Macrocyclic aminopyridine compounds as EGFR inhibitors

Abstract

The present invention provides novel macrocyclic aminopyridine compounds or pharmaceutically acceptable salts thereof containing -O-alkylene-NH- as a linking moiety, which exhibit inhibitory activity against specific mutant forms of EGFR.

Description

[Technical Field]

[0001] The present invention relates to novel macrocyclic aminopyridine compounds or pharmaceutically acceptable salts thereof containing -O-alkylene-NH- as a linking moiety, which exhibit inhibitory activity against specific mutant forms of EGFR. [Background technology]

[0002] Another subtype of lung cancer is epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Human EGFR is a membrane-bound receptor tyrosine kinase of the ErbB family. Activation triggers downstream effects through several signaling pathways, including RAS / RAF / MEK / ERK / MAPK and PI3K / PTEN / Akt / mTOR (Chen et al., 2020). The EGFR signaling pathway regulates a series of critical events that regulate cell-cell communication during development, including proliferation, migration, differentiation, and apoptosis (Wee et al., 2017; Huang et al., 2015; Yewale et al., 2013).

[0003] Approximately 10%–50% of NSCLC patients harbor EGFR-activating mutations, such as in-frame deletions of exon 19 (Del19) and missense mutations in exon 21 (L858R) ( Yang et al., 2018 ; Shigematsu et al., 2005 ; Shu et al., 2017 ; Zhang et al., 2010 ). These patients are treated with gefitinib (IRESSA). TM ), erlotinib (TARCEVA TM ), afatinib (GIOTRIF TMEGFR tyrosine kinase inhibitors (TKIs), such as EGFR-1, respond well to first- and second-generation TKIs and can be used as initial treatment for patients with advanced NSCLC harboring common EGFR mutations (Kashima et al., 2020; Mok et al., 2009; Zhou et al., 2011; Sequist et al., 2013). However, eventual acquired resistance to treatment with gefitinib or erlotinib is primarily caused by mutation of the gatekeeper residue T790M, which is detected in approximately half of clinically resistant patients, resulting in double mutants, L858R / T790M and Del19 / T790M.

[0004] To overcome this resistance, several third-generation EGFR-TKIs have been investigated. Currently, osimertinib is the only third-generation EGFR-TKI approved by major regulatory agencies for the treatment of T790M-positive patients who have progressed on first- or second-generation EGFR-TKIs (Leonetti et al., 2019; Soria et al., 2018).

[0005] Osimertinib is a potent inhibitor of EGFR mutations and the T790M resistance mutation, but it causes ineffective binding and subsequent C797S resistance in patients with NSCLC (Arulananda et al., 2017). Unfortunately, acquired resistance mutations have been reported in lung cancer patients after treatment with third-generation EGFR TKIs. The C797S mutation frequently occurs after the use of third-generation EGFR TKIs in 10%–30% of these patients (Ramalingam et al., 2018; Thress et al., 2015; Oxnard et al., 2018; Starrett et al., 2020; Mehlman et al., 2019; Rangachari et al., 2019; Zhou et al., 2019). Osimertinib resistance due to EGFR triple mutations (Del19 / T790M / C797S and L858R / T790M / C797S) has been reported, and next-generation EGFR-TKIs are needed to overcome osimertinib-resistant EGFR triple mutations ( Kashima et al., 2020 ).

[0006] During first-line treatment with third-generation TKIs, C797S develops in the absence of T790M (Chen et al., 2020). Osimertinib was also approved in 2018 as first-line therapy for locally advanced or metastatic EGFR-mutant NSCLC, regardless of T790M mutation status (Leonetti et al., 2019). When osimertinib was administered as frontline treatment, the frequency of C797S mutation was 7%, making it the second most common mechanism of drug resistance in this setting after MET amplification (Leonetti et al., 2019; Ramalingam et al., 2018).

[0007] When osimertinib was administered as a first-line treatment, the most common resistance mechanisms were C797S mutation (7%) and MET amplification (15%). Other mechanisms included HER2 amplification, PIK3CA, and RAS mutations (Ramalingam et al., 2018). Selectivity for wild-type (WT) EGFR is also important for EGFR-TKIs because inhibition of WT EGFR causes side effects such as rash and diarrhea, and these WT EGFR-related toxicities are dose-limiting (Kashima et al., 2020; Fakih et al., 2010; Takeda et al., 2015).

[0008] Next-generation EGFR compounds must inhibit Del19 / T790M / C797S, L858R / T790M / C797S, Del19 / C797S, and L858R / C797S and be highly selective against WT EGFR to avoid side effects. Recently, the mutation-selective inhibitors BI-4020 and BLU-945 have been reported as potential therapeutic strategies to overcome the EGFR Del19 / T790M / C797S mutation (Engelhardt et al., 2019; Schalm et al., 2020).

[0009] However, there are no reports that these compounds inhibit Del19 / C797S and L858R / C797S. Therefore, there is an urgent need for novel EGFR-TKIs that are potently effective against EGFR triple / double mutations.

[0010] To address this unmet need, we are developing next-generation TKIs targeting both the C797S triple and double mutants. There is a need to develop novel selective (next-generation) inhibitors for NSCLC patients with advanced or metastatic disease harboring Del19 / T790M / C797S, L858R / T790M / C797S, Del19 / C797S, and L858R / C797S mutations, depending on the second- or first-line use of third-generation EGFR-TKIs.

[0011] References Arulananda S, John T, Dobrovic A. et al. Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non-Small Cell Lung Cancer. Journal of Thoracic Oncology Vol. 12 No. 11: 1728-1732, 2017. Chen JS, Riess JW. Advances in targeting acquired resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors. Justin A. Chen, Jonathan W. Riess. J Thorac Dis 2020; 12(5):2859-2876. Engelhardt H, et al. Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors. Cite This: J. Med. Chem. 2019, 62, 10272-10293. Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr. Oncol. 2010; 17: S18-30. Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharm Sin B 2015; 5:390-401. Kashima K, et al. CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19 / T790M / C797S Mutation. Mol Cancer Ther; 19(11) November 2020. Leonetti A, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. British Journal of Cancer (2019) 121:725-737. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-57. Mehlman C, Cadranel J, Rousseau-Bussac G, Lacave R, Pujals A, Girard N, et al. Resistance mechanisms to osimertinib in EGFR-mutated advanced non-smallcell lung cancer: A multicentric retrospective French study. Lung Cancer 2019; 137:149-56. Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018; 4:1527-34. Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J. Clin. Oncol. 2018; 36:841-9. Rangachari D, To C, Shpilsky JE, VanderLaan PA, Kobayashi SS, MushajiangM, et al. EGFR-mutated lung cancers resistant to osimertinib through EGFR C797S respond to first-generation reversible EGFR inhibitors but eventually acquire EGFR T790M / C797S in preclinical models and clinical samples. J. Thorac. Oncol. 2019; 14:1995-2002. Schalm S, et al. BLU-945, a highly potent and selective 4th-generation EGFR TKI for the treatment of EGFR+ / T790M / C797S resistant NSCLC. 2020, ESMO. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 2013; 31:3327-34. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97:339-46. Shu Y, WuX, Tong X, WangX, Chang Z, MaoY, et al. Circulating tumor DNA mutation profiling by targeted next generation sequencing provides guidance for personalized treatments in multiple cancer types. Sci Rep 2017; 7:583. Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H. et al. Osimertinib in untreated EGFR -mutated advanced non-small cell lung cancer. N. Engl. J. Med 378, 113-125 (2018). Starrett JH,Guernet AA, CuomoME, Poels KE, van Alderwerelt van Rosenburgh IK, Nagelberg A, et al. Drug sensitivity and allele-specificity of first-line osimertinib resistance EGFR mutations. Cancer Res 2020; 80:2017-30. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer 2015; 88:74-9. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 2015; 21:560-2. Wee, P.; Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017, 9, 52. Yewale C, Baradia D, Vhora I, et al. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials 2013; 34:8690-707. Yang Z, Yang N, et al. Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Clin Cancer Res; 2018 Zhang Z, Stiegler AL, Boggon TJ, Kobayashi S, Halmos B. EGFR-mutated lung cancer: a paradigm of molecular oncology. Oncotarget 2010; 1:497-514. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomized, phase 3 study. Lancet Oncol. 2011; 12:735-42. Zhou Z, Zhao Y, Shen S, Gu L,Niu Summary of the Invention

