtain the title compound (865 mg, 41%). LC-MS(M+H) + =258.1.

[0221] Step 3: 2-amino-2-(4-bromo-2,6-dimethylphenyl)ethane-1-ol hydrochloride [ka] To a solution of LiBH4 in THF (2.5 M, 7.6 mL, 7.540 mmol), TMSCl (1.72 g, 15.00 mmol) and amino(4-bromo-2,6-dimethylphenyl) acetate hydrochloride (779 mg, 2.65 mmol) were added at room temperature. After 12 hours, the solution was cooled to 0°C, and MeOH (10 mL) and water (100 mL) were carefully added. After 15 minutes, saturated NaHCO3 (100 mL) was carefully added, and the mixture was extracted with SiO2 (250 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by C18 chromatography (MeOH in 0.1% aqueous HCl) to obtain the title compound (370 mg, 50%). LC-MS (M+H) + =244.0.

[0222] Step 4: 4-(4-bromo-2,6-dimethylphenyl)-1,3-oxazolidine-2-one [ka] To a solution of 2-amino-2-(4-bromo-2,6-dimethylphenyl)ethane-1-ol hydrochloride (231 mg, 0.83 mmol) and triethylamine (303 mg, 2.85 mmol) in DCM (15 mL), triphosgene (148 mg, 0.47 mmol) in DCM (5 mL) was added dropwise under nitrogen at 0°C. The mixture was warmed to room temperature and stirred for 3 hours. Water (20 mL) was added, and the mixture was extracted with DCM (80 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH:DCM = 1:9) to obtain the title compound (131 mg, 51%). LC-MS (M+H) + =270.0.

[0223] Step 5: 4-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidine-2-one [ka] Compound 5 (125 mg, 94%) was prepared from 4-(4-bromo-2,6-dimethylphenyl)-1,3-oxazolidine-2-one and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =318.3.

[0224] Step 6: 4-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylphenyl)oxazolidine-2-one Example A29 (16 mg, 12%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 4-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidine-2-one in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.12 (s, 1H), 7.96-7.91 (m, 1H), 7.59 (s, 1H), 7.51 (s, 2H), 6.73 (s, 2H), 5.47-5.37 (m, LC-MS(M+H) + =464.1.

[0225] Example A30 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(tert-butyl)-N-methylbenzenesulfonamide [ka] Step 1: 3-Bromo-5-tert-butylbenzene-1-sulfonyl chloride [ka] At -78°C, n-BuLi (2.5M, 0.2mL, 3.83 mmol) in hexane was added dropwise to a solution of 1,3-dibromo-5-tert-butylbenzene (1.00 g, 3.25 mmol) in THF (15 mL) under nitrogen. After 30 minutes, SO2 (g) was bubbling into the mixture at the same temperature for 1 hour. The mixture was warmed to room temperature, stirred overnight, and then concentrated under vacuum. DCM (15 mL) and NCS (457 mg, 3.25 mmol) were added to the crude product at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with DCM (50 mL x 3). The filtrate was concentrated under reduced pressure to obtain the title compound (900 mg, crude).

[0226] Step 2: 3-Bromo-5-tert-butyl-N-methylbenzenesulfonamide [ka] Compound 1 (74 mg, 8%) was prepared from 3-bromo-5-tert-butylbenzene-1-sulfonyl chloride in the same manner as in step 3 of Example A8. LC-MS(M+H) + =306.0.

[0227] Step 3: 3-tert-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (67 mg, 79%) was prepared from 3-bromo-5-tert-butyl-N-methylbenzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =354.2.

[0228] Step 4: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(tert-butyl)-N-methylbenzenesulfonamide Example A30 (18 mg, 21%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-tert-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.09 (s, 2H), 8.004-7.99 (m, 1H), 7.68-7.55 (m, 2H), 7.48-7.40 (m, 1H), 6.89 (s, 2H), 4.14-4.03 (m, 1H), 2.91-2.80 (m, 2H), 2.44-2.37 (m, 3H), 2.20 (s, 3H), 2.10-1.90 (m, 6H), 1.32 (s, 9H).LC-MS(M+H) + =500.3.

[0229] Example A31 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)tetrahydro-2H-pyran-4-sulfonamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)tetrahydro-2H-pyran-4-sulfonamide [ka] The title compound (123 mg, 48%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and oxan-4-sulfonyl chloride in the same manner as in step 5 of Example A20. LC-MS (M+H)+ =362.0.

[0230] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)tetrahydro-2H-pyran-4-sulfonamide [ka] The title compound (99 mg, 71%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)tetrahydro-2H-pyran-4-sulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =410.2.

[0231] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)tetrahydro-2H-pyran-4-sulfonamide Example A31 (19 mg, 14%) was prepared from bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)tetrahydro-2H-pyran-4-sulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.50 (s, 2H), 7.28-7.20 (m, 1H), 6.70 (s, 2H), 4.20-4.10 (m, 3H), 3.99-3.91 (m, 2H), 2.94-2.84 (m, 2H), 2.38 (s, 6H), 2.25 (s, 3H), 2.19-2.09 (m, 2H), 2.04-1.93 (m, 4H), 1.92-1.82 (m, 2H), 1.71-1.57 (m, 2H).LC-MS(M+H) + =556.4.

[0232] Example A32 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)cyclopropanesulfonamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)cyclopropanesulfonamide [ka] The title compound (215 mg, 82%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and cyclopropanesulfonyl chloride in the same manner as in step 5 of Example A20. LC-MS(M+H) + =318.0.

[0233] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopropanesulfonamide [ka] The title compound (119 mg, 71%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)cyclopropanesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+NH4) + =383.2.

[0234] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)cyclopropanesulfonamide Example A32 (8 mg, 6%) was prepared from bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopropanesulfonamide in the same manner as in the final step of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.11 (s, 1H), 7.58 (s, 1H), 7.49 (s, 2H), 7.13-7.05 (m, 1H), 6.69 (s, 2H), 4.23-4.08 (m, LC-MS(M+H) + =512.2.

[0235] Example A33 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-(difluoromethyl)-N-(2-(dimethylamino)ethyl)-6-methylbenzamide [ka] Step 1: Ethyl 4-(dibenzylamino)-2-(difluoromethyl)-6-methylbenzoate [ka] A mixture of pentane-2,4-dione (15 g, 150 mmol), dibenzylamine (44.3 g, 225 mmol), and zinc acetate (1.38 g, 7.5 mmol) was stirred under nitrogen at 50°C for 2 days. Ethyl 4,4-difluoro-3-oxobutanoate (24.9 g, 150 mmol) and AcOH (300 mL) were added, and the mixture was stirred under nitrogen at 120°C for 3 hours.

[0236] The mixture was concentrated under reduced pressure, and the residue was collected in water (300 mL). The pH of the mixture was adjusted to 8 with saturated NaHCO3, and the mixture was extracted with HCl (300 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (PE / HCl = 10 / 1 to 5 / 1) to obtain the title compound (3.0 g, 5%). LC-MS (M+H) + =410.1.

[0237] Step 2: Ethyl 4-amino-2-(difluoromethyl)-6-methylbenzoate [ka] Pd / C (10% load) was added under nitrogen to a solution of ethyl 4-(dibenzylamino)-2-(difluoromethyl)-6-methylbenzoate (3.0 g, 7.31 mmol) in EtOH (30 mL) and AcOH (15 mL), and the system was then flushed with hydrogen. The mixture was stirred overnight at room temperature. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was taken into water (50 mL), and the pH of the mixture was adjusted to 8 with saturated NaHCO3. The mixture was extracted with ELISA (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (PE / ELISA = 5 / 1 to 3 / 1) to obtain the title compound (1.4 g, 84%). LCMS (M+H) + =230.

[0238] Step 3: Ethyl 4-bromo-2-(difluoromethyl)-6-methylbenzoate [ka] Copper bromide (1.37 g, 6.11 mmol) and t-butylnitrite (1.57 g, 15.3 mmol) were suspended in CH3CN (40 mL). The mixture was cooled to 0°C, and ethyl 4-amino-2-(difluoromethyl)-6-methylbenzoate (1.4 g, 6.11 mmol) in CH3CN (10 mL) was added dropwise. After 1 hour, the mixture was warmed to room temperature and stirred for 4 hours. Water (30 mL) was added, and the pH of the solution was adjusted to 2 with aqueous HCl (2 M). The mixture was extracted with HCl (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (PE / HCl = 5 / 1 to 3 / 1) to obtain the title compound (1.1 g, 61%). LCMS (M+H) + = 293, 295.

[0239] Step 4: 4-Bromo-2-(difluoromethyl)-6-methylbenzoic acid [ka] A mixture of ethyl 4-bromo-2-(difluoromethyl)-6-methylbenzoate (1.1 g, 3.75 mmol) and NaOH (0.6 g, 15 mmol) in dioxane (20 mL) and water (10 mL) was stirred overnight at 80°C. The mixture was cooled to room temperature and concentrated. Water (10 mL) was added, and the pH of the mixture was adjusted to 2 with aqueous HCl (2 M). The precipitate was collected by filtration and dried under vacuum to obtain the title compound (0.60 g, 60%).

[0240] Step 5: 4-Bromo-2-(difluoromethyl)-N-(2-(dimethylamino)ethyl)-6-methylbenzamide [ka] The title compound (0.64 g, 84%) was prepared from 4-bromo-2-(difluoromethyl)-6-methylbenzoic acid and N1,N1-dimethylethane-1,2-diamine in the same manner as in step 5 of Example A1. LCMS(M+H) +=335,337.

[0241] Step 6: 2-(difluoromethyl)-N-(2-(dimethylamino)ethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] The title compound (0.40 g, 55%) was prepared from 4-bromo-2-(difluoromethyl)-N-(2-(dimethylamino)ethyl)-6-methylbenzamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =383.1.

[0242] Step 7: 4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-(difluoromethyl)-N-(2-(dimethylamino)ethyl)-6-methylbenzamide Example A33 (140 mg, 62%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 2-(difluoromethyl)-N-(2-(dimethylamino)ethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in the same manner as in step 6 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.9 (s, 1H) 7.88 (s, 1H) 7.58 (s, 1H), 7.14 - 6.83 (m, 3H), 4.16-4.06 (m, 1H), 3.38-3.34 (m, 2H), 2.90-2.81 (m, 2H), 2.38 (t, J = 6.5 Hz, 2H), 2.31 (s, 3H), 2.20 (s, 3H), 2.19 (s, 6H), 2.08 - 1.95 (m, 6H).LCMS(M+H) += 529.5.

[0243] Example A34 (R)-4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-(3-fluoropyrrolidine-1-yl)ethyl)-2,6-dimethylbenzamide [ka] Step 1: (R)-2-(3-fluoropyrrolidine-1-yl)acetonitrile [ka] (R)-3-Fluoropyrrolidine hydrochloride (1.0 g, 7.9 mmol), 2-bromoacetonitrile (0.55 mL, 7.9 mmol), and K2CO3 (3.3 g, 23.8 mmol) were suspended in CH3CN (30 mL), and the mixture was heated under reflux overnight. The mixture was cooled to room temperature and then partitioned between water (50 mL) and siRNA (40 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the title compound (1.0 g, 99%). LC-MS(M+H) + =129.0.

[0244] Step 2: (R)-2-(3-fluoropyrrolidine-1-yl)ethane-1-amine [ka] To a solution of (R)-2-(3-fluoropyrrolidine-1-yl)acetonitrile (1.0 g, 7.8 mmol) in THF (30 mL), LiAlH4 (740 mg, 19.5 mmol) was added at 0°C, and the mixture was heated under reflux overnight. The mixture was cooled to room temperature, and water (4.0 mL) was added. After 15 minutes, the mixture was filtered, and the filter cake was washed with THF (20 mL). The filtrate was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (240 mg, 24%). LC-MS(M+H) + =133.1.

[0245] Step 3: (R)-4-bromo-N-(2-(3-fluoropyrrolidine-1-yl)ethyl)-2,6-dimethylbenzamide [ka] The title compound (433 mg, 70%) was prepared from 4-bromo-2,6-dimethylbenzoic acid and (R)-2-(3-fluoropyrrolidine-1-yl)ethane-1-amine in the same manner as in Step 1 of Example A3. LC-MS(M+H) + =343.0.

[0246] Step 4: (R)-N-(2-(3-fluoropyrrolidine-1-yl)ethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] The title compound (90 mg, 30%) was prepared from (R)-4-bromo-N-(2-(3-fluoropyrrolidine-1-yl)ethyl)-2,6-dimethylbenzamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =391.2.

[0247] Step 5: (R)-4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-(2-(3-fluoropyrrolidine-1-yl)ethyl)-2,6-dimethylbenzamide Example A34 (10 mg, 7%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-N-(2-(3-fluoropyrrolidine-1-yl)ethyl)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO) δ 8.25 - 8.19 (m, 2H), 8.12 (s, 1H), 7.58 (s, 1H), 7.50 (s, 2H), 6.73 (s, 2H), 5.29 - 5.08 (m, 1H), 4.15-4.09 (m, 1H), 3.36 (d, J = 6.5 Hz, 1H), 2.91 - 2.78 (m, 5H), 2.70 - 2.53 (m, 3H), 2.35-2.30 (m, 1H), 2.23 (s, 6H), 2.20 (s, 3H), 2.18 - 1.77 (m, 9H).LC-MS(M+H) + = 537.3.

[0248] Example A35 5-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylphenyl)morpholin-3-one [ka] Step 1: 5-(4-bromo-2,6-dimethylphenyl)morpholin-3-one [ka] To a solution of 2-amino-2-(4-bromo-2,6-dimethylphenyl)ethane-1-ol hydrochloride (200 mg, 0.71 mmol) and triethylamine (203 mg, 1.91 mmol) in THF (15 mL), chloroacetyl chloride (91 mg, 0.76 mmol) was added dropwise under nitrogen at 0°C. After 15 minutes, water (10 mL) was added. The mixture was extracted with  (10 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was dissolved in THF (15 mL), and NaH (60%, 37 mg, 0.92 mmol) was partially added at 0°C. The mixture was warmed to room temperature and stirred for 1.5 hours. Saturated NH4Cl (50 mL) was added, and the mixture was extracted with  (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH / DCM = 1:12) to obtain the title compound (123 mg, 61%). LC-MS (M+H) + =284.0.

[0249] Step 2: 5-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one [ka] The title compound (123 mg, 96%) was prepared from 5-(4-bromo-2,6-dimethylphenyl)morpholine-3-one and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =332.3.

[0250] Step 3: 5-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylphenyl)morpholin-3-one Example A35 (16 mg, 16%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 5-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 6.71 (s, 2H), 5.13-5.03 (m, 1H), 4.18-4.10 (m, 3H), 3.95-3.84 (m, 1H), 3.72-3.59 (m, 1H), 2.90-2.79 (m, 2H), 2.37 (s, 6H), 2.20 (s, 3H), 2.13-1.93 (m, 6H).LC-MS(M+H) + =478.2.

[0251] Example A36 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-ethylurea [ka] Step 1: 1-(4-bromo-2,6-dimethylbenzyl)-3-ethylurea [ka] To a stirred solution of 1-(4-bromo-2,6-dimethylphenyl)methaneamine (150 mg, 0.70 mmol) and triethylamine (142 mg, 1.40 mmol) in DCM (5 mL), ethyl isocyanate (50 mg, 0.70 mmol) in DCM (5 mL) was added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was partitioned between water (10 mL) and DCM (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (144 mg, 72%). LC-MS(M+H) + =287.1.

[0252] Step 2: 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-ethylurea [ka] The title compound (82 mg, 59%) was prepared from 1-(4-bromo-2,6-dimethylbenzyl)-3-ethylurea and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =333.1.

[0253] Step 3: 1-[[4-(5-amino-6-[[1-(1-methylpiperidine-4-yl)pyrazole-4-yl]oxy]pyrazine-2-yl)-2,6-dimethylphenyl]methyl]-3-ethylurea Example A36 (18 mg, 19%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-ethylurea in the same manner as in step 7 of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.10 (s, 1H), 7.57 (s, 1H), 7.46 (s, 2H), 6.67 (s, 2H), 5.86-5.78 (m, 1H), 5.65-5.57 (m, 1H), 4.21-4.12 (m, 1H), 4.19-4.04 (m, 2H), 3.05-2.93 (m, 2H), 2.90-2.80 (m, 2H), 2.32 (s, 6H), 2.20 (s, 3H), 2.14-1.88 (m, 6H), 0.95 (t, J = 7.1 Hz, 3H).LC-MS(M+H) + =479.4.

[0254] Example A37 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-cyclopentylurea [ka] Step 1: 1-(4-bromo-2,6-dimethylbenzyl)-3-cyclopentylurea [ka] The title compound (68 mg, 45%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and cyclopentylamine in the same manner as in Step 1 of Example A26. LC-MS(MH) - =323.1.

[0255] Step 2: 1-Cyclopentyl-3-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)urea [ka] The title compound (33 mg, 53%) was prepared from 1-(4-bromo-2,6-dimethylbenzyl)-3-cyclopentylurea and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =373.2.

[0256] Step 3: 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-cyclopentylurea Example A37 (9 mg, 8%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 1-cyclopentyl-3-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)urea in the same manner as in the final step of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.10 (s, 1H), 7.57 (s, 1H), 7.46 (s, 2H), 6.66 (s, 2H), 5.75 -5.64 (m, 2H), 4.25-4.05 (m, 3H), 3.89-3.81 (m, 1H), 2.88-2.79 (m, 2H), 2.32 (s, 6H), 2.19 (s, 3H), 2.12-1.90 (m, 6H), 1.80-1.66 (m, 2H), 1.60-1.39 (m, 4H), 1.30-1.14 (m, 3H).LC-MS(M+H) + =519.4.

[0257] Example A38 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)benzenesulfonamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)benzenesulfonamide [ka] The title compound (116 mg, 23%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and benzenesulfonyl chloride in the same manner as in step 5 of Example A20. LC-MS(MH) - =352.0.

[0258] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzenesulfonamide [ka] The title compound (190 mg, 64%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(MH) - =400.1.

[0259] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)benzenesulfonamide Example A38 (24 mg, 10%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.10 (s, 1H), 7.91-7.84 (m, 2H), 7.72-7.59 (m, 4H), 7.58 (s, 1H), 7.45 (s, 2H), 6.70 (s, 2H), 4.19-4.07 (m, 1H), 3.92-3.84 (m, 2H), 2.92-2.82 (m, 2H), 2.21 (d, J = 13.2 Hz, 9H), 2.15- 1.93 (m, 6H).LC-MS(M+H) + =548.4.

[0260] Example A39 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-4-methoxybenzenesulfonamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)-4-methoxybenzenesulfonamide [ka] The title compound (107 mg, 20%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and 4-methoxybenzenesulfonyl chloride in the same manner as in step 5 of Example A20. LC-MS(MH) - =382.0.

[0261] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methoxybenzenesulfonamide [ka] The title compound (118 mg, 98%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)-4-methoxybenzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =432.3.

[0262] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-4-methoxybenzenesulfonamide Example A39 (26 mg, 18%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methoxybenzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.10 (s, 1H), 7.84-7.76 (m, 2H), 7.58 (s, 1H), 7.51-7.47 (m, 1H), 7.45 (s, 2H),7.18-7.10 (m, 2H), 6.70 (s, 2H), 4.22-4.07 (m, 1H), 3.87-3.81 (m, 5H), 2.95-2.85 (m, 2H), 2.26 (s, 3H), 2.21 (s, 6H), 2.14 (s, 3H), 2.17-1.97 (m, 6H).LC-MS(M+H) + =578.4.

[0263] Example A40 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)cyclopentanesulfonamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)cyclopentanesulfonamide [ka] The title compound (71 mg, 23%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and cyclopentanesulfonyl chloride in the same manner as in step 5 of Example A20. LC-MS(MH) + =344.0.

[0264] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopentanesulfonamide [ka] The title compound (78 mg, 96%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)cyclopentanesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(MH) - =392.2.

[0265] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)cyclopentanesulfonamide Example A40 (19 mg, 13%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopentanesulfonamide in the same manner as in the final step of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.10 (s, 1H), 7.57 (s, 1H), 7.48 (s, 2H), 7.12-7.03 (m, 1H), 6.69 (s, 2H), 4.19-4.05 (m, LC-MS(M+H) + =540.4.

[0266] Example A41 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(piperidine-1-yl)benzenesulfonamide [ka] Step 1: 3-bromo-5-fluoro-N-methylbenzenesulfonamide [ka] The title compound (1.62 g, 91%) was prepared from 3-bromo-5-fluorobenzenesulfonyl chloride in the same manner as in step 3 of Example A8. LC-MS(M+H) + =267.8.