[0012] The present invention relates to novel macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moiety, according to formula (I) shown below, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R1 is hydrogen or C 1-3 is alkyl, R2 is C 1-6 Alkoxy; C optionally substituted with one or more substituents selected from the group consisting of OH and halogen 3-6 cycloalkyl; Hydroxy, halogen, C 1-6Alkyl, Hydroxy-C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkoxy, C substituted with one or more halogens 1-6 Alkoxy, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C 1-6 Alkylcarbonylmethyl, and mono- or di-C 1-6 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkylaminomethyl; and -NR3R4 (wherein R3 and R4 are independently hydrogen, C optionally substituted with one or more halogens) 1-6 Alkyl, mono- or di-(C 1-6 Alkyl)amino-C 1-6 Alkyl, or 3- to 7-membered heterocyclyl-C 1-3 Alkyl (wherein 3-7 membered heterocyclyl is substituted with halogen and C 1-6 and optionally substituted with one or more substituents selected from the group consisting of alkyl. is selected from the group consisting of L is a linear or branched C 3-6 It is alkylene.

[0013] The present invention also relates to a method of treating a protein kinase mediated disease, particularly a mutant EGFR mediated disease, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] The present invention also relates to a pharmaceutically acceptable composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, which exhibits selective inhibitory activity against at least one mutant EGFR compared to wild-type EGFR. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of the Invention The present invention will now be described in more detail. Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Also, although the present invention has been described in connection with specific methods and samples, similar or equivalent methods and samples should also fall within the scope of the present invention. Furthermore, unless expressly stated otherwise, numerical values ​​described herein are considered to include the meaning of "about." All publications and other references mentioned herein are incorporated herein by reference in their entirety.

[0016] The definitions of residues used herein are detailed below. Unless otherwise indicated, each residue has the following definition and is used in the sense commonly understood by those skilled in the art.

[0017] As used herein, the terms "halo," "halogen," and "halide" include fluoro, chloro, bromo, and iodo.

[0018] As used herein, "alkyl" refers to an aliphatic hydrocarbon radical and includes both straight-chain and branched-chain hydrocarbon radicals. For example, C 1-6 Alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Unless otherwise defined, alkyl refers to any of the C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably C 1-3 refers to alkyl.

[0019] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where alkyl is defined as above. "Halo" refers to F, Cl, Br, or I, and this term is used interchangeably with "halogen." Unless otherwise defined, haloalkyl refers to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, or 2,2,2-trifluoroethyl.

[0020] As used herein, the term "alkoxy" refers to an -O-alkyl or alkyl-O- group, where the alkyl group is defined as above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy, and t-butoxy.

[0021] As used herein, the terms "hydroxy" or "hydroxyl," alone or in combination with other terms, mean --OH.

[0022] As used herein, the term "hydroxyalkyl" refers to any hydroxyl derivative of an alkyl radical. The term "hydroxyalkyl" includes any alkyl radical in which one or more hydrogen atoms have been replaced with a hydroxy group.

[0023] As used herein, "amino" refers to --NH.sub.2.

[0024] As used herein, the term "cycloalkyl" refers to a substituted or unsubstituted cyclic alkyl, such as C 3-20 Cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, unless otherwise defined, cycloalkyl refers to a C 3-8 Cycloalkyl or C 3-6 It may be cycloalkyl.

[0025] As used herein, "heterocyclyl" refers to an aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic ring system containing the specified number of ring atoms and including one or more heteroatoms selected from N, O, and S, where the heterocyclyl ring is connected to the base molecule through a C or N ring atom. Bicyclic ring systems may be connected via 1,1-fused (spiro), 1,2-fused (fused), or 1,2-fused (bridgehead).

[0026] As used herein, "heterocycloalkyl" refers to a monocyclic, bicyclic, tricyclic or higher cyclic alkyl having 3 to 10 carbon ring members and containing one or more, for example, 1 to 4 heteroatoms selected from N, O, and S. Heterocycloalkyls according to the present invention may also be fused or bridged heterocycloalkyls. Examples of non-aromatic rings include, but are not limited to, azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrazolopyridinyl, morpholinyl, indolinyl, thiomorpholinyl, azepanyl, diazepanyl, azaadamantanyl, diazamantanyl, and the like. Attachment of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom. A heterocycloalkyl group may be optionally substituted with one or more suitable groups via one or more of the aforementioned groups. Unless otherwise defined, heterocycloalkyl refers to a 4- to 12-membered heterocycloalkyl, preferably a 4- to 10-membered heterocycloalkyl, and more preferably a 4- to 7-membered heterocycloalkyl.

[0027] The present invention provides novel compounds, their pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, and solvates, which are useful for inhibiting epidermal growth factor receptor (EGFR) and treating protein kinase-mediated diseases and disorders, such as cell proliferative diseases and disorders such as cancer, immune diseases such as arthritis, rheumatoid arthritis, or autoimmune diseases, infectious diseases, cardiovascular diseases, and neurodegenerative diseases and disorders. In particular, the compounds of the present invention or their pharmaceutically acceptable salts exhibit excellent inhibitory activity against EGFR triple / double mutants and excellent kinase selectivity. Furthermore, the compounds of the present invention or their pharmaceutically acceptable salts exhibit excellent oral bioavailability along with improved pharmacokinetic properties.

[0028] The present invention also provides pharmaceutical compositions comprising at least one compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.

[0029] The present invention provides compositions and methods for modulating the activity of epidermal growth factor receptor (EGFR) mutants. In one aspect, the present invention provides compounds that act as inhibitors of EGFR mutants.

[0030] In one embodiment, provided herein is a compound of Formula (I) as shown below, a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, tautomer, prodrug, hydrate, or solvate thereof: [ka] During the ceremony, R1 is hydrogen or C 1-3 is alkyl, R2 is C 1-6 Alkoxy; C optionally substituted with one or more substituents selected from the group consisting of OH and halogen 3-6 cycloalkyl; Hydroxy, halogen, C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkoxy, C substituted with one or more halogens 1-6 Alkoxy, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C 1-6 Alkylcarbonylmethyl, and mono- or di-C 1-6 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkylaminomethyl; and -NR3R4 (wherein R3 and R4 are independently hydrogen, C optionally substituted with one or more halogens) 1-6 Alkyl, mono- or di-(C 1-6 Alkyl)amino-C 1-6 Alkyl, or 3- to 7-membered heterocyclyl-C 1-3 Alkyl (wherein 3-7 membered heterocyclyl is substituted with halogen and C 1-6 and optionally substituted with one or more substituents selected from the group consisting of alkyl. is selected from the group consisting of L is a linear or branched C 3-6 It is alkylene.

[0031] In certain embodiments, R1 may be hydrogen or methyl. Preferably, R1 may be methyl.

[0032] In certain embodiments, R2 is C 1-6 Alkoxy;C 3-6 Cycloalkyl; Hydroxy, Halogen, C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkoxy, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C 1-6Alkylcarbonylmethyl, and mono- or di-C 1-6 a 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkylaminomethyl; or -NR3R4. In said embodiment, the 3- to 7-membered heterocyclyl may be selected from the group consisting of pyrrolidine, azetidine, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.3]hexane, 2,6-diazaspiro[3.4]octane, and 2,7-diazaspiro[3.5]nonane.

[0033] In more particular embodiments, R and R are independently hydrogen, C 1-6 Alkyl, Halo-C 1-6 Alkyl, or di-(C 1-6 Alkyl)amino-C 1-6 It may also be alkyl.

[0034] In more particular embodiments, R3 is hydrogen or C 1-6 alkyl, and R4 is halogen and C 1-6 3- to 7-membered heterocyclyl-C optionally substituted with one or more substituents selected from the group consisting of alkyl 1-3 In the above embodiment, the 3- to 7-membered heterocyclyl-C 1-3 Alkyl is azetidinyl-C 1-3 Alkyl, piperazinyl-C 1-3 Alkyl, and morpholinyl-C 1-3 It may be selected from the group consisting of alkyl.

[0035] In more specific embodiments, L may be n-propylene, 1-methylpropylene, 3-methylpropylene, 2,2-dimethylpropylene, or n-butylene.

[0036] Representative compounds of formula (I) are listed below. (1) (S)-Cyclopropyl(1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (2) Cyclopropyl(1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4 5 -Il)methanone; (3) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (4) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (5) (S)-1-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-N,N-dimethylmethanesulfonamide; (6) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (7) (S)-(1 1 ,6-dimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (8) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (9) (S)-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (10) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2,2,2-trifluoroethyl)azetidin-1-yl)methanone; (11) Cyclopropyl(1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (12) Methyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate; (13) (S)-(1 1 ,6-dimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(pyrrolidin-1-yl)methanone; (14) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (15) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (16) (S)-N,N,1 1 ,6-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (17) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-hydroxypyrrolidin-1-yl)methanone; (18) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone; (19) Methyl (S)-1 1 ,8-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate; (20) Methyl 1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate; (21) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (22) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methanone; (23) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-fluoro-2-azaspiro[3.3]heptan-2-yl)methanone; (24) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (25) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (26) (S)-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (27) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2-fluoropropan-2-yl)azetidin-1-yl)methanone; (28) (S)-N-(2-(3-fluoroazetidin-1-yl)ethyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (29) (S)-N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (30) (S)-N,1 1 ,6-trimethyl-N-((1-methylazetidin-3-yl)methyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (31) (S)-N-(4-(dimethylamino)butyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (32) (S)-N-(3-(dimethylamino)propyl)-N,1 1 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (33) (S)-N-(3-(dimethylamino)-2,2-dimethylpropyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (34) (S)-1 1 ,6-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (35) (S)-1 1 ,6-dimethyl-N-(2-morpholinoethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (36) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)methanone; (37) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (38) (S)-N-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide; (39) (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (40) (S)-(6-(difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (41) (S)-1-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-3-methylbutan-2-one; (42) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5-yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone; (43) ((S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (44) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (45) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (46) ((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (47) (3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (48) (3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (49) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (50) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (51) (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; and (52) (S)-N-(2,2-difluoroethyl)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide.

[0037] Further representative compounds of formula (I) are listed below. (24) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (25) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (38) (S)-N-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide; (43) ((S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (44) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (45) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (46) ((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (47) (3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (48) (3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone; (49) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; and (50) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone.

[0038] More preferred representative compounds of formula (I) are listed below. (49) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone or a pharmaceutically acceptable salt thereof; and (50) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone or a pharmaceutically acceptable salt thereof.

[0039] Single stereochemical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts of the above-exemplified compounds are also within the scope of the present invention. Pharmaceutically acceptable salts may be derived, for example, from suitable inorganic and organic acids and bases.

[0040] Acid addition salts can be prepared by reacting the purified compound, if possible in free base form, with a suitable organic or inorganic acid and isolating the salt formed. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as formic acid, trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid.

[0041] Base addition salts can be prepared by reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt formed. Such salts include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium, and N + (C 1-4Examples include, but are not limited to, salts of alkyl).

[0042] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxybenzoate, and the like. Examples of suitable salts include cetane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0043] The compounds of the present invention can be synthesized by methods known in the art or by the methods illustrated in Examples 1-52 below.

[0044] Pharmaceutical compositions, methods and uses In one embodiment, the present invention relates to a method of treating a protein kinase-mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, tautomer, prodrug, hydrate, or solvate thereof. In certain embodiments, the protein kinase-mediated disease is cancer or an immune disease.

[0045] As used herein, the term "cancer" refers to the abnormal proliferation of cells that tend to grow uncontrolled and sometimes metastasize.Cancer types include but are not limited to solid tumors such as bladder cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, uterine cancer, heart cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, lymphoma, pancreatic cancer, head and neck cancer or other endocrine organ cancer (thyroid cancer), prostate cancer, skin cancer (melanoma) or blood tumor (such as leukemia).In another embodiment, cancer is non-small cell lung cancer (NSCLC).

[0046] In one embodiment, the methods disclosed herein relate to the treatment of cancer caused by at least one mutation in EGFR.

[0047] In one embodiment, the method of treating cancer is particularly useful for patients who are resistant to kinase inhibitors other than the compounds of the invention, or pharmaceutically acceptable salts, solvates, esters, or prodrugs thereof. In another embodiment, the kinase inhibitor is a mutant EGFR inhibitor.

[0048] The present invention also relates to a method for selectively inhibiting at least one mutant form of EGFR relative to wild-type EGFR in a biological sample or in a patient, comprising contacting the biological sample with a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the at least one variant is at least one single variant selected from Table 1 shown below.

[0050] In one embodiment, the at least one mutant is at least one double mutant selected from Table 1 below.

[0051] In one embodiment, the at least one mutant is at least one triple mutant selected from Table 1 below.

[0052] [Table 1]

[0053] The present invention also relates to methods of treatment and uses comprising administering the compounds of the present invention, or pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof, alone or in combination with other therapeutic or palliative agents. A further embodiment of the present invention relates to the compounds of the present invention for use as pharmaceuticals, particularly for use in the treatment of diseases in which inhibition of mutated EGFR protein (e.g., those listed in Table 1) activity can induce benefit, such as cancer. A further embodiment of the present invention relates to the use of the compounds of the present invention, or pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof, for the manufacture of a medicament having inhibitory activity against EGFR for the treatment of EGFR-mediated diseases and / or conditions, particularly the diseases and / or conditions listed above.

[0054] The term "therapeutically effective amount" refers to the amount of compound administered that will relieve to some extent one or more symptoms of the disorder being treated. In the context of treating cancer, a therapeutically effective amount refers to an amount that has the effect of reducing tumor size, inhibiting (i.e., slowing or stopping) tumor metastasis, inhibiting (i.e., slowing or stopping) tumor growth or tumor invasion, and / or alleviating to some extent one or more signs or symptoms associated with cancer.

[0055] A therapeutically effective amount can be readily determined by an attending diagnostician skilled in the art using conventional techniques and observing results obtained under similar circumstances. In determining a therapeutically effective amount, or dose, the attending physician will consider many factors, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the extent or severity of the disease involved; the response of the individual patient; the specific compound administered; the method of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of concomitant medications; and other relevant circumstances.

[0056] As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" also refers to the act of treating, as "treating" is defined immediately above. The term "treating" also includes adjuvant treatment of a mammal.

[0057] As used herein, the term "subject" or "patient" includes mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc.

[0058] As used herein, the term "biological sample" includes cells, tissues, and fluids obtained (isolated) from mammals, such as humans (e.g., patients with cancer), or the non-mammals exemplified above, and cultures thereof.

[0059] Administration of the compounds of the present invention can be achieved by any method that allows delivery of the compound to the site of action, including oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

[0060] Also provided herein in another aspect are pharmaceutical compositions comprising a compound of Formula (I) as an active ingredient, a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, tautomer, prodrug, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is for treating a protein kinase-mediated disease. In another embodiment, the pharmaceutical composition is for selectively inhibiting at least one mutant form of EGFR compared to wild-type EGFR.