[0267] Step 2: 3-Bromo-N-methyl-5-(piperidine-1-yl)benzenesulfonamide [ka] A mixture of 3-bromo-5-fluoro-N-methylbenzenesulfonamide (255 mg, 0.951 mmol), piperidine (476 mg, 5.6 mmol), and K2CO3 (309 mg, 2.24 mmol) in DMF (3 mL) was stirred under nitrogen at 120°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 chromatography to obtain the title compound (274 mg, 86%). LC-MS (M+H) + =334.9.

[0268] Step 3: N-methyl-3-(piperidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (257 mg, 82%) was prepared from 3-bromo-N-methyl-5-(piperidine-1-yl)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS (M-pin) + =299.1.

[0269] Step 4: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(piperidine-1-yl)benzenesulfonamide Example A41 (25 mg, 18%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-methyl-3-(piperidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.10 (s, 1H), 7.62-7.54 (m, 3H), 7.38-7.31 (m, 1H), 7.17-7.14 (m, 1H), 6.86 (s, 2H), 4.15-4.02 (m, 1H), 3.28-3.20 (m, 4H), 2.91-2.82 (m, 2H), 2.41 (d, J = 5.1 Hz, 3H), 2.21 (s, 3H), 2.10-1.89 (m, 6H), 1.67-1.55 (m, 6H).LC-MS(M+H) + = 527.3.

[0270] Example A42 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-morpholinobenzenesulfonamide [ka] Step 1: 3-Bromo-N-methyl-5-morpholinobenzenesulfonamide [ka] The title compound (279 mg, 88%) was prepared from 3-bromo-5-fluoro-N-methylbenzenesulfonamide and morpholine in the same manner as in step 2 of Example A41. LC-MS(M+H) + =334.8.

[0271] Step 2: N-methyl-3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (144 mg, 66%) was prepared from 3-bromo-N-methyl-5-(morpholine-4-yl)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) +=383.0.

[0272] Step 3: 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-morpholinobenzenesulfonamide Example A42 (28 mg, 21%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-methyl-3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.63-7.56 (m, 2H), 7.40-7.34 (m, 1H), 7.18 (s, 1H), 6.88 (s, 2H), 4.15-4.04 (m, 1H), 3.81-3.72 (m, 4H), 3.27-3.18 (m, 4H), 2.91-2.83 (m, 2H), 2.42 (d, J = 5.1 Hz, 3H), 2.21 (s, 3H), 2.11-1.88 (m, 6H).LC-MS(M+H) + =529.3.

[0273] Example A43 (R)-3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(2-methylpyrrolidine-1-yl)benzenesulfonamide [ka] Step 1: (R)-3-bromo-N-methyl-5-(2-methylpyrrolidine-1-yl)benzenesulfonamide [ka] The title compound (286 mg, 90%) was prepared from 3-bromo-5-fluoro-N-methylbenzenesulfonamide and (2R)-2-methylpyrrolidine in the same manner as in step 2 of Example A41. LC-MS(M+H) + =332.8.

[0274] Step 2: (R)-N-methyl-3-(2-methylpyrrolidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (202 mg, 74%) was prepared from (R)-3-bromo-N-methyl-5-(2-methylpyrrolidine-1-yl)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS (M-pin) + =299.1.

[0275] Step 3: (R)-3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(2-methylpyrrolidine-1-yl)benzenesulfonamide Example A43 (39 mg, 30%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-N-methyl-3-(2-methylpyrrolidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.38-7.30 (m, 1H), 7.19 (s, 1H), 6.89-6.75 (m, 3H), 4.15-4.01 (m, 1H), 3.97-3.90 (m, 1H), 3.49-3.38 (m, 1H), 3.23-3.11 (m, 1H), 2.93-2.81 (m, 2H), 2.42 (d, J = 5.1 Hz, 3H), 2.22 (s, 3H), 2.12-1.90 (m, 9H), 1.74-1.67 (m, 1H), 1.16-1.08 (m, 3H).LC-MS(M+H) + = 527.3.

[0276] Example A44 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)benzamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)benzamide [ka] Triethylamine (213 mg, 2.10 mmol) was added dropwise to a stirred mixture of 1-(4-bromo-2,6-dimethylphenyl)methaneamine (150 mg, 0.70 mmol) and benzoyl chloride (394 mg, 2.80 mmol) in DCM (5 mL) under nitrogen at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Â=8:1) to obtain the title compound (200 mg, 89%). LC-MS (M+H) + =318.1.

[0277] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide [ka] The title compound (146 mg, 66%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)benzamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =366.1.

[0278] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)benzamide Example A44 (7 mg, 3%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.51-8.44 (m, 1H), 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.88-7.80 (m, 2H), 7.59 (s, 1H), 7.54-7.46 (m, 3H), 7.46-7.39 (m, 2H), 6.69 (s, 2H), 4.53-4.43 (m, 2H), 4.19-4.07 (m, 1H), 2.90-2.78 (m, 2H), 2.39 (app s, 6H), 2.20 (s, 3H), 2.12-1.90 (m, 6H).LC-MS(M+H) + =512.4.

[0279] Example A45 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)acetamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)acetamide [ka] The title compound (131 mg, 84%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and AcCl in the same manner as in Step 1 of Example A44. LC-MS(M+H) + =256.0.

[0280] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acetamide [ka] The title compound (88 mg, 80%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)benzamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =304.3.

[0281] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)acetamide Example A45 (19 mg, 13%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acetamide in the same manner as in step 7 of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.10 (s, 1H), 7.87-7.80 (m, 2H), 7.57 (s, 1H), 7.50-7.45 (m, 2H), 6.68 (s, 2H), 4.28-4.20 LC-MS(M+H) + =450.4.

[0282] Example A46 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-methylbenzyl)methanesulfonamide [ka] Step 1: (4-bromo-2-methylphenyl)methanamine [ka] The title compound (2.29 g, 47%) was prepared from 4-bromo-2-methylbenzonitrile in the same manner as in Step 1 of Example A19. LC-MS(M+H) + =200.0.

[0283] Step 2: N-(4-bromo-2-methylbenzyl)methanesulfonamide [ka] The title compound (377 mg, 59%) was prepared from (4-bromo-2-methylphenyl)methaneamine and MsCl in the same manner as in step 5 of Example A20. LC-MS(M+H) + =277.7.

[0284] Step 2: N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide [ka] The title compound (142 mg, 71%) was prepared from N-(4-bromo-2-methylbenzyl)methanesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =326.2.

[0285] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-methylbenzyl)methanesulfonamide Example A46 (24 mg, 21%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.70-7.58 (m, 3H), 7.39 (t, J = 6.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.70 (s, 2H), 4.22-4.06 (m, 3H), 2.95-2.81 (m, 5H), 2.33 (s, 3H), 2.21 (s, 3H), 2.11-1.92 (m, 6H).LC-MS(M+H) + =472.3.

[0286] Example A47 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-methylbenzyl)-3-methylurea [ka] Step 1: 1-(4-bromo-2-methylbenzyl)-3-methylurea [ka] Triethylamine (473 mg, 4.58 mmol) was added under nitrogen at room temperature to a stirred mixture of 1-(4-bromo-2-methylphenyl)methaneamine (460 mg, 2.292 mmol) and N-methylcarbamoyl chloride (338 mg, 3.43 mmol) in DCM (5 mL). After 3 hours, the mixture was poured into water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (550 mg, 93%). LC-MS (M+H) + =259.0.

[0287] Step 2: 1-Methyl-3-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)urea [ka] The title compound (140 mg, 68%) was prepared from 1-(4-bromo-2-methylbenzyl)-3-methylurea and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =305.0.

[0288] Step 3: 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-methylbenzyl)-3-methylurea Example A47 (13 mg, 12%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 1-methyl-3-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)urea in the same manner as in step 7 of Example A1.1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.09 (s, 1H), 7.66-7.58 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 6.67 (s, 2H), 6.24 (t, J = 5.6 Hz, 1H), 5.77 (q, J = 4.8 Hz, 1H), 4.22-4.08 (m, 3H), 2.94-2.83 (m, 2H), 2.57 (d, J = 4.4 Hz, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.15-1.90 (m, 6H).LC-MS(M+H) + =451.4.

[0289] Example A48 5-(3,5-dimethyl-4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: 4-Bromo-2,6-dimethyl-N-(2,2,2-trifluoroethyl)benzamide [ka] 4-Bromo-2,6-dimethylbenzoic acid (1.5 g, 6.55 mmol) and DMF (2 drops) were dissolved in DCM (20 mL). Oxalyl chloride (1.1 mL, 13.1 mmol) was added dropwise at 0°C, and the mixture was warmed to room temperature and then stirred for 1 hour. The mixture was concentrated under vacuum. The crude product was dissolved in anhydrous THF (10 mL), and the solution was then added dropwise at 0°C to a mixture of 2,2,2-trifluoroethane-1-amine (714 mg, 7.20 mmol) and DIPEA (2.55 mL, 14.41 mmol) in anhydrous THF (20 mL). The mixture was warmed to room temperature and then stirred for 2 hours. Water (100 mL) was carefully added, and the mixture was extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and then concentrated under vacuum. The residue was purified by silica gel chromatography to obtain the title compound (1.8 g, 89%). LC-MS(M+H) + =311.0.

[0290] Step 2: N-(4-bromo-2,6-dimethylbenzyl)-2,2,2-trifluoroethane-1-amine [ka] 4-Bromo-2,6-dimethyl-N-(2,2,2-trifluoroethyl)benzamide (1.7 g, 5.48 mmol) was mixed with BH3-THF complex (1.0 M, 22 mL, 22 mmol), and the mixture was heated under reflux for 24 hours. The mixture was cooled to 0°C, and MeOH (10 mL) was added. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (600 mg, 37%). LC-MS(M+H) + =297.0.

[0291] Step 3: 5-(3,5-dimethyl-4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine A solution of N-(4-bromo-2,6-dimethylbenzyl)-2,2,2-trifluoroethane-1-amine (200 mg, 0.675 mmol), BPD (257 mg, 1.01 mmol), KOAc (133 mg, 1.35 mmol), and Pd(dppf)Cl2 (25 mg, 0.034 mmol) in 1,4-dioxane (20 mL) was heated under reflux under N2 for 2 hours. The solution was cooled to room temperature, and then 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (239 mg, 0.675 mmol), K2CO3 (186 mg, 1.35 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol), and water (10 mL) were added. The mixture was heated under reflux under N2 for 12 hours and then cooled to room temperature. The solvent was concentrated under reduced pressure to obtain Example A48 (80 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.47 (s, 2H), 6.67 (s, 2H), 4.14-4.10 (m, 1H), 3.75 (d, J = 6.5 Hz, 2H), 3.31-3.27 (m, 2H), 2.86 (d, J = 11.2 Hz, 2H), 2.36 (s, 6H), 2.21 (s, 3H), 2.11-1.96 (m, 6H).LC-MS(M+H) + =490.0.

[0292] Example A49 (R)-3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(3-methylmorpholino)benzenesulfonamide [ka] Step 1: 3-Bromo-5-chloro-N-methylbenzenesulfonamide [ka] The title compound (596 mg, 61%) was prepared from 3-bromo-5-chlorobenzenesulfonyl chloride in the same manner as in Step 1 of Example A7.

[0293] Step 2: (R)-3-chloro-N-methyl-5-(3-methylmorpholino)benzenesulfonamide [ka] To a stirred mixture of 3-bromo-5-chloro-N-methylbenzenesulfonamide (560 mg, 1.95 mmol) and (3R)-3-methylmorpholine (395 mg, 3.91 mmol) in dioxane (10 mL), Pd(dba)2 (112 mg, 0.20 mmol), JohnPhos (58 mg, 0.20 mmol), and t-BuOK (43.9 mg, 0.39 mmol) were added under nitrogen at room temperature. The mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by C18 flash chromatography to obtain the title compound (268 mg, 45%). LC-MS(M+H) + =305.0.

[0294] Step 3: (R)-N-methyl-3-(3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ka] The title compound (248 mg, 83%) was prepared from (R)-3-chloro-N-methyl-5-(3-methylmorpholino)benzenesulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS (M-pin) + =315.1.

[0295] Step 4: (R)-3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-N-methyl-5-(3-methylmorpholino)benzenesulfonamide Example A49 (32 mg, 21%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-N-methyl-3-(3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1 H), 8.10 (s, 1 H), 7.61-7.57 (m, 2 H), 7.53 (m, 1 H), 7.40-7.34 (m, 1 H), 7.12 (s, 1 H), 6.88 (s, 2 2.41 (d, J = 5.2 Hz, 3 H), 2.23 (s, 3 H), 2.13 -1.89 (m, 6 H), 1.04 (d, J = 6.5 Hz, 3 H).LC-MS(M+H) + = 543.3.

[0296] Example A50 (3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)dimethylsilanol [ka] Step 1: (3-bromo-5-methylphenyl)(chloromethyl)dimethylsilane [ka] To a solution of 1,3-dibromo-5-methylbenzene (2.0 g, 8.0 mmol) in THF (20 mL), n-BuLi (2.5 M in hexane, 3.2 mL, 8.0 mmol) was added under nitrogen at -78°C. After 1 hour, chloro(chloromethyl)dimethylsilane (1.7 g, 12 mmol) was added. After 3 hours, the mixture was warmed to room temperature and poured into water (60 mL). The mixture was extracted with  (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE: = 5:1) to obtain the title compound (2.0 g, 90%). 1 H NMR (400 MHz, CDCl3) δ 7.20 (s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 2.71 (s, 2H), 2.11 (s, 3H), 0.18 (s, 6H).

[0297] Step 2: ((3-bromo-5-methylphenyl)dimethylsilyl)methylacetate [ka] A mixture of (3-bromo-5-methylphenyl)(chloromethyl)dimethylsilane (2.0 g, 7.2 mmol) and KOAc (2.8 g, 28.8 mmol) in DMF (30 mL) was stirred at 90°C for 3 hours. The mixture was cooled to room temperature and then diluted with water (60 mL). The mixture was extracted with  (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE: = 5:1) to obtain the title compound (1.6 g, 74%). 1 H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 3.91 (s, 2H), 2.31 (s, 3H), 2.02 (s, 3H), 0.32 (s, 6H).

[0298] Step 3: ((3-bromo-5-methylphenyl)dimethylsilyl)methanol [ka] A solution of (3-bromo-5-methylphenyl)dimethylsilyl)methyl acetate (1.6 g, 5.31 mmol) and K2CO3 (1.46 g, 10.6 mmol) in MeOH (30 mL) was stirred at room temperature for 4 hours, and then diluted with water (50 mL). The mixture was extracted with toluene (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:toluene = 3:1) to obtain the title compound (1.2 g, 87%). 1 H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 3.57 (s, 2H), 2.33 (s, 3H), 0.34 (s, 6H).

[0299] Step 4: (3-bromo-5-methylphenyl)dimethylsilanol [ka] 6.8 g, 9.1 mmol of 10% sodium hypochlorite was slowly added to 0.50 M, 37 mL of aqueous NaHCO3 solution. The solution was then slowly added at 0°C to a solution of (3-bromo-5-methylphenyl)dimethylsilyl)methanol (1.2 g, 4.63 mmol), TEMPO (72 mg, 0.463 mmol), and KBr (55 mg, 0.463 mmol) in 60 mL of acetone. The mixture was warmed to room temperature and stirred for 2 hours. Saturated NH4Cl (30 mL) was then added, and the mixture was extracted with  (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE: = 3:1) to obtain the title compound (0.80 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 2.33 (s, 3H), 0.39 (s, 6H).

[0300] Step 5: Dimethyl(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)silanol [ka] The title compound (500 mg, 70%) was prepared from (3-bromo-5-methylphenyl)dimethylsilanol and BPD in the same manner as in step 6 of Example A1. 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 2.37 (s, 3H), 1.35 (s, 12H), 0.41 (s, 6H).LCMS(M+H) + =293.1.

[0301] Step 6: (3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)dimethylsilanol Example A50 (30 mg, 16%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and dimethyl(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)silanol in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.14 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.27 (s, 1H), 6.71 (s, 2H), 6.03 LCMS(M+H) + =439.3.

[0302] Example A51 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-(2,2,2-trifluoroethyl)urea [ka] Step 1: tert-butyl(4-bromo-2,6-dimethylbenzyl)carbamate [ka] To a solution of (4-bromo-2,6-dimethylphenyl)methaneamine (300 mg, 1.4 mmol) in THF (10 mL), triethylamine (283 mg, 2.8 mmol) and (Boc)2O (448 mg, 2.8 mmol) were added, and the mixture was stirred overnight at room temperature. SiO (10 mL) was added, and the mixture was successively washed with H2O (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:SiO = 20:1) to obtain the title compound (380 mg, 86%). LC-MS (M+H) + =314.2,316.2.

[0303] Step 2: tert-butyl(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] The title compound (250 mg, 69%) was prepared from tert-butyl(4-bromo-2,6-dimethylbenzyl)carbamate and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =362.3.

[0304] Step 3: tert-butyl(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)carbamate [ka] 5-Bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (188 mg, 0.5 mmol), tert-butyl(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (250 mg, 0.7 mmol), Pd(dppf)Cl 2. CH2Cl2 (43 mg, 0.05 mmol) and K2CO3 (219 mg, 1.6 mmol) were added to dioxane (10 mL) and H2O (1 mL) under nitrogen, and the mixture was heated under reflux overnight. The mixture was cooled to room temperature, and siRNA (15 mL) was added. The mixture was washed with brine (10 mL x 2), and the aqueous layer was extracted with siRNA (15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH = 15:1) to obtain the title compound (180 mg, 67%). LC-MS (M+H) + =508.6.

[0305] Step 4: 5-(4-(aminomethyl)-3,5-dimethylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine; bistrifluoroacetic acid [ka] To a solution of tert-butyl(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)carbamate (180 mg, 0.36 mmol) in DCM (4 mL), TFA (2 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to obtain the title compound (225 mg, 100%). LC-MS (M+H) + =408.5.

[0306] Step 5: 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-(2,2,2-trifluoroethyl)urea A mixture of 2,2,2-trifluoroethane-1-amine (121 mg, 1.2 mmol) and pyridine (240 mg, 3.1 mmol) in DCM (5 mL) was cooled to 0°C, and a solution of triphosgene (134 mg, 0.45 mmol) in DCM (5 mL) was added dropwise. The reaction mixture was heated to 35°C and stirred for 1 hour, then stirred at 25°C for 2 hours. An aliquot (1.0 mL) of the mixture was added at 0°C to a solution of 5-(4-(aminomethyl)-3,5-dimethylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine; bis-trifluoroacetic acid (20 mg, 0.031 mmol), and triethylamine (15 mg, 0.15 mmol) in DCM (1.0 mL). After 3 hours, DCM (10 mL) was added, the mixture was successively washed with H2O (5 mL) and brine (5 mL), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain Example A51 (2.8 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.49 (s, 2H), 6.70 (s, 2H), 6.26 (s, 2H), 4.24 (s, 2H), 4.16 -4.10 (m, 1H), 3.86 - 3.79 (m, 2H), 2.86- 2.81 (m, 2H), 2.34 (s, 6H), 2.21 (s, 3H), 2.03-1.92 (m, 6H).LC-MS (M+H) + =533.4.

[0307] Example A52 2-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)propan-2-ol [ka] Step 1: Methyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ka] The title compound (800 mg, 96%) was prepared from 3-bromo-5-methylbenzoate and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =277.2.

[0308] Step 2: Methyl 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylbenzoate [ka] The title compound (300 mg, 71%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and methyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the same manner as in step 7 of Example A1. LC-MS(M+H) + =423.3.

[0309] Step 3: 2-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)propan-2-ol To a solution of methyl 3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylbenzoate (84 mg, 0.10 mmol) in anhydrous THF (3 mL), MeLi (1.6 M, 0.63 mL, 1.0 mmol) in Et2O was added dropwise under nitrogen at -78°C. The mixture was slowly warmed to room temperature, and then saturated NH4Cl (50 mL) was added. The mixture was extracted with  (100 mL). The organic layer was concentrated under reduced pressure and purified by preparative HPLC to obtain Example A52 (20 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) 8.21 (s, 1H), 8.14 (s, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 6.68 (s, 2H), 5.02 (s, LCMS(M+H) + =423.3.

[0310] Example A53 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-(tert-butyl)urea [ka] 5-(4-(aminomethyl)-3,5-dimethylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine; bistrifluoroacetic acid (100 mg, 0.158 mmol); and Et3N (90 mg, 0.89 mmol) were stirred in THF (20 mL), to which 2-isocyanato-2-methylpropane (25 mg, 0.252 mmol) was added at 0°C. The mixture was warmed to room temperature, stirred for 3 hours, and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain Example A53 (19 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.49 (s, 1H), 7.43-7.35 (m, 1H), 6.91 (s, 2H), 4.65 - 4.52 (m, 1H), 3.59 (t, J = 4.6 Hz, 4H), 2.64-2.54 (m, 3H), 2.43 (d, J = 5.0 Hz, 6H), 2.37-2.25 (m, 6H).LC-MS(M+H) + =507.4.