[0061] The compound of the present invention can be administered orally.Oral administration can involve swallowing, so that compound enters the gastrointestinal tract, or can also use buccal or sublingual administration, so that compound enters the bloodstream directly from the mouth.The formulation suitable for oral administration includes solid formulations such as tablets, capsules containing particles, liquids, or powders, lozenges (including liquid-filled), chewable tablets, multi-particles and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesives), ovules, sprays and liquid formulations.

[0062] Liquid preparations include suspension, solution, syrup and elixir.Such preparations can be used as filler in soft capsule or hard capsule, and can typically contain carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oil, and one or more emulsifiers and / or suspending agents.Liquid preparations can also be produced by reconstituting solid.

[0063] Examples of carriers, additives, and diluents that can be included in the composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc. When formulating, commonly used diluents and additives such as fillers, stabilizers, binders, disintegrants, surfactants, etc. can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing the compound of the present invention with at least one additive, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple additives, lubricants such as magnesium stearate and talc can also be used. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various additives such as humectants, sweeteners, flavorings, and preservatives. Parenteral preparations include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions or suspensions may contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, and glycerogelatin. To prepare a preparation for parenteral administration, the compound of formula I or a pharmaceutically acceptable salt thereof is sterilized and mixed in water and / or contains auxiliary agents such as preservatives, stabilizers, hydrating powders or emulsifiers, salts for adjusting osmotic pressure and / or buffers, and other therapeutically useful substances to prepare a solution or suspension, which is then prepared in the form of a unit dose in an ampoule or vial.

[0064] General reaction scheme and synthetic route overview The present invention includes within its scope a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, tautomer, prodrug, hydrate, or solvate thereof, according to the following Scheme 1: [ka]

[0065] In Reaction Scheme 1, R1 and L are the same as above; R2' is C 1-6 Alkoxy or C 3-6 It is cycloalkyl.

[0066] Specifically, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof can be prepared using a process comprising the steps of: reacting a compound of formula (II) with NH-L-OH to obtain a compound of formula (III), reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V), and cyclizing the compound of formula (V) to obtain a compound of formula (Ia).

[0067] In the process of Reaction Scheme 1, compounds of formula (II), NH-L-OH, and (IV) are commercially available. The reaction of compound of formula (II) with NH-L-OH may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, or DIPEA. The reaction may be carried out in an organic solvent such as anhydrous THF, DMF, or DMA at room temperature or under heating, for example, at a temperature of 40 to 120°C.

[0068] A compound of formula (III) is coupled with a compound of formula (IV) via the Mitsunobu reaction to obtain a compound of formula (V). The reaction of compounds of formula (III) and (IV) may be carried out in the presence of a phosphorane ylide, such as (cyanomethylene)trimethylphosphorane or (cyanomethylene)tributylphosphorane. The reaction may also be carried out in an anhydrous organic solvent, such as 1,4-dioxane or toluene, under heating, for example, at a temperature of 90 to 130°C.

[0069] The compound of formula (V) is cyclized to give the compound of formula (Ia) by the Buchwald-Hartwig reaction. The cyclization reaction of the compound of formula (V) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, or cesium carbonate. The reaction may also be carried out in the presence of a palladium catalyst such as Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(dppf)Cl2, or BrettPhos Pd G1 methyl t-butyl ether adduct, and a ligand such as BINAP, SPhos, XPhos, Xantphos, or BrettPhos. The reaction may also be carried out in an anhydrous organic solvent such as 1,4-dioxane or toluene, under heating, for example, at a temperature of 90 to 130°C.

[0070] Alternatively, compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared according to the following Reaction Scheme 2: [ka]

[0071] In Reaction Scheme 2, R1 and L are the same as above; R2' is C 1-6 Alkoxy; R2 ’’ is hydroxy, halogen, C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkoxy, C substituted with one or more halogens1-6 Alkoxy, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C 1-6 Alkylcarbonylmethyl, and mono- or di-C 1-6 a 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkylaminomethyl; or -NR3R4 (wherein R3 and R4 are, independently of each other, hydrogen, C optionally substituted with one or more halogens). 1-6 Alkyl, mono- or di-(C 1-6 Alkyl)amino-C 1-6 Alkyl, or 3- to 7-membered heterocyclyl-C 1-3 Alkyl (wherein 3-7 membered heterocyclyl is substituted with halogen and C 1-6 alkyl).

[0072] Specifically, the compound of formula (Ib) can be prepared using a process comprising the steps of: hydrolyzing a compound of formula (Ia) to obtain a compound of formula (VI); and reacting the compound of formula (VI) with R2 ’’ -H to obtain a compound of formula (Ib).

[0073] In the process of reaction 2, the chemical formula R2 ’’ The compound of formula (Ia) may be commercially available. The hydrolysis reaction of the compound of formula (Ia) may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, or potassium hydroxide. The reaction may be carried out in an organic solvent such as THF, MeOH, or HO at room temperature or under heating, for example, at a temperature of 40 to 100°C.

[0074] Compounds of formula (VI) and R2 ’’The reaction with -H may be carried out in the presence of a base such as TEA or DIPEA and an amide coupling reagent such as HOBt, HBTU, BOP, PyBOP, or HATU. The reaction may be carried out in an anhydrous organic solvent such as DCM, DMF, or acetonitrile at room temperature or under heating, for example, at a temperature of 30 to 100°C.

[0075] In one embodiment, the compound of formula (IV) may be prepared according to the following reaction scheme 3: [ka]

[0076] In Reaction Scheme 3, R1 is the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0077] Specifically, the compound of formula (IV) can be prepared using a process comprising the steps of reacting a compound of formula (VII) with a compound of formula (VIII) to give a compound of formula (IX), and deprotecting (or hydrogenolyzing) the compound of formula (IX) to give a compound of formula (IV).

[0078] In the process of Scheme 3, the compound of formula (VII) is commercially available. The reaction of the compound of formula (VII) with the compound of formula (VIII) can be carried out in the presence of a base such as sodium carbonate or potassium carbonate and Pd(dppf)Cl. 2、 The reaction may be carried out in the presence of a ligand-bound palladium catalyst such as Pd(PPh3)4. Alternatively, the reaction may be carried out in an anhydrous organic solvent such as THF or 1,4-dioxane under heating, for example, at a temperature of 40 to 100°C.

[0079] The hydrogenolysis of compounds of formula (IX) may be carried out in the presence of a palladium on carbon catalyst such as Pd / C, Pd(OH)2 / C, etc., under a hydrogen atmosphere, and the reaction may be carried out in an anhydrous organic solvent such as THF, DCM, MeOH, etc., at room temperature or with heating.

[0080] In another embodiment, the compound of formula (VIII) may be prepared according to the following reaction scheme 4: [ka]

[0081] In Reaction Scheme 4, R1 is the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0082] Specifically, the compound of formula (VIII) can be prepared using a process comprising the steps of: reacting a compound of formula (X) with Bn-X to obtain a compound of formula (XI), halogenating the compound of formula (XI) to obtain a compound of formula (XII), and boronating the compound of formula (XII) to obtain a compound of formula (VIII).

[0083] In the process of Reaction Scheme 4, compounds of formula (X) and Bn-X are commercially available. The reaction of compound of formula (X) with Bn-X may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, or DIPEA. The reaction may be carried out in an organic solvent such as anhydrous THF, DMF, or DMA at room temperature or under heating, for example, at a temperature of 40 to 120°C.

[0084] The halogenation of the compound of formula (XI) may be carried out in the presence of a halogenating agent such as NIS, NBS, a halogen acid, an elemental halogen, etc. The reaction may also be carried out in an anhydrous organic solvent such as MeCN, DCM, or DCE at a temperature between 0 and 10°C.

[0085] The boronation of compounds of formula (XII) may be carried out in the presence of boron reagents such as B2Pin2, B2Cat2, i-proOBPin, and organometallic reagents such as iPrMgCl·LiCl complex under an argon atmosphere. The reaction may be carried out in an anhydrous organic solvent such as THF, hexane, or toluene at temperatures between −10 and 30° C. [Example]

[0086] The present invention is further illustrated by the following examples, which illustrate the preparation of compounds of formula (I) according to the present invention. The examples are for illustrative purposes only and are not intended to, and should not be construed as, limiting the present invention in any way. Those skilled in the art will understand that variations and modifications can be made without changing the scope of the present invention.

[0087] The compounds prepared in the following examples were analyzed as follows. Nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker 400 MHz spectrometer and an Agilent 600 MHz spectrometer, with chemical shifts reported in ppm. The molecular weights shown were measured using an Agilent 1260 Infinity Series liquid chromatography / mass selective detector (MSD) equipped with an electrostatic spray interface (using a single quadrupole, and the m / z values ​​shown are those in ESI+ (ESI-MS (cation)) represented by the [M + H] + peak). Column chromatography was performed on silica gel (Merck, 70-230 mesh) (WC Still, J. Org. Chem., 43, 2923, 1978). The starting materials in each example were known compounds, synthesized according to literature sources, or obtained commercially from suppliers such as Sigma-Aldrich. The abbreviations used in the following examples are as follows:

[0088] [Table 2] JPEG2026507653000009.jpg50166

[0089] Production example 1:(S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Step 1: Ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate To a solution of ethyl 4,6-dichloronicotinate (5.0 g, 24.3 mmol) and (S)-3-aminobutan-1-ol (4.65 mL, 48.6 mmol) in acetonitrile (100 mL) was added DIPEA (12.7 mL, 72.9 mmol). The reaction mixture was stirred at 60 °C for 12 h. After completion, the solvent was evaporated under reduced pressure. The residue was diluted with EA and washed with water and saturated brine. The organic layer was dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (EA / n-Hex = 0-50%) produced ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate as a white solid (5.02 g, 75.7%). 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.19 (d, 1H), 6.63 (s, 1H), 4.35-4.29 (m, 2H), 3.84-3.76 (m, 3H), 1.85-1.80 (m, 3H), 1.39-1.36 (m, 3H), 1.28 (d, 3H); MS (ESI) m / z=273.1 (M + H) +

[0090] Step 2: (S)-Ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate To a solution of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (3.0 g, 11.0 mmol) prepared in Step 1 in toluene (22 mL) was added (tributylphosphoranylidene)acetonitrile (8.65 mL, 33.0 mmol) and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (2.10 g, 11.0 mmol) prepared in Preparation 8. The reaction mixture was continued to stir at 100° C. for 4 hours. Upon completion, the mixture was cooled and diluted with EA. The organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography [MeOH / DCM=0-5%, (containing 1% NH4OH)] to produce (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate as a brown solid (3.37 g, 68.7%). 1 H-NMR (CDCl 3、 400 MHz) δ 8.66 (s, 1H), 8.22 (d, 1H), 8.15 (d, 1H), 7.96 (s, 1H), 6.64 (s, 1H), 6.18 (d, 1H), 4.83 (brs, 2H), 4.52-4.50 (m, 1H), 4.40-4.37 (m, 1H), 4.33-4.28 (m, 2H), 3.95-3.91 (m, 1H), 3.69 (s, 3H), 2.11-2.08 (m, 2H), 1.38-1.35 (m, 6H); MS (ESI) m / z=446.1 (M + H) +

[0091] Step 3: Ethyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate To a solution of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (3.37 g, 7.56 mmol) prepared in step 2 in 1,4-dioxane (300 mL) was added CsCO (7.39 g, 22.7 mmol), Pd(dba) (1.38 g, 1.51 mmol), and XPhos (1.44 g, 3.02 mmol). The reaction mixture was continued to stir at 120 °C for 6 h. Upon completion, the mixture was cooled and diluted with DCM. The organic layer was washed with water, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography [MeOH / DCM=0-5%, (containing 1% NH4OH)] to give ethyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The -carboxylate was prepared as a white solid (1.77 g, 57%). 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.33 (d, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 8.12 (s, 1H), 7.66 (brs, 1H), 6.37 (d, 1H), 4.74-4.71 (m, 1H), 4.35-4.26 (m, 3H), 4.08-4.06 (m, 1H), 3.80 (s, 3H), 2.16-2.15 (m, 2H), 1.47-1.45 (d, 2H), 1.41-1.37 (m, 3H); MS (ESI) m / z=409.1 (M + H) +

[0092] Step 4: (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid A 3N NaOH solution (4.88 mL, 14.654 mmol) in THF (24.0 mL) / 50% MeOH (12 mL) and the ethyl (S)-1 prepared in step 3 were added. 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 A suspension of methyl (S)-1-carboxylate (600 mg, 1.465 mmol) was stirred at 60° C. for 7 hours. After the reaction mixture was cooled, 9N HCl solution was added to adjust the pH to 2 and stirred for 15 minutes. The mixture was filtered and washed with water. The wet cake was dried to give methyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The carboxylic acid was prepared as a white solid (543 mg, 1.424 mmol, 97.16%). MS (ESI) m / z=381.9 (M + H). +

[0093] Production example 2: (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Step 1: Methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate The title compound was prepared as an off-white solid (1010 mg) in the same manner as in Step 1 of Preparation 1, except that methyl 4,6-dichloronicotinate (1000 mg, 4.854 mmol) and (R)-4-aminobutan-2-ol (562.45 mg, 6.31 mmol) were used instead of ethyl 4,6-dichloronicotinate and (S)-3-aminobutan-1-ol. MS (ESI) m / z=259.0 (M + H) +

[0094] Step 2: Methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate The title compound was prepared as a white solid (171 mg) in the same manner as in Step 2 of Preparation 1, except that methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate (270.62 mg, 1.046 mmol) prepared in Step 1 was used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate. 1 H-NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.05 (s, 1H), 5.24-5.16 (m, 1H), 4.80 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.58 (q, 2H), 2.24-2.16 (m, 1H), 2.10-2.02 (m, 1H), 1.28 (d, 3H)

[0095] Step 3: Methyl (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate The title compound was prepared as a white solid (64 mg) in the same manner as in Step 3 of Preparation 1, except that methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate (50 mg, 0.209 mmol) prepared in Step 2 was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate. 1H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.50 (t, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.68 (brs, 1H), 6.39 (d, 1H), 5.48-5.41 (m, 1H), 4.07-4.00 (m, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.59-3.49 (m, 1H), 2.31-2.22 (m, 1H), 1.95-1.89 (m, 1H), 1.12 (d, 3H); MS (ESI) m / z=396.0 (M+H) +

[0096] Step 4: (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Ethyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 Instead of the -carboxylate, the methyl (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The title compound was prepared as an off-white solid (65 mg) in a manner similar to Step 4 of Preparation 1, except that 1-carboxylate (100 mg, 0.253 mmol) was used. MS (ESI) m / z=381.9 (M + H). +

[0097] Manufacturing Example 3:1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Step 1: Methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate The title compound was prepared as a white solid (1166 mg) in the same manner as in Step 1 of Preparation 2, except that 3-amino-2,2-dimethylpropan-1-ol (650.91 mg, 6.31 mmol) was used instead of (R)-4-aminobutan-2-ol. 1 H-NMR (CDCl3, 400 MHz) δ8.66 (s, 1H), 8.46 (s, 1H), 6.64 (s, 1H), 3.91 (s, 3H), 3.51 (d, 2H), 3.13 (d, 2H), 1.83 (t, 1H), 1.05 (s, 6H)