[0311] Example A54 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)oxetan-3-ol [ka] Step 1: 3-(3-chloro-5-methylphenyl)oxetan-3-ol [ka] To a solution of 1-bromo-3-chloro-5-methylbenzene (2.0 g, 9.8 mmol) in THF (30 mL), n-BuLi in hexane (2.5 M, 3.9 mL, 9.8 mmol) was added under nitrogen at -78°C. After 1 hour, oxetane-3-one (1.06 g, 14.7 mmol) was added dropwise. The mixture was stirred at -78°C for 3 hours and then warmed to room temperature. The mixture was poured into water (100 mL) and then extracted with toluene (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:toluene = 3:1) to obtain the title compound (1.2 g, 62%). LC-MS (M+H) + =199.0.

[0312] Step 2: 3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] To a solution of 3-(3-chloro-5-methylphenyl)oxetan-3-ol (400 mg, 2.0 mmol) in dioxane (10 mL), BPD (667 mg, 2.6 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (179 mg, 0.24 mmol), and AcOK (297 mg, 3.03 mmol) were added. The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, and poured into water (100 mL). The mixture was extracted with  (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:Â=3:1) to obtain the title compound (184 mg, 31%). LC-MS(M+H) + =291.1.

[0313] Step 3: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)oxetan-3-ol To a mixture of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (150 mg, 0.43 mmol) in dioxane (9 mL) and water (3 mL), 3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (187 mg, 0.64 mmol), Pd(dppf)Cl2 (35 mg, 0.04 mmol), and K2CO3 (178 mg, 1.29 mmol) were added. The mixture was stirred at 95°C for 16 hours, cooled to room temperature, and then poured into water (100 mL). The mixture was extracted with ELISA (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain Example A54 (59 mg, 32%). 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.65-7.55 (m, 2H), 7.34 (s, 1H), 6.73 (s, 2H), 6.35 (s, 1H), 4.86-4.63 (m, 4H), 4.20-4.06 (m, 1H), 2.95-2.80 (m, 2H), 2.37 (s, 3H), 2.21 (s, 3H), 2.11-1.91 (m, 6H).LC-MS(M+H) + =437.3.

[0314] Example A55 5-(3,5-dimethyl-4-((oxetane-3-ylamino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)oxetane-3-amine [ka] To a solution of 4-bromo-2,6-dimethylbenzaldehyde (3.0 g, 14 mmol) in DCM (60 mL), oxetane-3-amine (0.85 g, 11.7 mmol) and NaBH(OAc)3 (5.0 g, 23.4 mmol) were added at room temperature. After 16 hours, the mixture was quenched with saturated NaHCO3 solution (50 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / siRNA = 5 / 1 to 1 / 1) to obtain the title compound (2.0 g, 63%). LCMS (M+H) + = 270, 272.

[0315] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxetane-3-amine [ka] The title compound (1.5 g, 63%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)oxetane-3-amine and BPD in the same manner as in step 6 of Example A1. LCMS(M+H) + =318.2.

[0316] Step 3: 5-(3,5-dimethyl-4-((oxetane-3-ylamino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A55 (310 mg, 24%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxetane-3-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.49-7.44 (m, 2H), 6.67 (s, 2H), 4.67-4.58 (m, 2H), 4.40-4.30 (m, 2H), 4.19-4.09 (m, 1H), 3.96-3.86 (m, 1H), 3.60-3.52 (s, 2H), 2.90-2.80 (m, 2H), 2.36 (s, 6H), 2.21 (s, 3H), 2.11-1.96 (m, 6H).LCMS(M+H) + =464.3.

[0317] Example A56 5-(3,5-dimethyl-4-(((1-methyl-1H-pyrazole-3-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)-1-methyl-1H-pyrazole-3-amine [ka] AcOH (50 mg, 0.78 mmol) was added at room temperature to a stirred mixture of 4-bromo-2,6-dimethylbenzaldehyde (1.14 g, 5.1 mmol) and 1-methylpyrazole-3-amine (400 mg, 3.9 mmol) in MeOH (5 mL). After 16 hours, the mixture was cooled to 0°C and NaBH3CN (492 mg, 7.8 mmol) was added. The mixture was warmed to room temperature, stirred for 2 hours, and then cooled again to 0°C. Water (5 mL) was added, and the precipitate was collected by filtration. The solid was washed with RINKAN (10 mL x 3) and dried under vacuum to obtain the title compound (600 mg, 35%). LC-MS (M+H) + =294.1.

[0318] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-methyl-1H-pyrazole-3-amine [ka] The title compound (116 mg, 50%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)-1-methyl-1H-pyrazole-3-amine and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =342.1.

[0319] Step 3: 5-(3,5-dimethyl-4-(((1-methyl-1H-pyrazole-3-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A56 (10 mg, 7%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-methyl-1H-pyrazole-3-amine in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.12 (s, 1 H), 7.59 (s, 1 H), 7.49 (s, 2 H), 7.33-7.28 (m, 1 H), 6.67 (s, 2 H), 5.44-5.40 (m, 1 H), 4.98 (t, J = 5.6 Hz, 1 H), 4.19-4.07 (m, 3 H), 3.63 (s, 3 H), 2.90-2.81(m, 2 H), 2.36 (s, 6 H), 2.20 (s, 3 H), 2.12-1.90 (m, 6 H).LC-MS(M+H) + =488.3.

[0320] Example A57 5-(3,5-dimethyl-4-(((1-methyl-1H-pyrazole-4-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)-1-methyl-1H-pyrazole-4-amine [ka] The title compound (216 mg, 35%) was prepared from 4-bromo-2,6-dimethylbenzaldehyde and 1-methylpyrazole-4-amine in the same manner as in Step 1 of Example A56. LC-MS(M+H) + =294.0.

[0321] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-methyl-1H-pyrazole-4-amine [ka] The title compound (162 mg, 57%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)-1-methyl-1H-pyrazole-4-amine and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =342.1.

[0322] Step 3: 5-(3,5-dimethyl-4-(((1-methyl-1H-pyrazole-4-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A57 (20 mg, 15%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-methyl-1H-pyrazole-4-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.12 (s, 1 H), 7.59 (s, 1 H), 7.50 (s, 2 H), 7.14 (s, 1 H), 6.99 (s, 1 H), 6.68 (s, 2 H), 4.30-4.22 (m, 1 H), 4.19-4.07 (m, 1 H), 3.96-3.87 (m, 2 H), 3.71 (s, 3 H), 2.90-2.81 (m, 2 H), 2.35 (s, 6 H), 2.20 (s, 3 H), 2.11-1.91 (m, 6 H).LC-MS(M+H) + =488.3.

[0323] Example A58 4-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydro-2H-pyran-4-ol [ka] Step 1: 4-(3-bromo-5-methylphenyl)tetrahydro-2H-pyran-4-ol [ka] To a solution of 1,3-dibromo-5-methylbenzene (2.0 g, 8.0 mmol) in THF (5 mL), n-BuLi (1.6 M, 5 mL, 8.0 mmol) in hexane was added dropwise under N2 at -78°C. After 0.5 hours, tetrahydro-4H-pyran-4-one (960 mg, 9.6 mmol) was added dropwise. After another 1 hour, saturated NH4Cl (10 mL) was added to the mixture. After warming to room temperature, the mixture was diluted with water (10 mL) and extracted with  (40 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (PE:Â=2:1) ​​to obtain the title compound (1.2 g, 55%). LC-MS (M+H) + =271.1,273.1.

[0324] Step 2: 4-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol [ka] A mixture of 4-(3-bromo-5-methylphenyl)tetrahydro-2H-pyran-4-ol (1.0 g, 3.7 mmol), BPD (1.88 g, 7.4 mmol), Pd(dppf)Cl2 (302 mg, 0.37 mmol), and AcOK (1.0 g, 11.1 mmol) in dioxane (30 mL) was heated overnight under reflux under nitrogen. The mixture was cooled to room temperature and then diluted with SiO2 (60 mL). The mixture was washed with brine (30 mL x 2), and the combined aqueous layer was extracted with SiO2 (30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / SiO2 = 2:1) to obtain the title compound (1.0 g, 85%). LC-MS (M + H) + =319.3.

[0325] Step 3: 4-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydro-2H-pyran-4-ol Example A58 (10 mg, 7%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 4-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.7 (s, 1H), 7.47 (s, 1H), 7.2 (s, 1H), 6.65 (s, 2H), 4.95 (s, 1H), 4.06-4.07 (m,1H), 3.77-3.64 (m, 4H), 2.82 (d, J=9.2, 2H), 2.29 (s, 3H), 2.15 (s, 3H), 2.0-1.9 (m, 7H), 1.5 (d, J=13.6).LC-MS(M+H) + =465.2.

[0326] Compound A59 (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(3-methylmorpholino)phenyl)oxetan-3-ol [ka] Step 1: (R)-4-(3,5-dibromophenyl)-3-methylmorpholine [ka] To a solution of 1,3-dibromo-5-iodobenzene (2.0 g, 5.5 mmol) in dioxane (20 mL), (R)-3-methylmorpholine (558 mg, 5.5 mmol), Pd2(dba)3 (250 mg, 0.28 mmol), XantPhos (310 mg, 0.55 mmol), and Cs2CO3 (2.0 g, 6.1 mmol) were added under nitrogen, and the mixture was heated under reflux overnight. The mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel chromatography (PE:Â=20:1) to obtain the title compound (1.0 g, 54%). LC-MS(M+H) + =335.9,337.9.

[0327] Step 2: (R)-3-(3-bromo-5-(3-methylmorpholino)phenyl)oxetan-3-ol [ka] The title compound (150 mg, 31%) was prepared from (R)-4-(3,5-dibromophenyl)-3-methylmorpholine and oxetan-3-one in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =328.0.

[0328] Step 3: (R)-3-(3-(3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (147 mg, 85%) was prepared from (R)-3-(3-bromo-5-(3-methylmorpholino)phenyl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =376.2.

[0329] Step 4: (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(3-methylmorpholino)phenyl)oxetan-3-ol Example A59 (10 mg, 5%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-3-(3-(3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.08 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 6.97 (s, 1H), 6.67 (s, 2H), 6.25 (s, 1H), 4.76-4.60 (m, 4H), 4.10-3.98 (m, 1H), 3.91-3.78 (m, 2H), 3.75-3.59 (m, 2H), 3.58-3.48 (m, 1H), 3.22-3.12 (m, 1H), 3.07-2.95 (m, 1H), 2.87-2.76 (m, 2H), 2.17 (s, 3H), 2.05-1.79 (m, 6H), 1.00-0.90 (m, 3H).LC-MS(M+H) + =522.2.

[0330] Example A60 5-(3,5-dimethyl-4-(((3-methyloxetane-3-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)-3-methyloxetane-3-amine [ka] The title compound (1.6 g, 81%) was prepared from 4-bromo-2,6-dimethylbenzaldehyde and 3-methyloxetane-3-amine in the same manner as in step 1 of compound A55. LC-MS(M+H) + =284,286.

[0331] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-methyloxetane-3-amine [ka] The title compound (0.70 g, 38%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)-3-methyloxetane-3-amine and BPD in the same manner as in step 6 of compound A1. LCMS(M+H) + =332.2.

[0332] Step 3: 5-(3,5-dimethyl-4-(((3-methyloxetan-3-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A60 (105 mg, 52%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-methyloxetane-3-amine in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.50-7.42 (m, 2H), 6.67 (s, 2H), 4.60-4.50 (m, 2H), 4.30-4.21 (m, 2H), 4.19-4.07 (m, 1H), 3.59 (s, 2H), 2.91-2.82 (m, 2H), 2.38 (s, 6H), 2.21 (s, 3H), 2.11-1.96 (m, 6H), 1.48 (s, 3H).LCMS(M+H) + =478.3.

[0333] Examples A61A / A61B (S)-5-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)pyrrolidine-2-one and (R)-5-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)pyrrolidine-2-one [ka] Step 1: 4-(3-bromo-5-methylphenyl)-2-hydroxy-4-oxobutanoic acid [ka] To a solution of 1-(3-bromo-5-methylphenyl)ethanone (4.26 g, 19.6 mmol) in AcOH (70 mL), 2-oxoacetic acid (2.90 g, 19.6 mmol) was added at room temperature. The mixture was stirred under nitrogen at 120 °C for 8 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:SiO=2:1) ​​to obtain the title compound (2.24 g, 40%). LC-MS (M+H) + =286.9.

[0334] Step 2: 4-(3-bromo-5-methylphenyl)-4-oxobuta-2-enoic acid [ka] A solution of 4-(3-bromo-5-methylphenyl)-2-hydroxy-4-oxobutanoic acid (2.8 g, 7.87 mmol) in AcOH (60 mL) was to be mixed dropwise with concentrated HCl (20 mL) at room temperature. The mixture was stirred overnight at 120 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, and filtered. The solvent was evaporated under reduced pressure to obtain the title compound (1.8 g, 84%). LC-MS(M+H) + =266.6.

[0335] Step 3: 4-(3-bromo-5-methylphenyl)-4-oxobutanoic acid [ka] Zn powder (500 mg, 7.26 mmol) was added at room temperature to a stirred solution of 4-(3-bromo-5-methylphenyl)-4-oxobuto-2-enoic acid (2.0 g, 6.63 mmol) in AcOH (18 mL) and H2O (6 mL). After 3 hours, the mixture was diluted with water (50 mL) and filtered. The solid was rinsed with ethyl acetate (10 mL). The filtrate was extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (PE:HCl = 3:1) to obtain the title compound (1.6 g, 89%). LC-MS (M+H) + =270.9.

[0336] Step 4: 5-(3-bromo-5-methylphenyl)pyrrolidine-2-one [ka] To a solution of 4-(3-bromo-5-methylphenyl)-4-oxobutanoic acid (400 mg, 1.47 mmol) in EtOH (10 mL), NH4OAc (7.2 g, 88.4 mmol) and NaBH3CN (488.0 mg, 7.38 mmol) were partially added at room temperature. The mixture was stirred under nitrogen at 80°C for 5 hours. The mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (246 mg, 66%). LC-MS(M+H) + =254.0.

[0337] Step 5: 5-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one [ka] The title compound (149 mg, 89%) was prepared from 5-(3-bromo-5-methylphenyl)pyrrolidine-2-one and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =302.2.

[0338] Step 6: (S)-5-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)pyrrolidine-2-one and (R)-5-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)pyrrolidine-2-one Examples A61A / A61B were prepared from 5-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1, and the isomers were then separated by chiral HPLC. Analytical chiral HPLC conditions: CHIRALPAK IC3, 4.6 × 50 mm; (Hexane:DCM = 3:1, containing 0.1% Et2NH): IPA = 1:1; 1 mL / min; 25°C.

[0339] Example A61A((R)-5-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)pyrrolidine-2-one):(34 mg, 20%) 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1 H), 8.12 (s, 1 H), 8.07 (s, 1 H), 7.60-7.53 (m, 3 H), 7.04 (s, 1 H), 6.74 (s, 2 H), 4.69-4.59 (m, 1 H), 4.20-4.10 (m, 1 H), 2.89-2.79 (m, 2 H), 2.48-2.40 (m, 1 H), 2.33 (s, 3 H), 2.29-2.20 (m, 2 H), 2.20 (s, 3 H), 2.12-1.91 (m, 6 H), 1.85-1.73 (m, 1 H).LC-MS(M+H) + =448.3. Chiral HPLC: tR=3.50 min.

[0340] Example A61B((S)-5-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)pyrrolidine-2-one):(30mg, 18%) 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1 H), 8.12 (s, 1 H), 8.07 (s, 1 H), 7.60-7.53 (m, 3 H), 7.04 (s, 1 H), 6.74 (s, 2 H), 4.69-4.59 (m, 1 H), 4.20-4.10 (m, 1 H), 2.89-2.79 (m, 2 H), 2.48-2.40 (m, 1 H), 2.33 (s, 3 H), 2.29-2.20 (m, 2 H), 2.20 (s, 3 H), 2.12-1.91 (m, 6 H), 1.85-1.73 (m, 1 H).LC-MS(M+H) + =448.3. Chiral HPLC: tR=5.00 min.

[0341] Example A62 5-(4-[[(dimethylsulfamoyl)amino]methyl]-3,5-dimethylphenyl)-3-[[1-(1-methylpiperidine-4-yl)pyrazole-4-yl]oxy]pyrazine-2-amine [ka] Step 1: [[(4-bromo-2,6-dimethylphenyl)methyl]sulfamoyl]dimethylamine [ka] The title compound (375 mg, 71%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine and dimethylsulfamoyl chloride in the same manner as in step 2 of Example A11. LC-MS(M+H) + =320.9.

[0342] Step 2: ([[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]sulfamoyl)dimethylamine [ka] The title compound (168 mg, 59%) was prepared from [[(4-bromo-2,6-dimethylphenyl)methyl]sulfamoyl]dimethylamine and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =369.0.

[0343] Step 3: 5-(4-[[(dimethylsulfamoyl)amino]methyl]-3,5-dimethylphenyl)-3-[[1-(1-methylpiperidine-4-yl)pyrazole-4-yl]oxy]pyrazine-2-amine Example A62 (35 mg, 17%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and ([[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]sulfamoyl)dimethylamine in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.10 (s, 1 H), 7.57 (s, 1 H), 7.48 (s, 2 H), 7.27 (t, J = 5.4 Hz, 1 H), 6.69 (s, 2 H), 4.18-4.08 (m, 1 H), 4.08-4.02 (m, 2 H), 2.90-2.78 (m, 2 H), 2.69 (s, 6 H), 2.36 (s, 6 H), 2.19 (s, 3 H), 2.13-1.90 (m, 6 H).LC-MS(M+H) + =515.2.

[0344] Example A63 3-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylphenyl)oxetan-3-ol [ka] Step 1: 3-(4-chloro-2,6-dimethylphenyl)oxetan-3-ol [ka] To a stirred solution of 5-chloro-2-iodo-1,3-dimethylbenzene (798 mg, 3.0 mmol) in anhydrous THF (10 mL), n-BuLi in hexane (2.5 M, 1.2 mL, 3.0 mmol) was added dropwise under nitrogen at -78°C. After 3 hours, oxetane-3-one (216 mg, 3.0 mmol) was added. The mixture was warmed to room temperature within 30 minutes, and then saturated NH4Cl solution (50 mL) was added. The mixture was extracted with  (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC to obtain the title compound (250 mg, 39%). LC-MS (M-OH) + =195.2.

[0345] Step 2: 3-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] A mixture of 3-(4-chloro-2,6-dimethylphenyl)oxetan-3-ol (250 mg, 1.17 mmol), BPD (444 mg, 1.75 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (258 mg, 0.35 mmol), and AcOK (344 mg, 3.51 mmol) in dioxane (30 mL) was heated under reflux overnight under nitrogen. The mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel chromatography (PE:Â=10:1) to obtain the title compound (350 mg, 98%). LC-MS(M-OH) + =287.2.

[0346] Step 3: 3-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylphenyl)oxetan-3-ol Example A63 (55 mg, 41%) was prepared from 3-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.11 (s, 1H), 7.58 (s, 1H), 7.44 (s, 2H), 6.71 (s, 2H), 6.13 (s, 1H), 5.05 (s, 2H), 4.58 (s, 2H), 4.18 - 4.04 (m, 1H), 2.90 - 2.80 (m, 2H), 2.21 (s, 3H), 2.13 (s, 6H), 2.08 - 1.94 (m, 6H).LCMS(M+H) + =451.2.

[0347] Example A64 1-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)-3-(1-(trifluoromethyl)cyclopropyl)urea [ka] A mixture of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (18 mg, 0.12 mmol), diphenylphosphonic acid azide (33 mg, 0.12 mmol), and Et3N (12 mg, 0.12 mmol) in toluene (1 mL) was heated under reflux for 2 hours. The mixture was concentrated under reduced pressure and redissolved in THF (1 mL). The solution was added dropwise at 0°C to a solution of 5-(4-(aminomethyl)-3,5-dimethylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine; bis-trifluoroacetic acid (50 mg, 0.079 mmol) and Et3N (24 mg, 0.24 mmol) in THF (1 mL). After 3 hours, toluene (10 mL) was added, and the organic layer was successively washed with H₂O (5 mL) and brine (5 mL). The mixture was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain Example A64 (24 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.49 (s, 2H), 6.70 (s, 2H), 6.58 (s,1H), 5.97 (s, 1H), 4.21 (s, 2H), 4.20 - 4.11 (m, 1H), 2.88 -2.83 (m, 2H), 2.33 (s, 6H), 2.21 (s, 3H), 2.11 - 1.94 (m, 6H), 1.16 (s, 2H), 1.02 (s, 2H).LC-MS (M+H)+ =559.3.

[0348] Example A65 1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopentan-1-ol [ka] Step 1: 1-(3-bromo-5-methylphenyl)cyclopentan-1-ol [ka] The title compound (1.5 g, 74%) was prepared from 1,3-dibromo-5-methylbenzene and cyclopentanone in the same manner as in Step 1 of Example A54. LCMS(M-OH) + =237,239.

[0349] Step 2: 1-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopentan-1-ol [ka] The title compound (1.2 g, 71%) was prepared from 1-(3-bromo-5-methylphenyl)cyclopentan-1-ol and BPD in the same manner as in step 6 of Example A1. LCMS(M-OH) + =285.

[0350] Step 3: 1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)cyclopentan-1-ol Example A65 (50 mg, 27%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 1-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopentan-1-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.08 (s, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.18 (s, 1H), 6.64 (s, 2H), 4.71 LCMS(M+H) +=449.4.

[0351] Example A66 5-(3,5-dimethyl-4-morpholinophenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: 4-(4-chloro-2,6-dimethylphenyl)morpholine [ka] A mixture of 2-bromo-5-chloro-1,3-dimethylbenzene (1.1 g, 5.0 mmol), morpholine (522 mg, 6.0 mmol), XantPhos (286 mg, 0.50 mmol), Pd(dba)2 (287 mg, 0.50 mmol), and t-BuOK (1.12 g, 10 mmol) in toluene (30 mL) was heated overnight under reflux under nitrogen. The mixture was cooled to room temperature, concentrated under vacuum, and then diluted with water (100 mL). The mixture was extracted with DCM (100 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EA = 10:1) to obtain the title compound (200 mg, 18%). LC-MS (M + H) + =226.1.

[0352] Step 2: 4-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine [ka] A mixture of 4-(4-chloro-2,6-dimethylphenyl)morpholine (100 mg, 0.44 mmol), BPD (168 mg, 0.66 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (96 mg, 0.13 mmol), and AcOK (130 mg, 1.32 mmol) in dioxane (10 mL) was heated under reflux overnight under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EA = 10:1) to obtain the title compound (130 mg, 93%). LC-MS (M+H) + =228.1.

[0353] Step 3: 5-(3,5-dimethyl-4-morpholinophenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A66 (28 mg, 30%) was prepared from 4-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.11 (s, 1H), 7.58 (s, 1H), 7.45 (s, 2H), 6.64 (s, 2H), 4.15 - 4.10 (m, 1H), 3.69 - 3.67 (m, 4H), 3.01 - 2.97 (m, 4H), 2.87 - 2.85 (m, 2H), 2.32 (s, 6H), 2.21 (s, 3H), 2.09 - 1.96 (m, 6H).LCMS(M+H) + =464.2.

[0354] Example A67 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)oxazole-2-amine [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)oxazole-2-amine [ka] To a solution of 4-bromo-2,6-dimethylbenzaldehyde (1.0 g, 4.72 mmol) in dioxane (30 mL), 4-methylbenzenesulfone hydrazide (877 mg, 4.72 mmol) was added. The solution was stirred at 60 °C for 3 hours and cooled to room temperature. Then, t-BuOLi (755 mg, 9.44 mmol), CuI (116 mg, 0.61 mmol), and oxazole-2-amine (265 mg, 3.16 mmol) were added. The mixture was stirred under nitrogen at 100 °C for 3 hours and cooled to room temperature. The mixture was poured into water (100 mL) and then extracted with siRNA (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (PE:Â=1:1) to obtain the title compound (580 mg, 44%). LC-MS(M+H) + =281.0,283.0.

[0355] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxazole-2-amine [ka] The title compound (500 mg, 74%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)oxazole-2-amine and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =329.3.

[0356] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)oxazole-2-amine Example A67 (62 mg, 30%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxazole-2-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 7.45 (s, 2H), 7.37 (s, 1H), 7.17 (s, 1H), 6.73 (s, 1H), 6.66 LC-MS(M+H) + =475.3.

[0357] Example A68 5-(3,5-dimethyl-4-(((1-methyl-1H-1,2,4-triazole-3-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)-1-methyl-1H-1,2,4-triazole-3-amine [ka] The title compound (400 mg, 29%) was prepared from 4-bromo-2,6-dimethylbenzaldehyde and 1-methyl-1H-1,2,4-triazole-3-amine in the same manner as in Step 1 of Example A67. LC-MS(M+H) + =295.1,297.2.

[0358] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-methyl-1H-1,2,4-triazole-3-amine [ka] The title compound (290 mg, 62%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)-1-methyl-1H-1,2,4-triazole-3-amine and BPD in the same manner as in step 7 of Example A1. LC-MS(M+H) + =343.3.

[0359] Step 3: 5-(3,5-dimethyl-4-(((1-methyl-1H-1,2,4-triazole-3-yl)amino)methyl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A68 (66 mg, 32%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-methyl-1H-1,2,4-triazole-3-amine in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.47 (s, 2H), 6.68 (s, 2H), 5.80 (s, 1H), 4.24 LC-MS(M+H) + =489.3.

[0360] Example A69 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydrofuran-3-ol [ka] Step 1: 3-(3-bromo-5-methylphenyl)oxolan-3-ol [ka] The title compound (434 mg, 44%) was prepared from 1,3-dibromo-5-methylbenzene and dihydrofuran-3-one in the same manner as in Step 1 of Example A54. LC-MS(M-OH) + =239.0.

[0361] Step 2: 3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol [ka] The title compound (89 mg, 78%) was prepared from 3-(3-bromo-5-methylphenyl)oxolan-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M-OH) + =287.3.

[0362] Step 3: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydrofuran-3-ol Example A69 (25 mg, 17%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1 H), 8.13 (s, 1 H), 7.76 (s, 1 H), 7.59 (s, 1 H), 7.54 (s, 1 H), 7.24 (s, 1 H), 6.71 (s, 2 H), 5.39 (s, 1 H), 4.17-4.05 (m, 1 H), 4.06-3.94 (m, 2 H), 3.83-3.72 (m, 2 H), 2.92-2.82 (m, 2 H), 2.34 (s, 3 H), 2.32-2.23 (m, 1 H), 2.21 (s, 3 H), 2.15-1.91 (m, 7 H).LC-MS(M+H) + =451.3.

[0363] Example A70 2-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)butan-2-ol [ka] Step 1: 2-(3-bromo-5-methylphenyl)butan-2-ol [ka] The title compound (447 mg, 41%) was prepared from 1,3-dibromo-5-methylbenzene and butan-2-one in the same manner as in Step 1 of Example A54. LC-MS(M-OH) + =224.9.

[0364] Step 2: 2-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-2-ol [ka] The title compound (207 mg, 90%) was prepared from 2-(3-bromo-5-methylphenyl)butan-2-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M-OH) + =273.1.

[0365] Step 3: 2-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)butan-2-ol Example A70 (20 mg, 19%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 2-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-2-ol in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1 H), 8.14 (s, 1 H), 7.69 (s, 1 H), 7.59 (s, 1 H), 7.47 (s, 1 H), 7.17 (s, 1 H), 6.65 (s, 2 H), 4.80 (s, 1 H), 4.17-4.05 (m, 1 H), 2.90-2.82 (m, 2 H), 2.33 (s, 3 H), 2.21 (s, 3 H), 2.11-1.92 (m, 6 H), 1.77-1.62 (m, 2 H), 1.40 (s, 3 H), 0.70 (t, J = 7.3 Hz, 3 H).LC-MS(M+H) + =437.3.

[0366] Example A71 N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)morpholine-4-sulfonamide [ka] Step 1: N-(4-bromo-2,6-dimethylbenzyl)morpholine-4-sulfonamide [ka] The title compound (295 mg, 62%) was prepared from 1-(4-bromo-2,6-dimethylphenyl)methaneamine hydrochloride and morpholine-4-sulfonyl chloride in the same manner as in step 2 of Example A11. LC-MS(M+H) + =362.9.

[0367] Step 2: N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine-4-sulfonamide [ka] The title compound (130 mg, 47%) was prepared from N-(4-bromo-2,6-dimethylbenzyl)morpholine-4-sulfonamide and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =411.1.

[0368] Step 3: N-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2,6-dimethylbenzyl)morpholine-4-sulfonamide Example A71 (19 mg, 13%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine-4-sulfonamide in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1 H), 8.12 (s, 1 H), 7.60 (s, 1 H), 7.50 (s, 3 H), 6.71 (s, 2 H), 4.22-4.12 (m, 1 H), 4.12-4.07 (m, 2 H), 3.59-3.52 (m, 4 H), 3.05-2.98 (m, 4 H), 2.94-2.87 (m, 2 H), 2.38 (s, 6 H), 2.25 (s, 3 H), 2.17-2.10 (m, 2 H), 2.10-1.92 (m, 4 H).LC-MS(M+H) + =557.4.

[0369] Example A72 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-morpholinophenyl)oxetan-3-ol [ka] Step 1: 4-(3,5-dibromophenyl)morpholine [ka] The title compound (1.2 g, 37%) was prepared from 1,3-dibromo-5-iodobenzene and morpholine in the same manner as in Step 1 of Example A59. LCMS(M+H) + =322.

[0370] Step 2: 3-(3-bromo-5-morpholinophenyl)oxetan-3-ol [ka] The title compound (0.75 g, 64%) was prepared from 4-(3,5-dibromophenyl)morpholine and oxetan-3-one in the same manner as in Step 1 of Example A54. LCMS(M+H) + =314,316.

[0371] Step 3: 3-(3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (0.73 g, 85%) was prepared from 3-(3-bromo-5-morpholinophenyl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LCMS(M+H) + =362.

[0372] Step 4: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-morpholinophenyl)oxetan-3-ol Example A72 (100 mg, 51%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.14 (s, 1H), 7.58 (s, 1H), 7.56 (s, 1H), 7.33 (s, 1H),7.06 (s, 1H), 6.73 (s, 2H), 6.31 (s, 1H), 4.79-4.69 (m, 4H), 4.16-4.04 (m, 1H), 3.81 - 3.72 (m, 4H), 3.22 - 3.12 (m, 4H), 2.91-2.83 (m, 2H), 2.22 (s, 3H), 2.11 - 1.94 (m, 6H).LCMS(M+H) + = 508.5.

[0373] Example A73 3-(5-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-2,3-dimethylphenyl)oxetane-3-ol [ka] Step 1: 1-Bromo-5-chloro-2,3-dimethylbenzene [ka] The title compound (385 mg, 46%) was prepared from 3-bromo-4,5-dimethylaniline in the same manner as in Step 1 of Example A84.

[0374] Step 2: 3-(5-chloro-2,3-dimethylphenyl)oxetan-3-ol [ka] The title compound (304 mg, 82%) was prepared from 1-bromo-5-chloro-2,3-dimethylbenzene and oxetan-3-one in the same manner as in Step 1 of Example A54. LC-MS(M-OH) + =195.0.

[0375] Step 3: 3-(2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (264 mg, 65%) was prepared from 3-(5-chloro-2,3-dimethylphenyl)oxetan-3-ol in the same manner as in Step 2 of Example A54. LC-MS(M-OH) + =287.1.

[0376] Step 4: 3-(5-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-2,3-dimethylphenyl)oxetan-3-ol Example A73 (23 mg, 19%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1 H), 8.07 (s, 1 H), 7.63-7.54 (m, 2 H), 7.50 (s, 1 H), 6.64 (s, 2 H), 6.10 (s, 1 H), 5.01 (d, J = 6.7 Hz, 2 H), 4.71 (d, J = 6.7 Hz, 2 H), 4.15-4.01 (m, 1 H), 2.92-2.80 (m, 2 H), 2.24 (s, 3 H), 2.19 (s, 3 H), 2.10-1.90 (m, 9 H).LC-MS(M+H) + =451.3.

[0377] Examples A74A / A74B (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydrofuran-3-ol and (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydrofuran-3-ol [ka] Example A69 (700 mg) was separated by chiral HPLC to obtain Examples A74A / A74B. Analytical chiral-HPLC conditions: CHIRALPAK IA3, 4.6 × 50 mm, 3 μm; (Hexane:DCM = 3:1, containing 0.1% Et2NH): EtOH = 9:1; 1 mL / min; 25°C.

[0378] Example A74A((S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydrofuran-3-ol):(228mg, 33%) 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.12 (s, 1 H), 7.74 (s, 1 H), 7.57 (s, 1 H), 7.52 (s, 1 H), 7.24 (s, 1 H), 6.68 (s, 2 H), 5.37 (s, 1 H), 4.15-4.03 (m, 1 H), 4.04-3.92 (m, 2 H), 3.81-3.70 (m, 2 H), 2.91-2.82 (m, 2 H), 2.34 (s, 3 H), 2.32-2.23 (m, 1 H), 2.21 (s, 3 H), 2.15-1.91 (m, 7 H)..LC-MS(M+H) + =451.3. Chiral HPLC: tR=1.59 min.

[0379] Example A74B((R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydrofuran-3-ol):(252 mg, 36%) 1 1H NMR (400 MHz, DMSO-d6) 1 H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1 H), 8.13 (s, 1 H), 7.76 (s, 1 H), 7.59 (s, 1 H), 7.54 (s, 1 H), 7.24 (s, 1 H), 6.69 (s, 2 H), 5.38 (s, 1 H), 4.17-4.05 (m, 1 H), 4.06-3.94 (m, 2 H), 3.83-3.72 (m, 2 H), 2.92-2.82 (m, 2 H), 2.34 (s, 3 H), 2.32-2.23 (m, 1 H), 2.21 (s, 3 H), 2.15-1.91 (m, 7 H).LC-MS(M+H) + =451.3. Chiral HPLC: tR=2.08 mins.

[0380] Example A75 5-(4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: 4-(4-bromo-2,6-dimethylphenyl)-3,6-dihydro-2H-pyran [ka] 5-bromo-2-iodo-1,3-dimethylbenzene (1.55 g, 5.0 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 g, 5.5 mmol), and Pd(dppf)Cl2 in dioxane (20 mL) and water (2 mL). . A mixture of DCM (204 mg, 0.25 mmol) and K2CO3 (2.07 g, 15 mmol) was stirred overnight under nitrogen at 100°C. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative silica gel TLC (PE:siRNA=10:1) to obtain the title compound (772 mg, 58%). LC-MS (M+H) + =267.0,269.1.

[0381] Step 2: 2-(4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] 4-(4-bromo-2,6-dimethylphenyl)-3,6-dihydro-2H-pyran (772 mg, 2.9 mmol), BPD (810 mg, 3.19 mmol), Pd(dppf)Cl2 .DCM (118 mg, 0.145 mmol) and AcOK (853 mg, 8.7 mmol) were added to dioxane (10 mL) under nitrogen. The reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (PE:Ã=10:1) to obtain the title compound (900 mg, 98%). LC-MS(M+H) + =315.3.

[0382] Step 3: 5-(4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethylphenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A75 (57 mg, 62%) was prepared from 2-(4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.43 (s, 2H), 6.61 (s, 2H), 5.47 - 5.40 (m, 1H), 4.13 (s, 3H), 3.81 - 3.72 (m, 2H), 2.94 - 2.79 (m, 2H), 2.25 - 1.88 (m, 17H).LCMS(M+H) + =461.3.

[0383] Example A76 (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(3-(methoxymethyl)morpholino)phenyl)oxetan-3-ol [ka] Step 1: (R)-4-(3,5-dibromophenyl)-3-(methoxymethyl)morpholine [ka] The title compound (0.41 g, 37%) was prepared from 1,3-dibromo-5-iodobenzene and (R)-3-(methoxymethyl)morpholine in the same manner as in Step 1 of Example A59. LCMS(M+H) + =366.

[0384] Step 2: (R)-3-(3-bromo-5-(3-(methoxymethyl)morpholino)phenyl)oxetan-3-ol [ka] The title compound (0.14 g, 35%) was prepared from (R)-4-(3,5-dibromophenyl)-3-(methoxymethyl)morpholine and oxetan-3-one in the same manner as in Step 1 of Example A54. LCMS(M+H) + =358,360.

[0385] Step 3: (R)-3-(3-(3-(methoxymethyl)morpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (0.14 g, 88%) was prepared from (R)-3-(3-bromo-5-(3-(methoxymethyl)morpholino)phenyl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LCMS(M+H) + =406.

[0386] Step 4: (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(3-(methoxymethyl)morpholino)phenyl)oxetan-3-ol Example A76 (45 mg, 21%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-3-(3-(3-(methoxymethyl)morpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.13 (s, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H), 7.04 (s, 1H), 6.73 (s, 2H), 6.31 (s, 1H), 4.78 - 4.69 (m, 4H), 4.15 - 4.05 (m, 1H), 3.98-3.86 (m, 3H), 3.70 - 3.53 (m, 3H), 3.32-3.26 (m, 1H), 3.19 (s, 3H), 3.17-3.13 (m, 1H), 3.12-3.03 (m, 1H), 2.91-2.82 (m, 2H), 2.21 (s, 3H), 2.07 - 1.93 (m, 6H).LCMS(M+H) + =552.2.

[0387] Example A77 5-(3,5-dimethyl-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: 6-(4-chloro-2,6-dimethylphenyl)-2-oxa-6-azaspiro[3.3]heptane [ka] A solution of 2-bromo-5-chloro-1,3-dimethylbenzene (200 mg, 0.87 mmol) in dioxane (6 mL) is mixed with 2-oxa-6-azaspiro[3.3]heptane (181 mg, 1.73 mmol), Cs2CO3 (891 mg, 2.60 mmol), P(t-Bu)3 paradacycle Gen.3 (53 mg, 0.09 mmol), and P(t-Bu)3 . HBF4 (27 mg, 0.09 mmol) was added at room temperature, and the mixture was then heated to 90°C and stirred under nitrogen for 5 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with MeOH in DCM (0% to 13% gradient), to obtain the title compound (163 mg, 79%). LC-MS (M+H) + =238.2.

[0388] Step 2: 6-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane [ka] The title compound (175 mg, 78%) was prepared from 6-(4-chloro-2,6-dimethylphenyl)-2-oxa-6-azaspiro[3.3]heptane in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =330.0.

[0389] Step 3: 5-(3,5-dimethyl-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example A77 (7 mg, 9%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 6-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2 H), 7.78 (s, 1 H), 7.28 (s, 2 H), 6.45 (s, 2 H), 4.68 (s, 4 H), 4.27 (s, 4 H), 4.17-4.07 (m, 1 H), 2.91-2.82 (m, 2 H), 2.23 (d, J = 14.3 Hz, 9 H), 2.13-1.91 (m, 6 H).LC-MS(M+H) + =476.4.

[0390] Example A78 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)oxetane-3ol [ka] Step 1: 6-(3-bromo-5-chlorophenyl)-2-oxa-6-azaspiro[3,3]heptane [ka] The title compound (650 mg, 49%) was prepared from 1-bromo-3-chloro-5-fluorobenzene and 2-oxa-6-azaspiro[3.3]heptane in the same manner as in Step 1 of Example A22. LC-MS(M+H) + =287.9.

[0391] Step 2: 3-(3-chloro-5-(2-oxa-6-azapiro[3,3]heptan-6-yl)phenyl)oxetan-3-ol [ka] The title compound (320 mg, 66%) was prepared from 6-(3-bromo-5-chlorophenyl)-2-oxa-6-azaspiro[3.3]heptane and 3-oxetanone in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =282.0.

[0392] Step 3: 3-(3-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (134 mg, 51%) was prepared from 3-(3-chloro-5-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =374.1.

[0393] Step 4: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)oxetan-3ol Example A78 (17 mg, 12%) was prepared from 3-(3-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 6 of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1 H), 8.14 (s, 1 H), 7.56 (s, 1 H), 7.43 (s, 1 H), 6.82 (s, 1 H), 6.69 (s, 2 H), 6.55 (s, 1 H), 6.27 LC-MS(M+H) + =520.4.

[0394] Example A79 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)phenyl)oxetan-3-ol [ka] Step 1: 4-(3,5-dibromophenyl)oxan-4-ol [ka] The title compound (3.2 g, 30%) was prepared from 1,3,5-tribromobenzene and tetrahydropyran-4-one in the same manner as in Step 1 of Example A58. 1 H NMR (300 MHz, DMSO-d6) δ 7.70-7.61 (m, 3H), 5.31 (s, 1H), 3.77-3.60 (m, 4H), 2.02-1.82 (m, 2H), 1.52-1.41 (m, 2H).