[0098] Step 2: Methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate The title compound was prepared as a white solid (382 mg) in the same manner as in Step 2 of Preparation 1, except that methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate (713.24 mg, 2.615 mmol) prepared in Step 1 was used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate. 1 H-NMR (CDCl3, 400 MHz) δ8.69 (s, 1H), 8.51 (s, 1H), 8.19 (d, 1H), 7.99 (s, 1H), 6.66 (s, 1H), 6.21 (d, 1H), 4.83 (s, 2H), 4.22 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.34 (d, 2H), 1.23 (s, 6H)

[0099] Step 3: Methyl 1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate The title compound was prepared as a white solid (49 mg) in the same manner as in Step 3 of Preparation 1, except that methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate (380 mg, 0.852 mmol) was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate. 1 H-NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 8.48 (t, 1H), 8.37 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 6.39 (d, 1H), 4.79 (brs, 1H), 4.21 (brs, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.54 (brs, 1H), 2.94 (brs, 1H), 1.41 (brs, 3H), 1.00 (brs, 3H); MS (ESI) m / z=410.0 (M + H) +

[0100] Step 4:1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Ethyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate instead of methyl 1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5The title compound was prepared as an off-white solid (33 mg) in a manner similar to Step 4 of Preparation 1, except that 45 mg of 1H-carboxylate (0.11 mmol) was used. MS (ESI) m / z=396.0 (M + H). +

[0101] Preparation Example 4: tert-Butyl (tert-butoxycarbonyl) (2-chloropyrimidin-4-yl)carbamate To a solution of 4-amino-2-chloropyrimidine (9.50 g, 73.33 mmol) in THF (146.66 mL) were added di-tert-butyl dicarbonate (50.54 mL, 219.99 mmol), triethylamine (40.88 mL, 293.32 mmol), and 4-dimethylaminopyridine (895.88 mg, 7.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours, quenched with water, and then diluted with EA. The reaction mixture was extracted with EA, and the combined organic extracts were concentrated. The residue was purified by silica gel column chromatography (EA / n-Hex = 0-20%) to prepare tert-butyl (tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (20.0 g, 60.6 mmol, yield: 82.7%). 1 H-NMR (CDCl3, 400 MHz) δ 8.47 (d, 1H), 7.73 (d, 1H), 1.57 (s, 18H); MS (ESI) m / z=329.9 (M+H) +

[0102] Preparation Example 5: 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one Step 1: 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one To a solution of 5-hydroxy-1-methyl-1H-pyrazole (3.00 g, 30.58 mmol) in MeCN (20 mL) was added potassium carbonate (16.90 g, 122.32 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (10.82 mL, 61.16 mmol). The reaction mixture was stirred at room temperature for 12 hours, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to produce 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as a pale yellow solid (3.54 g, 15.5 mmol, yield: 50.7%). 1 H-NMR (CDCl3, 400 MHz) δ 7.30 (s, 1H), 5.49 (s, 1H), 4.99 (s, 2H), 3.47-3.44 (m, 5H), 0.88 (t, 2H), 0.00 (s, 9H)

[0103] Step 2: 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one To a solution of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (1.00 g, 4.38 mmol) prepared in step 1 in MeCN (14.60 mL) was added N-bromosuccinimide (740.46 mg, 4.16 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and diluted with saturated NaSO and EA. The aqueous phase was extracted with EA. The combined organic phase was washed with saturated brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM=0-5%) to produce 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as a pale yellow solid (668.0 mg, 2.2 mmol, yield: 49.6%). 1H-NMR (CDCl3, 400 MHz) δ 7.43 (s, 1H), 4.97 (s, 2H), 3.50-3.46 (m, 5H), 0.86 (q, 2H), 0.00 (s, 9H); MS (ESI) m / z=307.0 (M+H) +

[0104] Preparation Example 6: 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one To a solution of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (80.0 mg, 0.26 mmol) prepared in Preparation 5 in MeCN (2.0 mL) and water (0.2 mL) was added tert-butyl(tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (343.45 mg, 1.04 mmol) prepared in Preparation 4, sodium carbonate (110.38 mg, 1.04 mmol), bis(pinacolato)diboron (264.47 mg, 1.04 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) (36.87 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then at 100 °C for 4 hours. The reaction mixture was filtered through a Celite pad, and the crude product was used in the next step without further purification. To a solution of tert-butyl (tert-butoxycarbonyl) (2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (70.0 mg, 0.13 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.40 mL) was added trifluoroacetic acid (0.14 mL, 1.88 mmol). The reaction mixture was stirred at room temperature for 10 hours, quenched with saturated NaHCO3, and diluted with DCM and water. The aqueous phase was extracted with DCM. The combined organic phase was washed with saturated brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM=5-10%) to produce 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as a pale yellow solid (20.0 mg, 0.06 mmol, yield: 26.4%). 1 H-NMR (CD3OD, 400 MHz) δ 8.34 (s, 1H), 8.03 (d, 1H), 6.33 (d, 1H), 5.39 (s, 2H), 3.57 (m, 5H), 0.92 (t, 2H), 0.00 (s, 9H); MS (ESI) m / z=322.1 (M+H)+

[0105] Preparation Example 7: (4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone Step 1: (6-chloro-4-((3-hydroxypropyl)amino)pyridin-3-yl)(cyclopropyl)methanone To a solution of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (2.0 g, 9.26 mmol) in MeCN (9.20 mL) was added DIPEA (2.59 mL, 18.51 mmol) and 3-amino-1-propanol (0.78 mL, 10.18 mmol). The reaction mixture was stirred at 60 °C overnight. The reaction mixture was then cooled to room temperature, added to water, and extracted with DCM. The combined organic layer was washed with saturated brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to produce (6-chloro-4-((3-hydroxypropyl)amino)pyridin-3-yl)(cyclopropyl)methanone (1.74 g, 6.8 mmol, yield: 73.9%). 1 H-NMR (CDCl3, 400 MHz) δ 9.18 (s, 1H), 8.77 (s, 1H), 6.56 (d, 1H), 3.78 (s, 2H), 3.32 (d, 2H), 2.54 (d, 1H), 1.90 (d, 2H), 1.20 (d, 2H), 1.02 (d, 2H); MS (ESI) m / z=255.1 (M+H) +

[0106] Step 2: (4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone To a solution of (6-chloro-4-((3-hydroxypropyl)amino)pyridin-3-yl)(cyclopropyl)methanone (657.0 mg, 2.58 mmol) prepared in Step 1 in DCM (5.16 mL) was added tert-butyldimethylchlorosilane (466.52 mg, 3.10 mmol), 4-dimethylaminopyridine (31.51 mg, 0.26 mmol), and triethylamine (0.72 mL, 0.34 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h, quenched with water, and then diluted with EA. The reaction mixture was extracted with EA, and the combined organic extracts were concentrated. The residue was purified by silica gel column chromatography (EA / n-Hex=0-20%) to produce (4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (786.0 mg, 2.13 mmol, yield: 82.6%). 1 H-NMR (CDCl3, 400 MHz) δ 9.18 (s, 1H), 8.82 (s, 1H), 6.63 (s, 1H), 3.72 (t, 2H), 3.30 (q, 2H), 2.58 (quin, 1H), 1.85 (q, 2H), 1.19 (s, 2H), 1.03 (d, 2H), 0.89 (s, 9H), 0.00 (s, 6H); MS (ESI) m / z=369.1 (M+H) +

[0107] Preparation 8: 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol Step 1: 5-(benzyloxy)-1-methyl-1H-pyrazole To a solution of 1-methyl-1H-pyrazol-5-ol (50.0 g, 0.51 mol) in DMF (500 mL) was added K2CO3 (106 g, 0.76 mol) and benzyl bromide (72.6 mL, 0.61 mol). The mixture was stirred at 60 °C for 6 h. Ice water (500 mL) was added to the mixture to quench the reaction, followed by extraction with EA. The combined organic layer was washed several times with ice water and saturated brine to remove DMF. It was then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EA / n-Hex = 0-20%) to produce 5-(benzyloxy)-1-methyl-1H-pyrazole as a colorless oil (36.4 g). 1 H NMR (CDCl3, 400 MHz) δ 7.41-7.40 (m, 4H), 7.38-7.34 (m, 2H), 7.29 (d, 1H), 5.06 (s, 2H), 3.66 (s, 3H); MS (ESI) m / z=189.0 (M+H) +

[0108] Step 2: 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole To a solution of 5-(benzyloxy)-1-methyl-1H-pyrazole (44.4 g, 236 mmol) prepared in step 1 in MeCN (675 mL) was added N-iodosuccinimide (53.1 g, 236 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Upon completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layers were washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (EA / n-Hex = 0-20%) gave 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole (41.5 g) as a pale yellow liquid. 1 H NMR (CDCl3, 400 MHz) δ 7.38 (s, 5H), 7.34 (s, 1H), 5.22 (s, 2H), 3.45 (s, 3H); MS (ESI) m / z=315.0 (M+H) +

[0109] Step 3: 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a stirred solution of 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole (41.5 g, 132 mmol) in THF (420 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 112 mL, 145 mmol) at -10 to 0 °C under an argon atmosphere. After stirring the mixture at 0 °C for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.3 mL, 159 mmol) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for an additional 1.5 h, after which the reaction was quenched by the slow addition of saturated NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA / n-Hex=0-20%) to produce 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (32.5 g). 1 H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 7.40-7.35 (m, 5H), 5.39 (s, 2H), 3.55 (s, 3H), 1.32 (s, 12H); MS (ESI) m / z=315.2 (M+H) +

[0110] Step 4: 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-bromopyrimidin-4-amine (16.0 g, 91.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28.9 g, 91.9 mmol) in 1,4-dioxane (460 mL) was added 3M K2CO3 solution (91.9 mL, 276 mmol) and Pd(dppf)Cl2 dichloromethane complex (7.51 g, 9.19 mmol). The mixture was degassed with argon and then heated to 90 °C under an argon atmosphere for 5–6 h. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (MeOH / DCM=0-5%) to produce 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (11.2 g). 1 H NMR (CD3OD, 400 MHz) δ 8.08 (d, 1H), 7.87 (s, 1H), 7.34 (s, 5H), 6.34 (d, 1H), 5.41 (s, 2H), 3.39 (s, 3H); MS (ESI) m / z=282.2 (M+H) +

[0111] Step 5: 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (12.3 g, 43.7 mmol) in methanol (120 mL) was added Pd(OH)2 on carbon (20% Pd, 120 mg) and stirred under an atmosphere of H2 at 25 °C for 6-8 h. Upon completion, the reaction mixture was filtered through a pad of Celite and washed thoroughly with MeOH. The solvent was evaporated under reduced pressure to produce 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (7.34 g) as a gray solid. 1H NMR (CD3OD, 400 MHz) δ 7.85 (d, 1H), 7.69 (s, 1H), 6.21 (d, 1H), 3.45 (s, 3H); MS (ESI) m / z=192.1 (M+H) +

[0112] Preparation Example 9: 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol Step 1: 5-(benzyloxy)-1,3-dimethyl-1H-pyrazole To a solution of 1,3-dimethyl-1H-pyrazol-5-ol (13.0 g, 116 mmol) in THF (500 mL) was added K2CO3 (24.0 g, 174 mmol) and benzyl bromide (16.5 mL, 139 mol). The mixture was stirred at 60 °C for 8 h. Ice water (500 mL) was added to the mixture to quench the reaction, followed by extraction with EA. The combined organic layer was washed several times with ice water and saturated brine to remove DMF. It was then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EA / n-Hex = 0-20%) to give 5-(benzyloxy)-1,3-dimethyl-1H-pyrazole as a colorless oil (9.20 g). 1 H NMR (CDCl3, 400 MHz) δ 7.41-7.40 (m, 4H), 7.38-7.34 (m, 2H), 7.29 (d, 1H), 5.06 (s, 2H), 3.66 (s, 3H); MS (ESI) m / z=189.0 (M+H) +

[0113] Step 2: 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole To a solution of 5-(benzyloxy)-1,3-dimethyl-1H-pyrazole (9.20 g, 45.5 mmol) prepared in step 1 in MeCN (100 mL) was added N-iodosuccinimide (10.2 g, 45.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layer was washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (EA / n-Hex = 0-20%) to give 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole (7.40 g) as a pale yellow liquid. 1 H NMR (CDCl3, 400 MHz) δ 7.37-7.36 (s, 5H), 5.19 (s, 2H), 3.39 (s, 3H), 2.18 (s, 3H); MS (ESI) m / z=328.9 (M+H) +

[0114] Step 3: 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a stirred solution of 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole (7.40 g, 22.6 mmol) in THF (75 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 26 mL, 33.8 mmol) at -10 to 0 °C under an argon atmosphere. After stirring the mixture at 0 °C for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.90 mL, 33.8 mmol) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for an additional 1.5 h, after which the reaction was quenched by the slow addition of saturated NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA / n-Hex=0-20%) to produce 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (6.48 g). 1 H NMR (CDCl3, 400 MHz) δ 7.41-7.33 (m, 5H), 5.29 (s, 2H), 3.43 (s, 3H), 2.31 (s, 3H), 1.31 (s, 12H); MS (ESI) m / z=329.1 (M+H) +

[0115] Step 4: 2-(5-(benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-bromopyrimidin-4-amine (530 mg, 3.05 mmol) and 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 3.05 mmol) in 1,4-dioxane (15 mL) was added 3 M K2CO3 solution (3.05 mL, 9.14 mmol) and Pd(dppf)Cl2 dichloromethane complex (249 mg, 0.31 mmol). The mixture was degassed with argon and then heated to 90 °C under an argon atmosphere overnight. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (MeOH / DCM=0-5%) to produce 2-(5-(benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (160 mg). 1 H NMR (CD3OD, 400 MHz) δ 8.12 (d, 1H), 7.31-7.30 (s, 5H), 6.34 (d, 1H), 5.16 (s, 2H), 3.37 (s, 3H), 2.37 (s, 3H); MS (ESI) m / z=296.0 (M+H) +

[0116] Step 5: 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (1.26 g, 4.27 mmol) in methanol (15 mL) was added Pd(OH) on carbon (20% Pd, 126 mg) and stirred under H atmosphere at 25 °C for 6 h. Upon completion, the reaction mixture was filtered through a pad of Celite and washed thoroughly with MeOH. The solvent was evaporated under reduced pressure to produce 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol as a grey solid (710 mg). 1H NMR (CD3OD, 400 MHz) δ 7.85 (d, 1H), 6.17 (d, 1H), 3.40 (s, 3H), 2.39 (s, 3H); MS (ESI) m / z=206.0 (M+H) +

[0117] Example 1: (S)-Cyclopropyl (1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone Step 1: (S)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone A mixture of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (2.00 g, 9.257 mmol), (S)-3-aminobutan-1-ol (825.14 mg, 9.257 mmol), and DIPEA (2.59 mL, 18.513 mmol) in MeCN (10 mL) was stirred at 60 °C overnight. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to prepare (S)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (2.08 g, 7.740 mmol, yield: 83.61%). 1 H-NMR (CDCl3, 400MHz) δ 8.77 (s, 1H), 6.67 (s, 1H), 3.87-3.74 (m, 3H), 2.58-2.52 (m, 1H), 2.24-2.22 (m, 1H), 1.85-1.78 (m, 2H), 1.27 (d, 3H), 1.21-1.15 (m, 2H), 1.05-1.01 (m, 2H); MS (ESI) m / z=269.1 (M + H) +