[0395] Step 2: 4-(3,5-dibromophenyl)-tetrahydro-2H-pyran [ka] A mixture of 4-(3,5-dibromophenyl)oxan-4-ol (300 mg, 0.89 mmol), Et3SiH (1.56 g, 13.4 mmol), and TFA (1.63 g, 14.3 mmol) in DCM (5 mL) was stirred overnight at 40°C under nitrogen. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by reverse-phase chromatography to obtain the title compound (100 mg, 28%).

[0396] Step 3: 3-(3-bromo-5-(tetrahydro-2H-pyran-4-yl)phenyl)oxetan-3-ol [ka] The title compound (150 mg, 17%) was prepared from 4-(3,5-dibromophenyl)oxane and 3-oxetanone in the same manner as in Step 1 of Example A54.

[0397] Step 4: 3-(3-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (44 mg, 13%) was prepared from 3-(3-bromo-5-(tetrahydro-2H-pyran-4-yl)phenyl)oxetan-3-ol in the same manner as in step 6 of Example A1.

[0398] Step 5: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(tetrahydro-2H-pyran-4-yl)phenyl)oxetan-3-ol Example A79 (22 mg, 10%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(3-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1 H), 8.16 (s, 1 H), 7.92 (s, 1 H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.40 (s, 1 H), 6.73 (s, 2 H), 6.35 (s, 1 H), 4.82-4.71 (m, 4 H), 4.18-4.04 (m, 1 H), 4.02-3.93 (m, 2 H), 3.53-3.39 (m, 2 H), 2.92-2.76 (m, 3 H), 2.22 (s, 3 H), 2.11-1.92 (m, 6 H), 1.79-1.67 (m, 4 H).LC-MS(M+H) + =507.0.

[0399] Examples A80A / A80B (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol and (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol [ka] Step 1: 3-(3-bromo-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol [ka] The title compound (500 mg, 48%) was prepared from (3R)-4-(3,5-dibromophenyl)-3-methylmorpholine and dihydrofuran-3-one in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =341.9.

[0400] Step 2: 3-(3-((R)-3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol [ka] The title compound (300 mg, 65%) was prepared from 3-(3-bromo-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =390.1.

[0401] Step 3: (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol and (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol Examples A80A / A80B were prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(3-((R)-3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol in the same manner as in step 7 of Example A1, and the isomers were then separated by chiral HPLC. Analytical chiral HPLC conditions: CHIRALPAK IA3, 4.6 × 50 mm, 3 μm; (Hexane:DCM = 3:1, containing 0.1% Et2NH): IPA = 4:1; 1 mL / min; 25°C.

[0402] Example A80A((S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol):(22mg, 35%) 1 H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1 H), 8.12 (s, 1 H), 7.58 (s, 1 H), 7.39 (s, 1 H), 7.22 (s, 1 H), 6.99 (s, 1 H), 6.69 (s, 2 H), 5.35 (s, 1 H), 4.18-3.51 (m, 10 H), 3.26-3.16 (m, 1 H), 3.13-2.98 (m, 1 H), 2.92-2.82 (m, 2 H), 2.39-2.24 (m, 1 H), 2.22 (s, 3 H), 2.17-1.88 (m, 7 H), 1.00 (d, J = 6.4 Hz, 3 H).LC-MS(M+H) + =536.4. Chiral HPLC: tR=1.55 min.

[0403] Example A80B((R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydrofuran-3-ol):(23mg, 39%) 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1 H), 8.12 (s, 1 H), 7.58 (s, 1 H), 7.39 (s, 1 H), 7.22 (s, 1 H), 6.99 (s, 1 H), 6.69 (s, 2 H), 5.35 (s, 1 H), 4.18-3.51 (m, 10 H), 3.26-3.16 (m, 1 H), 3.13-2.98 (m, 1 H), 2.92-2.82 (m, 2 H), 2.39-2.24 (m, 1 H), 2.22 (s, 3 H), 2.17-1.88 (m, 7 H), 1.00 (d, J = 6.4 Hz, 3 H).LC-MS(M+H) + =536.4. Chiral HPLC: tR=2.57 mins.

[0404] Example A81 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-(prop-1-in-1-yl)phenyl)oxetan-3-ol [ka] Step 1: 1-Bromo-5-chloro-2-iodo-3-methylbenzene [ka] A suspension of 2-bromo-4-chloro-6-methylaniline (5.0 g, 22.8 mmol) in water (40 mL) and concentrated HCl (30 mL) was cooled to -5°C. An aqueous solution of NaNO2 (1.73 g, 25.1 mmol) was added dropwise to the suspension while maintaining the temperature below 0°C. After 30 minutes, the mixture was slowly added to KI (4.54 g, 27.4 mmol) in 300 mL of ice water with vigorous stirring. The mixture was stirred overnight at room temperature. The mixture was extracted with siRNA (400 mL x 2). The combined organic layers were washed with NaHSO3, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using PE to obtain the title compound (4.5 g, 60%).

[0405] Step 2: 1-Bromo-5-chloro-3-methyl-2-(propa-1-in-1-yl)benzene [ka] To a solution of 1-bromo-5-chloro-2-iodo-3-methylbenzene (2.0 g, 6.1 mmol) in toluene (30 mL), trimethyl(prop-1-in-1-yl)silane (680 mg, 6.1 mmol), triethylamine (1.85 g, 18.3 mmol), CuI (348 mg, 1.8 mmol), Pd(PPh3)4 (352 mg, 0.3 mmol), and TBAF (1.6 g, 6.1 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen. Ether (100 mL) was added, and the organic phase was successively washed with H2O (50 mL) and brine (50 mL). The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using PE to obtain the title compound (1.2 g, 82%). 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.43 (s, 1H), 2.40 (s, 3H), 2.15 (s, 3H).

[0406] Step 3: 3-(5-chloro-3-methyl-2-(prop-1-in-1-yl)phenyl)oxetan-3-ol [ka] To a solution of 1-bromo-5-chloro-3-methyl-2-(prop-1-in-1-yl)benzene (1.2 g, 5.0 mmol) in THF (10 mL), n-BuLi (2.5 M in hexane, 2 mL) was added dropwise under nitrogen at -78°C. After 40 minutes, oxetane-3-one (357 mg, 5.0 mmol) was added dropwise at -78°C, and the mixture was stirred for a further 2 hours. The mixture was quenched with saturated NH4Cl (30 mL), warmed to room temperature, diluted with siRNA (40 mL), and washed with brine (15 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using PE:siRNA = 14:5 to obtain the title compound (770 mg, 66%). LC-MS (M+H) + =237.2.

[0407] Step 4: 3-(3-methyl-2-(propa-1-in-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] To a solution of 3-(5-chloro-3-methyl-2-(prop-1-in-1-yl)phenyl)oxetan-3-ol (300 mg, 1.3 mmol) in dioxane (10 mL), BPD (645 mg, 2.6 mmol), KOAc (250 mg, 2.5 mmol), Pd2(dba)3 (116 mg, 0.13 mmol), and XPhos (121 mg, 0.25 mmol) were added. The mixture was stirred overnight under nitrogen at 110 °C. The mixture was cooled to room temperature, diluted with  (40 mL), and then sequentially washed with H2O (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using PE:Â=1:1 to obtain the title compound (360 mg, 86%). LC-MS(M+H) + =329.3.

[0408] Step 5: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-(prop-1-in-1-yl)phenyl)oxetan-3-ol A solution of 3-(3-methyl-2-(prop-1-in-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetane-3-ol (300 mg, 0.91 mmol) in dioxane (10 mL) and water (1 mL) is prepared by adding 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (322 mg, 0.91 mmol), K2CO3 (628 mg, 4.6 mmol), and Pd(dppf)Cl2 . DCM (74 mg, 0.09 mmol) was added, and the mixture was then heated to 100°C under nitrogen. After 1 hour, the mixture was cooled to room temperature, diluted with  (30 mL), and then washed sequentially with H2O (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative silica gel TLC with MeOH:DCM = 1:4, and then further purified by preparative HPLC to obtain Example A81 (6 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 6.81 (s,2H), 6.04 (s, 1H), 5.11 (d, J = 6.9 Hz, 2H), 4.68 (d, J = 6.9 Hz, 2H), 4.17 - 4.06 (m, 1H), 2.90 - 2.83 (m,2H), 2.38 (s, 3H), 2.21 (s, 3H), 2.09 (s, 3H), 2.06 - 1.94 (m, 6H).LC-MS (M+H) + =475.4.

[0409] Example A82 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(methoxymethyl)phenyl)oxetan-3-ol [ka] Step 1: (3,5-dibromophenyl)methanol [ka] To a solution of 3,5-dibromobenzoic acid (2.0 g, 7.1 mmol) in THF (20 mL), BH3 (1.0 M, 14 mL, 14 mmol) in THF was added. The mixture was stirred overnight at room temperature, and then methanol (10 mL) was carefully added. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE:HCl=5:1) to obtain the title compound (1.8 g, 95%). LC-MS (M+H) + =265.8,267.8.

[0410] Step 2: 1,3-Dibromo-5-(methoxymethyl)benzene [ka] To a solution of (3,5-dibromophenyl)methanol (1.8 g, 6.7 mmol) in THF (20 mL), NaH (60%, 330 mg, 8.25 mmol) was added at room temperature. After 1 hour, MeI (0.70 mL, 11.2 mmol) was added. The mixture was stirred overnight at room temperature. Saturated NH4Cl (10 mL) and water (10 mL) were added. The mixture was extracted with HCl (40 mL × 2). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:HCl = 5:1) to obtain the title compound (1.5 g, 78%). LC-MS (M+H) + =278.9,280.9.

[0411] Step 3: 3-(3-bromo-5-(methoxymethyl)phenyl)oxetan-3-ol [ka] The title compound (550 mg, 34%) was prepared from 1,3-dibromo-5-(methoxymethyl)benzene and oxetan-3-one in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =273.0,275.0.

[0412] Step 4: 3-(3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (500 mg, 77%) was prepared from 3-(3-bromo-5-(methoxymethyl)phenyl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =321.2.

[0413] Step 5: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(methoxymethyl)phenyl)oxetan-3-ol Example A82 (20 mg, 15%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 6.78 (s, 2H), 6.42 (s, 1H), 4.79-4.71 (m, 4H), 4.47 (s, 2H), 4.11-4.08 (m, 1H), 3.32(s, 3H), 2.88-2.85(m, 2H), 2.21(s, 3H), 2.0-1.9(m, 6H).LC-MS(M+H) + =467.2.

[0414] Example A83 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)tetrahydrofuran-3-ol [ka] Step 1: 3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-amine [ka] A mixture of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (2.0 g, 5.66 mmol), BPD (2.88 g, 11.3 mmol), Pd2(dba)3 (0.26 g, 0.283 mmol), tricyclohexylphosphine (0.12 g, 0.425 mmol), and KOAc (1.11 g, 11.3 mmol) in dioxane (20 mL) was stirred overnight at 110 °C under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography using acetonitrile / water to obtain the title compound (1.5 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1 H), 7.90 (s, 1 H), 7.56 (s, 1 H), 6.97 (s, 2 H), 4.15-4.03 (m, 1 H), 2.87-2.78 (m, 4 H), 2.20 (s, 3 H), 2.08-1.79 (m, 4 H), 1.16 (s, 12 H).LC-MS(M-pin+H) + =319.0.

[0415] Step 2: 6-(2-bromo-4-chloro-6-methylphenyl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a solution of 1-bromo-5-chloro-2-iodo-3-methylbenzene (2.0 g, 5.5 mmol) in dioxane (20 mL) and 2-oxa-6-azaspiro[3.3]heptane (630 mg, 6.04 mmol), Cs2CO3 (2.83 g, 8.24 mmol), Pd2(dba)3 (159 mg, 0.17 mmol), and XantPhos (201 mg, 0.33 mmol) were added under nitrogen, and the mixture was then heated to 90°C. After 16 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with siRNA in PE (0%~30% gradient) to obtain the title compound (1.52 g, 91%). LC-MS(M+1) + =301.9.

[0416] Step 3: 3-(5-chloro-3-methyl-2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)tetrahydrofuran-3-ol [ka] The title compound (150 mg, 37%) was prepared from 6-(2-bromo-4-chloro-6-methylphenyl)-2-oxa-6-azaspiro[3.3]heptane and dihydrofuran-3-one in the same manner as in Step 1 of Example A54. LC-MS(M+1)+ =310.0.

[0417] Step 4: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)tetrahydrofuran-3-ol To a solution of 3-(5-chloro-3-methyl-2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)tetrahydrofuran-3-ol (100 mg, 0.31 mmol) in dioxane (2 mL) and H2O (0.20 mL), 3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-amine (230 mg, 0.57 mmol), K2CO3 (89 mg, 0.62 mmol), and dichlorobis(tricyclohexylphosphine)palladium(II) (24 mg, 0.03 mmol) were added by nitrogen. The mixture was heated to 100°C and stirred for 2 hours. The mixture was cooled to room temperature and diluted with water (30 mL). The mixture was extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example A83 (25 mg, 15%). 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.12 (s, 1 H), 7.76 (s, 1 H), 7.59 (s, 2 H), 6.72 (s, 2 H), 5.93 (s, 1 H), 4.82-4.76 (m, 4 H), 4.21-3.96 (m, 7 H), 3.94-3.85 (m, 1 H), 3.76 (d, J = 8.9 Hz, 1 H), 2.92-2.83 (m, 2 H), 2.41 (s, 3 H), 2.37-2.25 (m, 1 H), 2.22 (s, 3 H), 2.20-2.14 (m, 1 H), 2.08-1.97 (m, 6 H).LC-MS(M+H) +=548.4.

[0418] Example A84 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-chloro-3-methylphenyl)oxetane-3-ol [ka] Step 1: 1-Bromo-2,5-dichloro-3-methylbenzene [ka] To a solution of 2-bromo-4-chloro-6-methylaniline (1.5 g, 6.46 mmol) in acetonitrile (10 mL), t-BuNO2 (1.05 g, 9.7 mmol) and CuCl2 (1.10 g, 7.8 mmol) were added under nitrogen. The mixture was heated to 60°C and stirred for 15 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography using DCM in PE (0% to 10% gradient) to obtain the title compound (1.36 g, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1 H), 7.55 (s, 1 H), 2.44 (s, 3 H).

[0419] Step 2: 3-(2,5-dichloro-3-methylphenyl)oxetan-3-ol [ka] The title compound (159 mg, 48%) was prepared from 1-bromo-2,5-dichloro-3-methylbenzene and 3-oxetanone in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =233.0.

[0420] Step 3: 3-(2-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (125 mg, 63%) was prepared from 3-(2,5-dichloro-3-methylphenyl)oxetan-3-ol and BPD in the same manner as in step 2 of Example A54. LC-MS(M+H) + =325.0.

[0421] Step 4: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-chloro-3-methylphenyl)oxetan-3-ol [ka] Example A84 (19 mg, 18%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(2-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1 H), 8.10 (s, 1 H), 7.81 (s, 1 H), 7.65-7.57 (m, 2 H), 6.81 (s, 2 H), 6.23 (s, 1 H), 5.08 (d, J = 7.1 Hz, 2 H), 4.71 (d, J = 7.0 Hz, 2 H), 4.18-4.05 (m, 1 H), 2.91-2.83 (m, 2 H), 2.37 (s, 3 H), 2.21 (s, 3 H), 2.10-1.95 (m, 6 H).LC-MS(M+H) + =471.3.

[0422] Example A85 (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(2-(hydroxymethyl)pyrrolidine-1-yl)phenyl)oxetan-3-ol [ka] Step 1: (S)-(1-(3,5-dibromophenyl)pyrrolidine-2-yl)methanol [ka] The title compound (1.87 g, 20%) was prepared from 1,3-dibromo-5-iodobenzene and (S)-prolinol by the same method as in step 1 of A59. LC-MS(M+H) + =335.8.

[0423] Step 2: (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(3,5-dibromophenyl)pyrrolidine [ka] To a stirred solution of (S)-(1-(3,5-dibromophenyl)pyrrolidine-2-yl)methanol (1.0 g, 3.0 mmol) in DMF (10 mL), TBSCl (0.90 g, 6.0 mmol) and imidazole (0.41 g, 6.0 mmol) were added at room temperature. The mixture was stirred under nitrogen at 50 °C for 16 hours. The mixture was cooled to room temperature, poured into water (30 mL), and then extracted sequentially with DCM (30 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in PE (0%~20% gradient) to obtain the title compound (787 mg, 59%). LC-MS (M+H) + =449.1.

[0424] Step 3: (S)-3-(3-bromo-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-yl)phenyl)oxetan-3-ol [ka] The title compound (292 mg, 42%) was prepared from (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(3,5-dibromophenyl)pyrrolidine and 3-oxetanone in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =443.9.

[0425] Step 4: (S)-3-(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (127 mg, 58%) was prepared from 3(S)-3-(3-bromo-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-yl)phenyl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =490.2.

[0426] Step 5: (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-yl)phenyl)oxetan-3-ol [ka] The title compound (117 mg, 90%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (S)-3-(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. LC-MS(M+H) + =636.4.

[0427] Step 6: 3(S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(2-(hydroxymethyl)pyrrolidine-1-yl)phenyl)oxetan-3-ol To a stirred solution of (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-yl)phenyl)oxetan-3-ol (100 mg, 0.157 mmol) in THF (5 mL), TBAF (82.3 mg, 0.314 mmol) was added at room temperature and the mixture was held under nitrogen for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example A85 (31 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.13 (s, 1 H), 7.60 (s, 1 H), 7.33 (s, 1 H), 6.99 (s, 1 H), 6.76 (s, 1 H), 6.66 (s, 2 H), 6.23 (s, 1 H), 4.81 (s, 1 H), 4.76-4.72 (m, 4 H), 4.17-4.04 (m, 1 H), 3.81-3.72 (m, 1 H), 3.58-3.50 (m, 1 H), 3.48-3.39 (m, 1 H), 3.26-3.16 (m, 1 H), 3.16-3.06 (m, 1 H), 2.90-2.81 (m, 2 H), 2.21 (s, 3 H), 2.10-1.83 (m, 10H).LC-MS(M+H) + =522.4.

[0428] Example A86 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-3-methylphenyl)oxetan-3-ol [ka] Step 1: 4-(2-bromo-4-chloro-6-methylphenyl)-3,6-dihydro-2H-pyran [ka] The title compound (446 mg, 56%) was prepared from 1-bromo-5-chloro-2-iodo-3-methylbenzene and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the same manner as in Step 1 of Example A75. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1 H), 7.38 (s, 1 H), 5.60 (s, 1 H), 4.27-4.11 (m, 2 H), 3.91-3.75 (m, 2 H), 2.62-2.58 (m, 2 H), 2.27 (s, 3 H).

[0429] Step 2: 3-(5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-methylphenyl)oxetan-3-ol [ka] The title compound (286 mg, 66%) was prepared from 4-(2-bromo-4-chloro-6-methylphenyl)-3,6-dihydro-2H-pyran and 3-oxetanone in the same manner as in Step 1 of Example A54. 1 H NMR (300 MHz, DMSO-d6) δ 7.27 (s, 1 H), 7.02 (s, 1 H), 6.20 (s, 1 H), 5.59 (s, 1 H), 5.05 (d, J = 7.1 Hz, 1 H), 4.91 (d, J = 6.9 Hz, 1 H), 4.55-4.45 (m, 2 H), 4.23-4.03 (m, 2 H), 3.87-3.66 (m, 2 H), 2.55-2.46 (m, 2 H), 2.21 (s, 3 H).

[0430] Step 3: 3-(2-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (369 mg, 97%) was prepared from 3-(5-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-methylphenyl)oxetan-3-ol and BPD in the same manner as in step 2 of Example A54. LC-MS(M-H2O+H) + =355.2.

[0431] Step 4: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-3-methylphenyl)oxetan-3-ol Example A86 (20 mg, 49%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(2-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1 H), 8.10 (s, 1 H), 7.64 (s, 1 H), 7.60 (s, 1 H), 7.43 (s, 1 H), 6.72 (s, 2 H), 6.10 (s, 1 H), 5.59 (s, 1 H), 5.11 (d, J = 6.9 Hz, 1 H), 4.96 (d, J = 6.7 Hz, 1 H), 4.54 (t, J = 6.3 Hz, 2 H), 4.21-4.05 (s, 3 H), 3.87-3.70 (m, 2 H), 2.92-2.82 (m, 2 H), 2.43-2.29 (m, 2 H), 2.27-2.17 (m, 6 H), 2.11-1.92 (m, 6 H).LC-MS(M+H) + =519.4.

[0432] Example A87 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-(1,3-dioxolan-2-yl)-3-methylphenyl)oxetan-3-ol [ka] Step 1: 2-Bromo-4-chloro-6-methylbenzaldehyde [ka] To a solution of 4-chloro-2-methylbenzaldehyde (14 g, 86 mmol) in DCE (280 mL), NBS (N-bromosuccinimide) (19.3 g, 103 mmol), TFA (56.0 mL, 757 mmol), 4-chloro-2-(trifluoromethyl)aniline (3.54 g, 17.2 mmol), and Pd(OAc)2 (2.03 g, 8.60 mmol) were added at room temperature. The mixture was stirred overnight at 60°C under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography with elution in DCM (0% to 25% gradient) to obtain the title compound (17 g, 85%). 1 H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1 H), 7.79 (s, 1 H), 7.51 (s, 1 H), 2.50 (s, 3H).

[0433] Step 2: 2-(2-bromo-4-chloro-6-methylphenyl)-1,3-dioxolane [ka] To a stirred solution of 2-bromo-4-chloro-6-methylbenzaldehyde (14.0 g, 59.9 mmol) in toluene (500 mL), TsOH (2.17 g, 12.0 mmol) and ethylene glycol (5.87 g, 89.9 mmol) were added at room temperature. The mixture was stirred overnight at 120 °C under a Dean-Stark receiver. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM in PE (0% to 40% gradient) to obtain the title compound (13.0 g, 79%). 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1 H), 7.37 (s, 1 H), 6.13 (s, 1 H), 4.22-3.93 (m, 4H).

[0434] Step 3: 3-(5-chloro-2-(1,3-dioxolan-2-yl)-3-methylphenyl)oxetan-3-ol [ka] The title compound (9.45 g, 77%) was prepared from 2-(2-bromo-4-chloro-6-methylphenyl)-1,3-dioxolane and 3-oxetanone in the same manner as in Step 1 of Example A54. 1 H NMR (300 MHz, DMSO-d6) δ 7.28 (s, 1 H), 7.18 (s, 1 H), 6.49 (s, 1 H), 5.52 (s, 1 H), 4.99 (d, J = 6.9 Hz, 2 H), 4.68 (d, J = 6.7 Hz, 2 H), 4.15-4.08 (m, 2 H), 3.95-3.88 (m, 2 H), 2.38 (s, 3 H).LC-MS(M+H) + =271.0.

[0435] Step 4: 3-(2-(1,3-dioxolan-2-yl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka] The title compound (240 mg, 95%) was prepared from 3-(5-chloro-2-(1,3-dioxolan-2-yl)-3-methylphenyl)oxetan-3-ol and BPD in the same manner as in step 2 of Example A54. LC-MS(M+H) + =363.2.

[0436] Step 5: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-(1,3-dioxolan-2-yl)-3-methylphenyl)oxetan-3-ol Example A87 (33 mg, 30%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(2-(1,3-dioxolan-2-yl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetane-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1 H), 8.11 (s, 1 H), 7.65 (s, 1 H), 7.60 (s, 1 H), 7.54 (s, 1 H), 6.80 (s, 2 H), 6.38 (s, 1 H), 5.56 (s, 1 H), 5.07-4.98 (m, 2 H), 4.75-4.67 (m, 2 H), 4.20-4.07 (m, 3 H), 3.94-3.88 (m, 2 H), 2.92-2.82 (m, 2 H), 2.41 (s, 3 H), 2.21 (s, 3 H), 2.13-1.92 (m, 6 H).LC-MS(M+H) + =509.3.

[0437] Example A88 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydro-2H-pyran-3-ol [ka] Step 1: 3-(3-bromo-5-methylphenyl)tetrahydro-2H-pyran-3-ol [ka] The title compound (1.8 g, 83%) was prepared from 1,3-dibromo-5-methylbenzene and dihydro-2H-pyran-3(4H)-one in the same manner as in Step 1 of Example A54. LCMS(M-OH) + = 253, 255.

[0438] Step 2: 3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol [ka] The title compound (2.0 g, 94%) was prepared from 3-(3-bromo-5-methylphenyl)tetrahydro-2H-pyran-3-ol and BPD in the same manner as in step 6 of Example A1. LCMS(M-OH) + =301.

[0439] Step 3: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-methylphenyl)tetrahydro-2H-pyran-3-ol Example A88 (165 mg, 84%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and 3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol in the same manner as in step 7 of Example A1. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.27 (s, 1H), 6.71 (s, 2H), 5.26 (s, 1H), 4.20-4.05 (m, 1H), 3.88-3.74 (m, 1H), 3.64-3.58 (m, 1H), 3.56 - 3.38 (m, 2H), 2.94-2.81 (m, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.11 - 1.96 (m, 8H), 1.77-1.67 (m, 1H), 1.48-1.37 (m, 1H).LCMS(M+H) + =465.5.

[0440] Example A89 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol [ka] Step 1: 3-(3-bromo-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol [ka] To a solution of (R)-4-(3,5-dibromophenyl)-3-methylmorpholine (900 mg, 2.70 mmol) in THF (20 mL), n-BuLi (2.5 M in hexane, 1.08 mL) was added dropwise under nitrogen at -78°C, and the mixture was stirred at -78°C for 30 minutes. Dihydro-2H-pyran-3(4H)-one (405 mg, 4.05 mmol) was added dropwise at the same temperature, and the mixture was stirred for a further 2 hours. The mixture was quenched with saturated NH4Cl (30 mL), warmed to room temperature, and extracted with  (100 mL). The organic layer was successively washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC using PE:Â=1:3 to obtain the title compound (800 mg, 83%). LC-MS(M+H) + =356.2,358.3.

[0441] Step 2: 3-(3-((R)-3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol [ka] A solution of 3-(3-bromo-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol (800 mg, 2.25 mmol) in dioxane (15 mL) is prepared by adding BPD (744 mg, 2.93 mmol), KOAc (331 mg, 3.37 mmol), and Pd(dppf)Cl2 . CH2Cl2 (184 mg, 0.22 mmol) was added. The mixture was stirred overnight at 100°C under nitrogen. The mixture was cooled to room temperature, diluted with ₹ (50 mL), washed sequentially with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC using ₹ to obtain the title compound (684 mg, 75%). LC-MS(M+H) + =404.2.

[0442] Step 3: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol A solution of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (300 mg, 0.85 mmol) in dioxane (10 mL) and water (1 mL) is prepared by adding 3-(3-((R)-3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol (684 mg, 1.69 mmol), K2CO3 (351 mg, 2.55 mmol), and Pd(dppf)Cl 2. CH2Cl2 (69 mg, 0.08 mmol) was added, and the mixture was stirred under nitrogen at 100°C for 5 hours. The mixture was cooled to room temperature, diluted with ₹ (50 mL), washed sequentially with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC using MeOH:DCM=1:7, followed by preparative HPLC, to obtain the title compound (190 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.69 (s, 2H), 5.17 (s, 1H), 4.15-4.05 (m, 1H), 3.94-3.85 (m, 2H), 3.83-3.70 (m, 2H), 3.68-3.40 (m, 5H), 3.26-3.13 (m, 1H), 3.13-2.91 (m, 1H), 2.93-2.79 (m, 2H), 2.22 (s, 3H), 2.14-1.90 (m, 8H), 1.79-1.65 (m, 1H), 1.51-1.38 (m, 1H), 1.03-0.94 (m, 3H).LC-MS (M+H) + =550.2.

[0443] Examples 90A / 90B (S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol and (R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol [ka] Examples A90A / A90B were prepared by chiral HPLC separation of 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)tetrahydro-2H-pyran-3-ol (97 mg). Analytical chiral-HPLC conditions: CHIRALPAK IH3, 4.6 × 50 mm, 3 μm; (MTBE, including 0.1% Et2NH): EtOH = 9:1; 1 mL / min; 25°C.

[0444] Example A90A: (38mg, 39%) 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.68 (s, 2H), 5.16 (s, 1H), 4.20-4.04 (m, 1H), 3.94-3.85 (m, 2H), 3.83-3.70 (m, 2H), 3.68-3.40 (m, 5H), 3.25-3.16 (m, 1H), 3.10-2.99 (m, 1H), 2.93-2.79 (m, 2H), 2.23 (s, 3H), 2.13-1.93 (m, 8H), 1.75-1.65 (m, 1H), 1.51-1.38 (m, 1H), 1.03-0.94 (m, 3H).LC-MS (M+H) + =550.2.Kura HPLC: tR=1.28 points.

[0445] Example A90B: (45.2mg, 46%) 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.69 (s, 2H), 5.17 (s, 1H), 4.15-4.05 (m, 1H), 3.94-3.85 (m, 2H), 3.83-3.70 (m, 2H), 3.68-3.40 (m, 5H), 3.26-3.13 (m, 1H), 3.09-2.98 (m, 1H), 2.93-2.79 (m, 2H), 2.22 (s, 3H), 2.14-1.90 (m, 8H), 1.79-1.69 (m, 1H), 1.48-1.38 (m, 1H), 1.03-0.94 (m, 3H).LC-MS (M+H) + =550.4.Kura HPLC: tR=1.73 points.

[0446] Example A91 1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(3-hydroxyoxetane-3-yl)phenyl)pyrrolidine-2-one [ka] Step 1: 1-(3,5-dibromophenyl)-2,5-dimethyl-1H-pyrrole [ka] A solution of 3,5-dibromoaniline (5.0 g, 20 mmol), hexane-2,5-dione (2.5 g, 22 mmol), and TsOH (68.8 mg, 0.4 mmol) in toluene (30 mL) was heated under reflux for 3 hours under a Dean-Stark receiver. The mixture was cooled to room temperature, diluted with SiO2 (50 mL), and successively washed with 1N HCl (30 mL) and brine (30 mL). It was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the title compound (6.0 g, 90%). LC-MS(M+H) + =327.9,329.9,331.9. 0

[0447] Step 2: 3-(3-bromo-5-(2,5-dimethyl-1H-pyrrole-1-yl)phenyl)oxetan-3-ol [ka] To a solution of 1-(3,5-dibromophenyl)-2,5-dimethyl-1H-pyrrole (6.0 g, 18.2 mmol) in THF (20 ml), n-BuLi (2.5 M in hexane, 8 mL, 20.2 mmol) was added under nitrogen at -78°C. After 0.5 hours, oxetane-3-one (1.9 g, 27.3 mmol) was added dropwise. The mixture was stirred at -78°C for 1 hour. Saturated NH4Cl (10 mL) was added, the mixture was warmed to room temperature, and then extracted with siRNA (40 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the title compound (4.0 g, 68%). LC-MS(M+H) + =322.0.

[0448] Step 3: 3-(3-amino-5-bromophenyl)oxetan-3-ol [ka] To a solution of 3-(3-bromo-5-(2,5-dimethyl-1H-pyrrole-1-yl)phenyl)oxetan-3-ol (1.0 g, 3.1 mmol) in EtOH (14 mL) and water (7 mL), hydroxylamine hydrochloride (6.5 g, 93 mmol) and KOH (3.4 g, 62 mmol) were added. The mixture was heated overnight to 100 °C and then cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with  (40 mL × 2). The combined organic layers were washed with brine (50 mL × 3), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to obtain the title compound (700 mg, 92%). LC-MS(M+H) + =244.0.

[0449] Step 4: Ethyl 4-((3-bromo-5-(3-hydroxyoxetan-3-yl)phenyl)aminobutanoate [ka] To a solution of 3-(3-amino-5-bromophenyl)oxetan-3-ol (400 mg, 1.64 mmol) in DMF (5 mL), K2CO3 (452 ​​mg, 3.28 mmol) and ethyl 4-bromobutanoate (703 mg, 3.6 mmol) were added. The mixture was stirred overnight at 100°C. The mixture was cooled to room temperature, and then water (20 mL) was added. The mixture was extracted with  (40 mL × 2). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to obtain the title compound (120 mg, 20%). LC-MS (M+H) + =358.1.

[0450] Step 5: 1-(3-bromo-5-(3-hydroxyoxetan-3-yl)phenyl)pyrrolidine-2-one [ka] To a solution of ethyl 4-((3-bromo-5-(3-hydroxyoxetan-3-yl)phenyl)amino)butanoate (120 mg, 0.33 mmol) in 1,4-dioxane (5 mL), TFA (190 mg, 1.67 mmol) was added, and the mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature and concentrated. The crude product was purified by preparative TLC to obtain the title compound (80 mg, 76%). LC-MS (M+H) + =312.1

[0451] Step 6: 1-(3-(3-hydroxyoxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one [ka] A mixture of 1-(3-bromo-5-(3-hydroxyoxetan-3-yl)phenyl)pyrrolidine-2-one (80 mg, 0.25 mmol), BPD (127 mg, 0.5 mmol), Pd(dppf)Cl2 (20 mg, 0.025 mmol), and AcOK (73.5 mg, 0.75 mmol) in dioxane (10 mL) was heated overnight under reflux under nitrogen. The mixture was cooled to room temperature,  (60 mL) was added, the organic layer was washed with brine (20 mL x 2), and the combined aqueous layer was extracted with  (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to obtain the title compound (50 mg, 54%). LC-MS(M+H) + =360.2.

[0452] Step 7: 1-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(3-hydroxyoxetan-3-yl)phenyl)pyrrolidine-2-one A mixture of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (50 mg, 0.14 mmol), 1-(3-(3-hydroxyoxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one (50 mg, 0.14 mmol), Pd(dppf)Cl2 (12 mg, 0.014 mmol), and K2CO3 (38 mg, 0.28 mmol) in dioxane (10 mL) and H2O (3 mL) was heated overnight under reflux under nitrogen. The mixture was cooled to room temperature, and then butyl (30 mL) was added. The mixture was washed with brine (10 mL x 2), and the aqueous layer was extracted with butyl (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example A91 (13 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.23 ​​(s, 1H), 8.10 (s, 1H), 7.8 (s, 1H), 7.59 (s, 1H), 6.81 (s, 2H), 6.45 (s, 1H), 4.79-4.73 (m, 4H), 4.15-4.18 (m, 1H), 3.91-3.90 (m, 2H), 2.88-2.86 (m, 2H), 2.48-2.50(m, 2H), 2.21(s, 3H), 2.11-1.98(m, 8H).LC-MS(M+H) + =506.2.

[0453] Example A92 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-(7-oxa-2-azaspiro[3.5]nonane-2-yl)phenyl)tetrahydrofuran-3-ol [ka] Step 1: 2-(2-bromo-4-chloro-6-methylphenyl)-7-oxa-2-azaspiro[3.5]nonane [ka] The title compound (1.13 g, 63%) was prepared from 1-bromo-5-chloro-2-iodo-3-methylbenzene and 7-oxa-2-azaspiro[3.5]nonane in the same manner as in step 2 of Example A83. LC-MS(M+H) + =330.0.

[0454] Step 2: 3-(5-chloro-3-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)tetrahydrofuran-3-ol [ka] The title compound (100 mg, 31%) was prepared from 2-(2-bromo-4-chloro-6-methylphenyl)-7-oxa-2-azaspiro[3.5]nonane and dihydrofuran-3-one in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =338.1.

[0455] Step 3: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-(7-oxa-2-azaspiro[3.5]nonanane-2-yl)phenyl)tetrahydrofuran-3-ol Example A92 (32 mg, 25%) was prepared from 3-(5-chloro-3-methyl-2-(7-oxa-2-azaspiro[3.5]nonanane-2-yl)phenyl)tetrahydrofuran-3-ol and 3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-amine in the same manner as in step 4 of Example A83. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.12 (s, 1 H), 7.77 (d, J = 2.2 Hz, 1 H), 7.59 (d, J = 2.9 Hz, 2 H), 6.72 (s, 2 H), 6.29 (s, 1 H), 4.15-4.07 (m, 1 H), 4.05-3.98 (m, 1 H), 4.02-3.93 (m, 1 H), 3.97-3.88 (m, 1 H), 3.86-3.77 (m, 3 H), 3.69 (d, J = 6.5 Hz, 2 H), 3.59-3.52 (m, 4H), 2.90-2.83 (m, 2 H), 2.56 (s, 3 H), 2.43-2.31 (m, 1 H), 2.21 (s, 3 H), 2.19-2.10 (m, 1 H), 2.10-1.94 (m, 6 H), 1.85-1.78 (m, 4 H).LC-MS(M+H) + = 576.5.

[0456] Example A93 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-fluoro-3-methylphenyl)tetrahydrofuran-3-ol [ka] Step 1: 3-(5-chloro-2-fluoro-3-methylphenyl)-tetrahydrofuran-3-ol [ka] The title compound (400 mg, 95%) was prepared from 1-bromo-5-chloro-2-fluoro-3-methylbenzene and dihydrofuran-3-one in the same manner as in Step 1 of Example A54. LC-MS(M-OH) + =213.0.

[0457] Step 2: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-2-fluoro-3-methylphenyl)tetrahydrofuran-3-ol Example A93 (36 mg, 14%) was prepared from 3-(5-chloro-2-fluoro-3-methylphenyl)-tetrahydrofuran-3-ol and 3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-amine in the same manner as in step 4 of Example A83. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1 H), 8.14 (s, 1 H), 7.94-7.87 (m, 1 H), 7.73-7.67 (m, 1 H), 7.61 (s, 1 H), 6.73 (s, 2 H), 5.56 (s, 1 H), 4.18-4.06 (m, 1 H), 4.06-3.82 (m, 4 H), 2.90-2.83 (m, 2 H), 2.42-2.30 (m, 1 H), 2.29-2.24 (m, 3 H), 2.23-2.16 (m, 4 H), 2.11- 1.93 (m, 6 H).LC-MS(M+H) + =469.1.

[0458] Example A94 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol [ka] Step 1: 3-(3-bromo-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol [ka] To a solution of (R)-4-(3,5-dibromophenyl)-3-methylmorpholine (570 mg, 1.7 mmol) in THF (5 mL), n-BuLi (2.5 M in hexane, 0.68 mL, 1.7 mmol) was added dropwise under nitrogen at -78°C, and the mixture was stirred at -78°C for 30 minutes. 2-methyldihydrofuran-3(2H)-one (257 mg, 2.6 mmol) was added dropwise at the same temperature, and the mixture was stirred for a further 2 hours. The mixture was quenched with saturated NH4Cl (15 mL) and warmed to room temperature. The mixture was extracted with  (25 mL), washed sequentially with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC using PE:Â=1:3 to obtain the title compound (500 mg, 82%). LC-MS(M+H) + =356.1,358.1.

[0459] Step 2: 2-Methyl-3-(3-((R)-3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol [ka] A solution of 3-(3-bromo-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol (500 mg, 1.4 mmol) in dioxane (10 mL) is prepared by adding BPD (715 mg, 2.8 mmol), KOAc (275 mg, 2.8 mmol), and Pd(dppf)Cl2 . CH2Cl2 (115 mg, 0.1 mmol) was added, and the mixture was stirred overnight at 100°C under nitrogen. The mixture was cooled to room temperature, diluted with  (30 mL), washed with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC using  to obtain the title compound (550 mg, 97%). LC-MS(M+H) + =404.4.

[0460] Step 3: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol A solution of 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine (480 mg, 1.4 mmol) in dioxane (10 mL) and water (1 mL) is prepared by adding 2-methyl-3-(3-((R)-3-methylmorpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol (550 mg, 1.4 mmol), K2CO3 (565 mg, 4.1 mmol), and Pd(dppf)Cl2 . CH2Cl2 (112 mg, 0.14 mmol) was added, and the mixture was stirred under nitrogen at 100°C for 5 hours. The mixture was cooled to room temperature and diluted with siRNA (40 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC using MeOH:DCM=1:7, followed by preparative HPLC, to obtain Example A94 (66 mg, 9%). 1HNMR (400MHz, DMSO-d6) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.57 (s, 1H), 7.41 - 7.36 (m, 1H), 7.19 (s, 1H), 7.04 - 6.98 (m, 1H), 6.69 (s, 2H), 5.10 (s, 1H), 4.14 - 4.04 (m, 1H), 4.04 - 3.96 (m, 1H), 3.95 - 3.85 (m, 3H), 3.84 - 3.78 (m, 1H), 3.77 - 3.68 (m, 2H), 3.62 - 3.53 (m, 1H), 3.23 - 3.17 (m, 1H), 3.09 - 3.00 (m, 1H), 2.90 - 2.82 (m, 2H), 2.21 (s, 3H), 2.16 - 1.94 (m, 7H), 0.98 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.1 Hz, 3H).LC-MS(M+H) + =550.3.

[0461] Examples A95A / A95B (2R,3S)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol and (2S,3R)-3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol [ka] Examples A95A / A95B were prepared by chiral HPLC separation of 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-((R)-3-methylmorpholino)phenyl)-2-methyltetrahydrofuran-3-ol (66 mg). Analytical chiral-HPLC conditions: CHIRALPAK IA3, 4 × 50 mm, 3 μm; (Hexane, containing 0.5% 2 M NH3 in MeOH): EtOH = 7:3; 1 mL / min; 25°C.

[0462] Example A95A: (23 mg, 35%) 1 H NMR (400MHz, DMSO-d6) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.57 (s, 1H), 7.41 - 7.36 (m, 1H), 7.19 (s, 1H), 7.04 - 6.98 (m, 1H), 6.69 (s, 2H), 5.10 (s, 1H), 4.14 - 4.04 (m, 1H), 4.04 - 3.96 (m, 1H), 3.95 - 3.85 (m, 3H), 3.84 - 3.78 (m, 1H), 3.77 - 3.68 (m, 2H), 3.62 - 3.53 (m, 1H), 3.23 - 3.17 (m, 1H), 3.09 - 3.00 (m, 1H), 2.90 - 2.82 (m, 2H), 2.23 (s, 3H), 2.16 - 1.94 (m, 7H), 0.98 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.1 Hz, 3H).LC-MS(M+H) + =550.3. Chiral HPLC: tR=2.19 min.

[0463] Example A95B: (23 mg, 35%) 1H NMR (400MHz, DMSO-d6) δ 8.25 (s, 1H), 8.12 (s, 1H), 7.57 (s, 1H), 7.41 - 7.36 (m, 1H), 7.19 (s, 1H), 7.04 - 6.98 (m, 1H), 6.69 (s, 2H), 5.10 (s, 1H), 4.14 - 4.04 (m, 1H), 4.04 - 3.96 (m, 1H), 3.95 - 3.85 (m, 3H), 3.84 - 3.78 (m, 1H), 3.77 - 3.68 (m, 2H), 3.62 - 3.53 (m, 1H), 3.25 - 3.17 (m, 1H), 3.09 - 3.00 (m, 1H), 2.93 - 2.82 (m, 2H), 2.22 (s, 3H), 2.16 - 1.94 (m, 7H), 0.98 (d, J = 6.5Hz, 3H), 0.94 (d, J = 6.1Hz, 3H).LC-MS(M+H) + =550.3. Chiral HPLC: tR=2.99 min.

[0464] Example A96 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol [ka] Step 1: 4-(2-bromo-4-chloro-6-methylphenyl)morpholine [ka] A mixture of 1-bromo-5-chloro-2-iodo-3-methylbenzene (3.0 mg, 8.3 mmol), Pd2(dba)3 (241 mg, 0.25 mmol), XantPhos (304 mg, 0.50 mmol), t-BuONa (927 mg, 9.2 mmol), and morpholine (764 mg, 8.3 mmol) in toluene (30 mL) was stirred under nitrogen at 110 °C for 16 hours. The mixture was filtered, and the filtrate was washed with DCM (15 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the title compound (820 mg, 31%). LC-MS(M+H) + =291.9.

[0465] Step 2: 4-(4-chloro-2-(2,5-dihydrofuran-3-yl)-6-methylphenyl)morpholine [ka] The title compound (473 mg, 47%) was prepared from 4-(2-bromo-4-chloro-6-methylphenyl)morpholine and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the same manner as in Step 1 of Example A75. LC-MS(M+H) + =280.1.

[0466] Step 3: 3-(5-chloro-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol [ka] At 0°C, a solution of tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (108 mg, 0.17 mmol) and 4-(4-chloro-2-(2,5-dihydrofuran-3-yl)-6-methylphenyl)morpholine (500 mg, 1.70 mmol) in DCM (5 mL) was mixed with i-PrOH (3.5 mL) and phenylsilane (387 mg, 3.40 mmol). The mixture was stirred under oxygen at 0°C for 3 hours. The mixture was concentrated under vacuum. The residue was purified by reverse-phase chromatography to obtain the title compound (170 mg, 34%). LC-MS(M+H) + =298.2.

[0467] Step 4: 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol Example A96 (90 mg, 35%) was prepared from 3-(5-chloro-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol and 3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-amine in the same manner as in step 4 of Example A83. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1 H), 8.11 (s, 1 H), 7.76 (s, 1 H), 7.61-7.55 (m, 2 H), 6.72 (s, 2 H), 5.95 (s, 1 H), 4.36-4.29 (m, 1 H), 4.17-4.07 (m, 1 H), 3.99-3.89 (m, 2 H), 3.87-3.81 (m, 1 H), 3.81-3.74 (m, 2 H), 3.70-3.59 (m, 2 H), 3.56-3.46 (m, 1 H), 3.39-3.34 (m, 1 H), 2.91-2.82 (m, 3 H), 2.74-2.67 (m, 1 H), 2.43 (s, 3 H), 2.42-2.31 (m, 1 H), 2.30-2.23 (m, 1 H), 2.21 (s, 3 H), 2.07-1.96 (m, 6 H).LC-MS(M+H) + =536.4.

[0468] Examples A97A / A97B (S)-3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol and (R)-3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol [ka] Examples A97A / A97B were prepared by chiral HPLC separation of 3-(5-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-3-methyl-2-morpholinophenyl)tetrahydrofuran-3-ol (58 mg). Analytical chiral-HPLC conditions: CHIRALPAK IA3, 4.6 × 50 mm, 3 μm; (Hexane:DCM = 3:1, containing 0.1% Et2NH):EtOH = 7:3; 1 mL / min; 25°C.

[0469] Example A97A: (26 mg, 45%) 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1 H), 8.10 (s, 1 H), 7.76 (s, 1 H), 7.61-7.55 (m, 2 H), 6.72 (s, 2 H), 5.95 (s, 1 H), 4.35-4.29 (m, 1 H), 4.15-4.07 (m, 1 H), 3.99-3.87 (m, 2 H), 3.87-3.81 (m, 1 H), 3.81-3.73 (m, 2 H), 3.70-3.59 (m, 2 H), 3.56-3.45 (m, 1 H), 3.42-3.30 (m, 1H), 2.91-2.82 (m, 3 H), 2.74-2.66 (m, 1 H), 2.43 (s, 3 H), 2.42-2.31 (m, 1 H), 2.31-2.22 (m, 1 H), 2.20 (s, 3 H), 2.09-1.93 (m, 6 H).LC-MS(M+H) + =536.4. Chiral HPLC: tR=1.54 min.

[0470] Example A97B: (26 mg, 45%) 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1 H), 8.10 (s, 1 H), 7.76 (s, 1 H), 7.61-7.55 (m, 2 H), 6.72 (s, 2 H), 5.95 (s, 1 H), 4.36-4.29 (m, 1 H), 4.17-4.07 (m, 1 H), 3.99-3.87 (m, 2 H), 3.87-3.81 (m, 1 H), 3.81-3.73 (m, 2 H), 3.70-3.59 (m, 2 H), 3.56-3.45 (m, 1 H), 3.42-3.32 (m, 1 H), 2.91-2.83 (m, 3 H), 2.74-2.67 (m, 1 H), 2.43 (s, 3 H), 2.39-2.31 (m, 1 H), 2.31-2.23 (m, 1 H), 2.21 (s, 3 H), 2.09-1.94 (m, 6 H).LC-MS(M+H) + =536.4. Chiral HPLC: tR=2.14 mins.

[0471] Example A98 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(1,4-oxazepan-4-yl)phenyl)tetrahydrofuran-3-ol [ka] Step 1: 4-(3,5-dibromophenyl)-1,4-oxazepane [ka] The title compound (365 mg, 42%) was prepared from 1,3-dibromo-5-iodobenzene and 1,4-oxazepane in the same manner as in Step 1 of Example A59. LC-MS(M+H) + =335.9.

[0472] Step 2: 3-(3-bromo-5-(1,4-oxazepan-4-yl)phenyl)tetrahydrofuran-3-ol [ka] The title compound (83 mg, 50%) was prepared from 4-(3,5-dibromophenyl)-1,4-oxazepane and dihydrofuran-3-one in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =342.0.

[0473] Step 3: 3-(3-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-5-(1,4-oxazepan-4-yl)phenyl)tetrahydrofuran-3-ol Example A98 (27 mg, 22%) was prepared from 3-(3-bromo-5-(1,4-oxazepan-4-yl)phenyl)tetrahydrofuran-3-ol and 3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-amine in the same manner as in step 4 of Example A83. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.59 (s, 1 H), 7.19 (s, 1 H), 7.05 (s, 1 H), 6.81 (s, 1 H), 6.65 (s, 2 H), 5.29 (s, 1 H), 4.14-3.95 (m, 3 H), 3.82-3.73 (m, 2 H), 3.76-3.69 (m, 2 H), 3.65-3.53 (m, 6 H), 2.89-2.82 (m, 2 H), 2.35-2.23 (m, 1 H), 2.20 (s, 3H), 2.14-1.86 (m, 10 H).LC-MS(M+H) + =536.4.

[0474] Example B1 5-(2-(diethylamino)-6-((methylamino)methyl)pyridine-4-yl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: Methyl 4-chloro-6-(diethylamino) picolinate [ka] To a solution of methyl 4,6-dichloropyridine-2-carboxylate (4.0 g, 18.4 mmol) in toluene (25 mL), diethylamine (11.4 g, 148 mmol), Pd(OAc)2 (218 mg, 0.922 mmol), XPhos (1481 mg, 2.95 mmol), and K2CO3 (4025 mg, 27.7 mmol) were added at room temperature. The mixture was stirred overnight at 100 °C under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (siRNA:hexane = 1:4) to obtain the title compound (2.1 g, 47%). LC-MS (M+H) + =243.2.

[0475] Step 2: (4-Chloro-6-(diethylamino)pyridine-2-yl)methanol [ka] To a solution of methyl 4-chloro-6-(diethylamino)picolinate (2.20 g, 8.36 mmol) in THF (20 mL), BH3 (1 M, 28.7 mL, 28.7 mmol) in THF was added dropwise over 5 minutes at 0°C. The mixture was heated to 70°C under nitrogen. After 2 hours, the mixture was cooled to 0°C, and then MeOH (5 mL) was carefully added. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (siRNA:hexane = 1:4) to obtain the title compound (1.47 g, 82%). LC-MS (M+H) + =215.2.

[0476] Step 3: 4-Chloro-6-(diethylamino)picolinaldehyde [ka] To a solution of (4-chloro-6-(diethylamino)pyridine-2-yl)methanol (1.50 g, 6.24 mmol) in DCM (20 mL), Dess-Martin periodinane (7.96 g, 17.8 mmol) was added at room temperature. After 2 hours, saturated NaHCO3 (10 mL) and saturated Na2S2O3 (10 mL) were added at 0°C. The mixture was extracted with siRNA (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.24 g, 93%). LC-MS (M+H) + =213.2.

[0477] Step 4: 4-Chloro-N,N-diethyl-6-((methylamino)methyl)pyridine-2-amine [ka] To a stirred solution of 4-chloro-6-(diethylamino)picoline aldehyde (1.16 g, 5.437 mmol) in MeOH (15 mL) and methylamine in THF (2 M, 3.9 mL, 7.8 mmol), HOAc (1 mL) was added at room temperature. After 15 minutes, the solution was cooled to 0°C, and NaBH3CN (0.58 g, 8.8 mmol) was partially added. The mixture was warmed to room temperature, stirred for 1 hour, and then cooled to 0°C. Water (50 mL) was added, and the mixture was extracted with RINKAN (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g, 88%). LC-MS(M+H) + =228.3.

[0478] Step 5: tert-butyl((4-chloro-6-(diethylamino)pyridine-2-yl)methyl)(methyl)carbamate [ka] The title compound (400 mg, 88%) was prepared from 4-chloro-N,N-diethyl-6-((methylamino)methyl)pyridine-2-amine in the same manner as in Step 1 of Example A20. LC-MS(M+H) + =328.3.

[0479] Step 6: tert-butyl((6-(diethylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)methyl)(methyl)carbamate [ka] The title compound (249 mg, 52%) was prepared from tert-butyl((4-chloro-6-(diethylamino)pyridine-2-yl)methyl)(methyl)carbamate and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =420.4.

[0480] Step 7: tert-butyl((4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-6-(diethylamino)pyridine-2-yl)methyl)(methyl)carbamate [ka] The title compound (35 mg, 34%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and tert-butyl((6-(diethylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)methyl)(methyl)carbamate in the same manner as in step 7 of Example A1. LC-MS(M+H) + = 566.5.

[0481] Step 2: 5-(2-(diethylamino)-6-((methylamino)methyl)pyridine-4-yl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example B1 (3 mg, 11%) was prepared from tert-butyl((4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-6-(diethylamino)pyridine-2-yl)methyl)(methyl)carbamate in the same manner as in step 4 of Example A20. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.06 (s, 1H), 7.61 (s, 1H), 6.98 (s, 1H), 6.90 (s, 2H), 6.80 (s, 1H), 4.14-4.03 (m, 1H), 3.57 (s, 2H), 3.55-3.45 (m, 4H), 2.90-2.82 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.09-1.90 (m, 6H), 1.10 (t, J = 6.9 Hz, 6H).LC-MS(M+H) + =466.3.

[0482] Example B2 (R)-5-(2-((methylamino)methyl)-6-(2-methylpyrrolidine-1-yl)pyridine-4-yl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine [ka] Step 1: Methyl(R)-4-chloro-6-(2-methylpyrrolidine-1-yl)picolinate [ka] The title compound (1.8 g, 31%) was prepared from methyl 4,6-dichloropyridine-2-carboxylate and (2R)-2-methylpyrrolidine using the same method as in Step 1 of Example B1. LC-MS(M+H)+ =255.2.

[0483] Step 2: (R)-(4-chloro-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)methanol [ka] The title compound (1.1 g, 68%) was prepared from methyl(R)-4-chloro-6-(2-methylpyrrolidine-1-yl) picolinate in the same manner as in step 2 of Example B1. LC-MS (M+H) + = 227.2.

[0484] Step 3: (R)-4-chloro-6-(2-methylpyrrolidine-1-yl)picolinealdehyde [ka] The title compound (864 mg, 85%) was prepared from (R)-(4-chloro-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)methanol in the same manner as in step 3 of Example B1. LC-MS(M+H) + =225.2.

[0485] Step 4: (R)-1-(4-chloro-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)-N-methylmethanamine [ka] The title compound (864 mg, 85%) was prepared from (R)-4-chloro-6-(2-methylpyrrolidine-1-yl)picoline aldehyde by the same method as in step 4 of Example B1. LC-MS(M+H) + =240.2.

[0486] Step 5: tert-butyl(R)-((4-chloro-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)methyl)(methyl)carbamate [ka] The title compound (1.05 g, 86%) was prepared from (R)-1-(4-chloro-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)-N-methylmethanamine in the same manner as in Step 1 of Example A20. LC-MS(M+H) + =340.2.

[0487] Step 6: tert-butyl(R)-methyl((6-(2-methylpyrrolidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)methyl)carbamate [ka] The title compound (473 mg, 87%) was prepared from tert-butyl(R)-((4-chloro-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)methyl)(methyl)carbamate and BPD in the same manner as in step 6 of Example A1. LC-MS (M-pin) + =350.3.

[0488] Step 7: tert-butyl(R)-((4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)methyl)(methyl)carbamate [ka] The title compound (94 mg, 46%) was prepared from tert-butyl(R)-methyl((6-(2-methylpyrrolidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)methyl)carbamate and 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine in the same manner as in step 7 of Example A1. LC-MS(M+H) + =578.4.

[0489] Step 8: (R)-5-(2-((methylamino)methyl)-6-(2-methylpyrrolidine-1-yl)pyridine-4-yl)-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine Example B2 (6 mg, 7%) was prepared from tert-butyl(R)-((4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-6-(2-methylpyrrolidine-1-yl)pyridine-2-yl)methyl)(methyl)carbamate in the same manner as in step 4 of Example A20. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.11 (s, 1H), 7.73 (s, 1H), 6.99 (s, 1H), 6.94 (s, 2H), 6.84 (s, 1H), 4.45-4.37 (m, 2H), 3.58 (s, 3H), 3.55-3.47 (m, 4H), 3.10 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 1.12 (t, J = 7.0 Hz, 6H).LC-MS(M+H) + =478.4.

[0490] Example B3 (R)-2-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-6-(3-methylmorpholino)pyridine-2-yl)propan-2-ol [ka] Step 1: Methyl 4-chloro-6-fluoropicolinate [ka] To a solution of methyl 4-chloropyridine-2-carboxylate (5.0 g, 27.7 mmol) in acetonitrile (120 mL), AgF (5.55 g, 41.5 mmol) was added under nitrogen at room temperature. After 24 hours, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate in PE (0% to 50% gradient) to obtain the title compound (4.17 g, 80%). LC-MS (M+H) + =189.9.

[0491] Step 2: (R)-Methyl 4-chloro-6-(3-methylmorpholino) picolinate [ka] A mixture of methyl 4-chloro-6-fluoropyridine-2-carboxylate (1.36 g, 7.2 mmol), DIPEA (2.63 mL, 14.3 mmol), and (3R)-3-methylmorpholine (840 mg, 7.9 mmol) in DMSO (20 mL) was stirred under nitrogen at 50°C. The mixture was cooled to room temperature, diluted with brine (30 mL), and extracted sequentially with RINKAN (30 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to obtain the title compound (864 mg, 44%). LC-MS(M+H) + =270.9.

[0492] Step 3: (R)-2-(4-chloro-6-(3-methylmorpholino)pyridine-2-yl)propan-2-ol [ka] At 0°C, a solution of (R)-methyl 4-chloro-6-(3-methylmorpholino) picolinate (700 mg, 2.48 mmol) in ethyl ether (10 mL) was met with dropwise addition of MeMgBr (3.0 M, 2.2 mL, 6.6 mmol) in ethyl ether under nitrogen. The mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NH4Cl (10 mL). The aqueous layer was extracted with ethyl phosphate (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl phosphate in PE (0% to 50% gradient) to obtain the title compound (500 mg, 74%). LC-MS (M+H) + =271.0.

[0493] Step 4: (R)-2-(6-(3-methylmorpholino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)propan-2-ol [ka] The title compound (276 mg, 69%) was prepared from (R)-2-(4-chloro-6-(3-methylmorpholino)pyridine-2-yl)propan-2-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =362.2.

[0494] Step 5: (R)-2-(4-(5-amino-6-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-yl)-6-(3-methylmorpholino)pyridine-2-yl)propan-2-ol Example B3 (32 mg, 22%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-2-(6-(3-methylmorpholino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)propan-2-ol in the same manner as in step 7 of Example A1. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1 H), 8.15 (s, 1 H), 7.59 (s, 1 H), 7.38 (s, 1 H), 7.00-6.88 (m, 3 H), 5.07 (s, 1 H), 4.42-4.34 (m, 1 H), 4.16-4.06 (m, 1 H), 3.99-3.82 (m, 2 H), 3.78-3.60 (m, 2 H), 3.58-3.46 (m, 1 H), 3.14-3.01 (m, 1 H), 2.92-2.82 (m, 2 H), 2.22 (s, 3 H), 2.12-1.90 (m, 6 H), 1.42 (s, 6 H), 1.11 (d, J = 6.5 Hz, 3 H).LC-MS(M+H) + =509.4.

[0495] Example B4 (R)-3-(4-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-6-(3-methylmorpholino)pyridine-2-yl)oxetan-3-ol [ka] Step 1: (R)-4-(6-bromo-4-chloropyridine-2-yl)-3-methylmorpholine [ka] The title compound (2.4 g, 59%) was prepared from 2,6-dibromo-4-chloropyridine and (3R)-3-methylmorpholine using the same method as in step 1 of B1. LC-MS(M+H) + =291.0.

[0496] Step 2: (R)-3-(4-chloro-6-(3-methylmorpholino)pyridine-2-yl)oxetan-3-ol [ka] The title compound (280 mg, 48%) was prepared from (R)-4-(6-bromo-4-chloropyridine-2-yl)-3-methylmorpholine and 3-oxetanone in the same manner as in Step 1 of Example A54. LC-MS(M+H) + =285.1.

[0497] Step 3: (R)-3-(6-(3-methylmorpholino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxetan-3-ol [ka] The title compound (90 mg, 69%) was prepared from (R)-3-(4-chloro-6-(3-methylmorpholino)pyridine-2-yl)oxetan-3-ol and BPD in the same manner as in step 6 of Example A1. LC-MS(M+H) + =295.2.

[0498] Step 4: (R)-3-(4-(5-amino-6-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yloxy)pyrazine-2-yl)-6-(3-methylmorpholino)pyridine-2-yl)oxetan-3-ol (compound 4, 005-2468-0) [ka] Example B4 (26 mg, 22%) was prepared from 5-bromo-3-((1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)oxy)pyrazine-2-amine and (R)-3-(6-(3-methylmorpholino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxetan-3-ol in the same manner as in step 7 of Example A1. 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1 H), 8.10 (s, 1 H), 7.56 (s, 1 H), 7.33 (s, 1 H), 7.05 (s, 1 H), 6.96 (s, 2 H), 6.30 (s, 1 H), 4.94-4.86 (m, 2 H), 4.62-4.54 (m, 2 H), 4.49-4.41 (m, 1 H), 4.16-4.00 (m, 1 H), 4.00-3.89 (m, 2 H), 3.79-3.70 (m, 1 H), 3.70-3.60 (m, 1 H), 3.58-3.44 (m, 1 H), 3.17-3.03 (m, 1 H), 2.91-2.81 (m, 2 H), 2.20 (s, 3 H), 2.11-1.84 (m, 6 H), 1.13 (d, J = 6.6 Hz, 3 H).LC-MS(M+H) + =523.4.

[0499] biological activity HPK kinase activity assay at 1 mM ATP HPK kinase activity assay at 1 mM ATP The compounds disclosed herein were tested for inhibition of HPK1 kinase (aa1-346, Life Technologies) activity in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The assay was performed using HPK1 kinase (40 nM), 1 mM ATP, 0.5 μM STK1 substrate, and 50 mM HEPES, 0.01% BSA, 0.1 mM ortho-vanadate, 10 mM MgCl2, and 1 mM The reaction was carried out in a 384-well low-volume black plate in a reaction mixture containing 0-10 μM of the compound in a buffer containing DTT, pH=7.0, and 0.005% Tween-20. The reaction was initiated by incubating the kinase with the compounds disclosed herein or DMSO at room temperature for 60 minutes, followed by the addition of ATP and the STK1 substrate. After reacting at room temperature for 120 minutes, an equal volume of stop / detection solution was added according to the manufacturer's instructions (CisBio). The stop / detection solution contained STK antibody-cryptate and XL665-conjugated streptavidin in detection buffer. The TR-FRET signal (ratio of fluorescence emission at 665 nm to emission at 620 nm due to excitation at 337 nm wavelength) was recorded using a PHERAstar FS plate reader (BMG Labtech). Phosphorylation of the STK1 substrate was detected by a fluorescent donor (Eu 3+ Placing the cryptotate in close proximity to the acceptor (streptavidin-XL665) leads to STK antibody-cryptate binding with the biotinylated STK1 substrate, thus resulting in high fluorescence resonance energy transfer. Inhibition of HPK1 in the presence of increasing compound concentrations was calculated based on the fluorescence ratio at 665 nm and 620 nm. IC 50 The determination was made using Dotmatics by fitting the percentage inhibition curve to the logarithm of the inhibitor concentration. The compounds disclosed herein exhibited enzyme activity values ​​as shown in Table 1. [Table 2-1] [Table 2-2]

[0500] Cellular pSLP76(S376)HTRF assay This study used the Jurkat cell line. Cells were maintained in RPMI 1640 supplemented with thermoinactivated 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin, and streptomycin (Thermo Fisher), and maintained at 37°C in a humidified atmosphere of 5% CO2 air. Cells were restored from frozen stocks of no more than 30 passages from the purchased original cells. After starving cells for 18 hours in assay buffer (RPMI 1640 supplemented with thermoinactivated 0.1% fetal bovine serum), cells were seeded in round-bottom 96-well plates at a density of 150,000 cells per well. Cells were treated with a nine-point dilution series of the test compound. The final compound co...

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, During the ceremony, X is N or CR ２ where R ２ is hydrogen, -C １－８ alkyl, -C ２－８ alkynyl, halogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NR ｃ R ｄ , -OR ｄ , -(CR ａ R ｂ )( ｎ -R ｄ , -(CR ａ R ｂ )( ｎ -NR ｃ R ｄ , -(CR ａ R ｂ )( ｎ -CONR ｃ R ｄ , -CONR ｃ -(CR ａ R ｂ )( ｎ -R ｄ , -(CR ａ R ｂ )( ｎ -NR ｃ COR ｄ , -NR ｃ -CO-(CR ａ R ｂ )( ｎ -R ｄ , -(CR ａ R ｂ )( ｎ -SO ２ -NR ｃ R ｄ , -(CR ａ R ｂ )( ｎ -NR ｃ -SO ２ -R ｄ , -SO ２ -NR ｃ -(CR ａ R ｂ )( ｎ -R ｄ , -(CR ａ R ｂ )( ｎ -NR ｃ -CS-NR ｄ R ｅ , or - (CR ａ R ｂ ) ｎ -NR ｃ -CO-NR ｄ R ｅ Selected from, the above-C １－８ Each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups optionally contains at least one R ｆ Replaced by, R １ and R ３ are each independently hydrogen, -C １－８ alkyl, halogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NR ｃ R ｄ , -OR ｄ , -SiR ａ R ｂ R ｃ , -(CR ａ R ｂ ) ｎ -R ｄ , -(CR ａ R ｂ ) ｎ -NR ｃ R ｄ , -(CR ａ R ｂ )[[ID=4I]] ｎ -CONR ｃ [[ID=q4]]R ｄ , -CONR ｃ -(CR ａ R ｂ ) ｎ -R ｄ , -(CR ａ R ｂ ) ｎ -NR ｃ COR ｄ , -NR ｃ -CO-(CR ａ R ｂ ) ｎ -R ｄ , -(CR ａ R ｂ ) ｎ -SO ２ -NR ｃ R ｄ , -(CR ａ R ｂ ) ｎ -NR ｃ -SO ２ -R ｄ -SO ２ -NR ｃ -(CR ａ R ｂ ) ｎ -R ｄ , or -(CR ａ R ｂ ) ｎ -NR ｃ -CO-NR ｄ R ｅ Selected from, the above-C １－８ Each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups optionally contains at least one R ｆ Replaced by, R ４ However, hydrogen, -C １－８ Selected from alkyl, cycloalkyl, and heterocyclyls (such as monocyclic heterocyclyls) containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur as ring members (may be more than one), the -C １－８ Each of alkyl, cycloalkyl, or heterocyclyl is optionally R ｆ Replaced by, Each R ｆ However, independently, oxo, halogen, -C １－８ Alkyl, hydroxy, -NR １ｃ R １ｄ , -C １－８ Selected from alkoxy or heterocyclyl, the heterocyclyl or -C １－８ The alkyl group optionally has at least one R ｇ Replaced with R １ｃ and R １ｄ However, each independently, hydrogen or -C １－８ It is alkyl, R ５１ , R ５２ , R ６１ , R ６２ , R ７１ , R ７２ , R ８１ , R ８２ , and R ９ However, each independently, hydrogen, halogen, and -C １－８ Alkyl, or -C １－８ Selected from alkoxy, or (R ５１ and R ６１ ), (R ５１ and R ６２ ), (R ５２ and R ６１ ), or (R ５２ and R ６２ ) together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, wherein the cross-link contains 1-6 atoms selected from carbon, oxygen, nitrogen, or sulfur. R ａ and R ｂ However, each independently, hydrogen, -C １－８ It is alkyl, or heterocycline, or R ａ and R ｂ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. R ｃ , R ｄ , and R ｅ However, each independently, hydrogen, -C １－８ Alkyl, aryl, CN, hydroxyl, -C １－８ Alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or -NR １ｃ R １ｄ And the above-C １－８ Each of the alkyl, cycloalkyl, aryl, or heterocyclyl or heteroaryl groups optionally contains at least one R ｇ Replaced with R １ｃ and R １ｄ However, each independently, hydrogen or -C １－８ It is alkyl, Each R ｇ However, independently, oxo, hydroxy, halogen, haloalkyl, and -C are present. １－８ Alkyl, -C １－８ The compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from alkoxy, cycloalkyl, or heterocyclyl, wherein n is independently 0, 1, 2, 3, or 4.

2. X is N or CR ２ And R ２ However, hydrogen, -C １－８ Alkyl, -C ２－８ Alkinyl, C ３－７ Cycloalkyl, aryl, 5-6 membered heteroaryls containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur as ring members, 3-7 membered heterocyclyls containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur as ring members, -NR ｃ R ｄ ,-(CR ａ R ｂ ) ｎ -R ｄ ,-(CR ａ R ｂ ) ｎ -NR ｃ R ｄ ,-(CR ａ R ｂ ) ｎ -CONR ｃ R ｄ , -CONR ｃ - (CR ａ R ｂ ) ｎ -R ｄ ,-(CR ａ R ｂ ) ｎ -NR ｃ COR ｄ ,-(CR ａ R ｂ ) ｎ -SO ２ -NR ｃ R ｄ ,-(CR ａ R ｂ ) ｎ -NR ｃ -CO-NR ｄ R ｅ ,-(CR ａ R ｂ ) ｎ -NR ｃ -CS-NR ｄ R ｅ ,-(CR ａ R ｂ ) ｎ -NR ｃ -SO ２ -R ｄ , or - (CR ａ R ｂ ) ｎ -NR ｃ -CO-NR ｄ R ｅ Selected from, the above-C １－８ Alkyl, C ３－７ Each of the cycloalkyl, aryl, 3- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally contains at least one R ｆ Replaced by, R １ However, hydrogen, -C １－８ Alkyl, halogen, C ３－７ Cycloalkyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl containing independently 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidizable sulfur as ring members, -NR ｃ R ｄ , or -OR ｄ Selected from, the above-C １－８ Alkyl, C ３－７ Each of the cycloalkyl, 5-6 membered heteroaryl, or 3-7 membered heterocyclyl optionally contains at least one R ｆ Replaced by, R ３ However, hydrogen, -C １－８ Alkyl, C ３－７ Cycloalkyls, independently comprising 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, silicon, or optionally oxidized sulfur as ring members, 3- to 7-membered heterocyclines, -(CR ａ R ｂ ) ｎ -NR ｃ R ｄ ,-(CR ａ R ｂ ) ｎ -CONR ｃ R ｄ , -SiR ａ R ｂ R ｃ ,-(CR ａ R ｂ ) ｎ -NR ｃ COR ｄ , -CONR ｃ - (CR ａ R ｂ ) ｎ -R ｄ ,-(CR ａ R ｂ ) ｎ -SO ２ -NR ｃ R ｄ , -SO ２ -NR ｃ - (CR ａ R ｂ ) ｎ -R ｄ ,-(CR ａ R ｂ ) ｎ -NR ｃ -SO ２ -R ｄ ,-(CR ａ R ｂ ) ｎ -NR ｃ -CO-NR ｄ R ｅ , or - (CR ａ R ｂ ) ｎ -NR ｃ R ｄ Selected from, the above-C １－８ Alkyl, C ３－７ A cycloalkyl or 3- to 7-membered heterocycline optionally contains at least one R ｆ Replaced by, R ４ However, hydrogen, -C １－８ Alkyl, C ３－７ Cycloalkyls are independently selected from 3- to 7-membered heterocyclines containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, each of the -C １－８ Alkyl, C ３－７ A cycloalkyl or 3- to 7-membered heterocycline is optionally R ｆ Replaced by each R ｆ However, independently, oxo, halogen, -C １－８ Alkyl, hydroxy, -NR １ｃ R １ｄ , -C １－８ Selected from alkoxys and 3- to 7-membered heterocyclines, the heterocycline or -C １－８ The alkyl group optionally has at least one R ｇ Replaced with R １ｃ and R １ｄ However, each independently, hydrogen or -C １－８ It is alkyl, R ５１ , R ５２ , R ６１ , R ６２ , R ７１ , R ７２ , R ８１ , and R ８２ However, each independently, hydrogen, halogen, and -C １－８ Alkyl, or -C １－８ Selected from alkoxy, or (R ５１ and R ６１ ), (R ５１ and R ６２ ), (R ５２ and R ６１ ), or (R ５２ and R ６２ ) together with the atoms to which they are bonded, form a 7-12 membered cross-linked heterocycline, wherein the cross-link contains 1-6 atoms selected from carbon, oxygen, nitrogen, or sulfur. R ａ and R ｂ However, each independently, hydrogen, -C １－８ It is alkyl, or heterocycline, or R ａ and R ｂ Together with the carbon atoms to which they are bonded, they form a 3- to 6-membered ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, R ｃ , R ｄ , and R ｅ However, each independently, hydrogen, -C １－８ Alkyl, 5-6 member heteroaryl, aryl, CN, hydroxyl, -C １－８ Alkoxy, C ３－７ Cycloalkyls, independently, 3- to 7-membered heterocyclines containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or optionally oxidizable sulfur, or -NR １ｃ R １ｄ and each of the above-C １－８ Alkyl, 5-6 member heteroaryl, C ３－７ A cycloalkyl, aryl, or 3- to 7-membered heterocycline optionally contains at least one R ｇ Replaced with R １ｃ and R １ｄ However, each independently, hydrogen or -C １－８ It is alkyl, and each R ｇ However, independently, oxo, hydroxy, halogen, -C １－８ Alkyl, -C １－８ Selected from alkoxy or 3- to 7-membered heterocyclyl, The compound according to claim 1, wherein n is independently 0, 1, 2, 3, or 4.

3. R １ However, halogen, -NR ｃ R ｄ , or -OR ｃ , -C １－４ Alkyl, C ３－６ A 4-6 member C-linked heterocycline containing 1-3 heteroatoms selected from cycloalkyl, nitrogen, oxygen, silicon, or sulfur; a 4-6 member Si-linked heterocycline containing 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, or sulfur; a 5, 6, or 7 member N-linked heterocycline containing 0, 1, or 2 additional heteroatoms selected as ring members (may be multiple) from nitrogen, oxygen, or optionally oxidized sulfur; or a 5-6 member heteroaryl, selected from these. Said-C １－４ Alkyl, C ３－６ Each of the cycloalkyl, 4-6 member C-linked heterocyclyl, 4-6 member Si-linked heterocyclyl, or 5, 6, or 7 member N-linked heterocyclyl, or 5-6 member heteroaryl may optionally contain a halogen, hydroxyl, oxo, or -NH(C) １－４ Alkyl), or -C １－４ Substituted with at least one substituent selected from alkyl groups, R ｃ and R ｄ However, each independently, hydrogen or -C １－４ The compound according to claim 1, wherein it is alkyl.

4. R １ However, hydrogen, methyl, tert-butyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-methylpropyl, butyl, pentyl, hexyl, chloro, fluoro, methoxy, -CHF ２ , - NHCH ３ , -N(C ２ H ５ ) ２ , -OCH(CH ３ ) ２ , -S(O) ２ - NHCH ３ , -Si(CH ３ ) ２ OH, -Si(C) ２ H ５ ) ２ OH, -CH(CH ３ ) ２ OH, -CH ２ OCH ３ , 【Chemistry 2】 A compound according to claim 1, selected from the following.

5. X is -CR ２ And R ２ However, hydrogen, -C １－４ Alkyl, aryl, 5-6 membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur, 3-7 membered heterocyclyls containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidizable sulfur, -(CH ２ ) ｎ - CONHR ｄ , -CONH-(CH ２ ) ｎ -R ｄ , -CONH-R ｄ ,-(CH ２ ) ｎ - NHR ｄ ,-(CH ２ ) ｎ - NHCOR ｄ ,-(CH ２ ) ｎ -R ｄ , -SO ２ -NH-(CH ２ ) ｎ -R ｄ ,-(CH ２ ) ｎ -SO ２ - NHR ｄ ,-(CH ２ ) ｎ -NH-CO-NR ｄ R ｅ ,-(CH ２ ) ｎ -NH-CS-NR ｄ R ｅ , or - (CH ２ ) ｎ -NH-SO ２ -R ｄ Selected from the above, each of the aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclyl is optionally -C １－４ Substituted with at least one selected from alkyl or oxo, where n is 1 or 2. R ｄ and R ｅ However, each is independent of hydrogen, hydroxyl, and -C. １－４ Alkyl, phenyl, -C １－４ Alkoxy, C ３－６ Cycloalkyl, aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, or -NR １ｃ R １ｄ Selected from, the above-C １－４ Alkyl, C ３－６ Each of the cycloalkyl, aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl optionally contains at least one halogen, CF ３ , -C １－４ Substituted with alkyl or oxo, R １ｃ and R １ｄ However, each independently, hydrogen or -C １－４ The compound according to claim 1, wherein it is alkyl.

6. R ２ However, hydrogen, hydroxyl, methyl, halogen, 【Chemistry 3-1】 【Chemistry 3-2】 A compound according to claim 1, selected from the following.

7. R ３ However, hydrogen, -C １－４ Alkyl, C ３－６ A 4-6 membered heterocycline containing 1-3 heteroatoms selected from cycloalkyl, nitrogen, oxygen, silicon, or sulfur, -(CH ２ ) ｎ - CONHR ｄ , -CONH-(CH ２ ) ｎ -R ｄ , -CONH-R ｄ ,-(CH ２ ) ｎ - NHCOR ｄ , -SO ２ -NH-(CH ２ ) ｎ -R ｄ ,-(CH ２ ) ｎ -SO ２ - NHR ｄ ,-(CH ２ ) ｎ -NH-CO-NR ｄ R ｅ ,-(CH ２ ) ｎ -NH-SO ２ -R ｄ , -SiR ａ R ｂ R ｃ , 【Chemistry 4】 , or selected from 5-6 member heteroaryls, and the -C １－４ Alkyl, C ３－６ Cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, optionally with -C １－４ Substituted with alkyl, halogen, oxo, or hydroxy, n is 0, 1, or 2, R ｄ and R ｅ However, each independently, hydrogen, -C １－４ Alkyl, phenyl, -C １－４ Alkoxy, CN, C ３－６ Cycloalkyl, 5-6 membered heterocyclyl, or -NR １ｃ R １ｄ Selected from, each of the above-C １－４ Alkyl, C ３－６ Cycloalkyl, aryl, or 5-6 membered heterocyclyl, optionally -C １－４ Substituted with at least one of alkyl, halogen, or oxo, R １ｃ and R １ｄ However, each independently, hydrogen or -C １－４ The compound according to claim 1, wherein it is alkyl.

8. R ３ However, methyl, ethyl, propyl, cyclopropyl, CH(OH)CH ３ , -C(OH)(CH ３ ) ２ , -SO ２ NHCH ３ , -SO ２ NH ２ , -SO ２ NHC ２ H ５ , -CH(OH)CF ３ , -C(OH)(CF ３ ) ２ , -C(OH)(CH ３ ) ２ Si(CH ３ ) ２ OH, -Si(C) ２ H ５ ) ２ OH, -CH ２ NHCH ３ , 【Transformation 5】 A compound according to claim 7, selected from the above.

9. R ４ However, C ３－６ -C is substituted with a cycloalkyl group or optionally with a 4- to 6-membered monocyclic heterocycline. １－４ A compound according to any one of claims 1 to 8, selected from alkyl groups.

10. R ４ However, methyl, ethyl, isopropyl, cyclopropyl, or 【Transformation 6】 A compound selected from (oxetane-3-ylmethyl) according to any one of claims 1 to 9.

11. R ５１ , R ５２ , R ６１ , and R ６２ The compound according to any one of claims 1 to 10, wherein the compound is hydrogen.

12. R ５１ and R ６１ Together with the atoms to which they are bonded, they form an 8-membered cross-linked heterocycline, and the cross-link is between two carbon atoms (i.e., -CH ２ -CH ２ -) including R ５２ and R ６２ The compound according to any one of claims 1 to 10, wherein the compound is hydrogen.

13. R ７１ , R ７２ , R ８１ , and R ８２ , and R ９ The compound according to any one of claims 1 to 12, wherein the compound is hydrogen.

14. Equation (II) is given, 【Transformation 7】 In the formula, R １ , R ２ , R ３ , and R ４ The compound according to claim 1, wherein it is as defined in claim 1.

15. Compounds selected from the following: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 【Chemistry 8-6】 【Chemistry 8-7】 【Chemistry 8-8】 [Chemistry 8-9] 【Chemistry 8-10】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

16. The compound is 【Chemistry 9】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

17. The compound is 【Chemistry 10】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

18. The compound is 【Chemistry 11】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

19. The compound is 【Chemistry 12】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

20. The compound is 【Chemistry 13】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

21. The compound is 【Chemistry 14】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

22. The compound is 【Chemistry 15】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

23. The compound is 【Chemistry 16】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

24. The compound is 【Chemistry 17】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

25. The compound is [Chemistry 18] The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

26. The compound is 【Chemistry 19】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

27. ​​The compound is 【Chemistry 20】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

28. The compound is 【Chemistry 21】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

29. The compound is 【Chemistry 22】 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

31. A composition for treating cancer comprising a compound according to any one of claims 1 to 29, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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