[0118] Step 2: (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone A mixture of (S)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (1.23 g, 4.593 mmol) prepared in Step 1, tert-butylchlorodimethylsilane (830.79 mg, 5.512 mmol), DMAP (56.12 mg, 0.459 mmol), and TEA (1.28 mL, 9.187 mmol) in DCM (4 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with EA, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-15%) to produce (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (1.70 g, 4.439 mmol, yield: 96.63%). 1 H-NMR (CDCl3, 400MHz) δ 9.12 (brs, 1H), 8.81 (s, 1H), 6.69 (s, 1H), 3.83-3.77 (m, 1H), 3.69-3.63 (m, 2H), 2.60-2.54 (m, 1H), 1.81-1.63 (m, 2H), 1.25 (d, 3H), 1.20-1.16 (m, 2H), 1.04-1.00 (m, 2H), 0.91 (s, 9H), 0.03 (s, 6H); MS (ESI) m / z=384.1 (M + H) +

[0119] Step 3: (S)-(6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone A mixture of (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (68.07 mg, 0.178 mmol) prepared in Step 2, 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.00 mg, 0.178 mmol), cesium carbonate (173.74 mg, 0.533 mmol), XPhos (33.89 mg, 0.071 mmol), and Pd(dba) (32.55 mg, 0.036 mmol) in 1,4-dioxane (1 mL) was stirred at 130 °C for 2 hours. The reaction mixture was cooled, filtered through a pad of Celite, and concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-20%) to produce (S)-(6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (20.00 mg, 0.032 mmol, yield: 17.92%). MS (ESI) m / z=628.1 (M + H). +

[0120] Step 4: (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone A mixture of (S)-(6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (20.00 mg, 0.032 mmol) prepared in Step 3 and 10% Pd / C (40.00 mg) in MeOH (1 mL) was stirred under a H atmosphere at room temperature for 2 hours. The reaction mixture was filtered through a pad of Celite and then concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-20%) to produce (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (7.50 mg, 0.014 mmol, yield: 42.53%). MS (ESI) m / z=538.1 (M + H). +

[0121] Step 5: (S)-Cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone A mixture of (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (15.52 mg, 0.029 mmol) prepared in Step 4 and TBAF (1.0 M, 0.43 mL, 0.433 mmol) in THF (1 mL) was stirred at 50° C. for 7 hours. The reaction mixture was cooled, filtered through a pad of Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-20%) to produce (S)-cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone (7.50 mg, 0.018 mmol, yield: 61.36%). 1 H-NMR (CD3OD, 400MHz) δ 9.01 (s, 1H), 8.14 (d, 1H), 7.80 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 3.98-3.93 (m, 1H), 3.73-3.67 (m, 2H), 3.51 (s, 3H), 2.81-2.77 (m, 1H), 1.88-1.83 (m, 2H), 1.33 (d, 3H), 1.15-1.11 (m, 4H); MS (ESI) m / z=424.1 (M + H) +

[0122] Step 6: (S)-Cyclopropyl (1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone A mixture of (S)-cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone (7.50 mg, 0.018 mmol) prepared in Step 5 and (tributylphosphoranylidene)acetonitrile (0.12 mL, 0.117 mmol) in toluene (1 mL) was stirred at 130 °C for 3 h. After completion of the reaction, the volatiles were removed and the crude product was purified by column chromatography (MeOH / DCM = 0-10%) to give (S)-cyclopropyl(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone was prepared (2.80 mg, 0.007 mmol, yield: 38.99%). 1 H-NMR (CD3OD, 400MHz) δ 8.86 (brs, 1H), 8.42-8.40 (m, 3H), 8.03 (s, 1H), 6.74 (d, 1H), 4.70-4.64 (m, 1H), 4.25-4.20 (m, 2H), 3.81 (s, 3H), 2.76-2.72 (m, 1H), 2.22-2.13 (m, 1H), 1.43 (d, 3H), 1.13-1.08 (m, 2H), 1.05-1.00 (m, 2H); MS (ESI) m / z=406.1 (M + H) +

[0123] Example 2: Cyclopropyl (1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4 5 -Il)methanone Step 1: (6-chloro-4-((4-hydroxybutyl)amino)pyridin-3-yl)(cyclopropyl)methanone A mixture of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (2.00 g, 9.257 mmol), 4-aminobutan-1-ol (907.66 mg, 10.182 mmol), and DIPEA (2.59 mL, 18.513 mmol) in MeCN (10 mL) was stirred at 60 °C overnight. After cooling, the reaction mixture was diluted with EA, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (6-chloro-4-((4-hydroxybutyl)amino)pyridin-3-yl)(cyclopropyl)methanone (2.00 g, 7.442 mmol, yield: 80.40%). 1 H-NMR (CD3OD, 400MHz) δ 9.33 (brs, 1H), 8.84 (s, 1H), 6.79 (s, 1H), 3.63-3.59 (m, 2H), 3.32-3.27 (m, 3H), 2.78-2.72 (m, 1H), 1.77-1.60 (m, 4H), 1.15-1.14 (m, 4H); MS (ESI) m / z=269.1 (M + H) +

[0124] Step 2: (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone A mixture of (6-chloro-4-((4-hydroxybutyl)amino)pyridin-3-yl)(cyclopropyl)methanone (1.23 g, 4.593 mmol) prepared in Step 1, tert-butylchlorodimethylsilane (830.79 mg, 5.512 mmol), DMAP (56.12 mg, 0.459 mmol), and TEA (1.28 mL, 9.187 mmol) in DCM (4 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with EA, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (1.70 g, 4.439 mmol, yield: 96.63%). 1H-NMR (CDCl3, 400MHz) δ 9.14 (brs, 1H), 8.82 (s, 1H), 6.56 (s, 1H), 3.67-3.64 (m, 2H), 3.23-3.18 (m, 2H), 2.60-2.54 (m, 1H), 1.77-1.58 (m, 4H), 1.21-1.17 (m, 2H), 1.05-1.00 (m, 2H), 0.91 (s, 9H), 0.03 (s, 6H); MS (ESI) m / z=384.1 (M + H) +

[0125] Step 3: (6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)pyridin-3-yl)(cyclopropyl)methanone A mixture of (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (204.22 mg, 0.533 mmol) prepared in Step 2, 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (150.00 mg, 0.533 mmol), cesium carbonate (521.22 mg, 1.600 mmol), XPhos (101.68 mg, 0.213 mmol), and Pd(dba) (97.66 mg, 0.107 mmol) in 1,4-dioxane (1 mL) was stirred at 130 °C for 5 h. The reaction mixture was cooled, filtered through a pad of Celite, and concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-20%) to produce (6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)pyridin-3-yl)(cyclopropyl)methanone (80.00 mg). MS (ESI) m / z=628.1 (M + H). +

[0126] Step 4: (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone The title compound was prepared as a pale yellow solid (50.00 mg, 0.093 mmol, yield: 72.97%) in the same manner as in Step 4 of Example 1, except that (6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)pyridin-3-yl)(cyclopropyl)methanone (80.00 mg, 0.127 mmol) prepared in Step 3 was used instead of (S)-(6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone. MS (ESI) m / z=538.1 (M+H) +

[0127] Step 5: Cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutyl)amino)pyridin-3-yl)methanone The title compound was prepared as a pale yellow solid (30.00 mg) in the same manner as in Step 5 of Example 1, except that (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (50.00 mg, 0.127 mmol) prepared in Step 4 was used instead of (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone. MS (ESI) m / z=424.1 (M+H) +

[0128] Step 6: Cyclopropyl (1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4 5 -Il)methanone The title compound was prepared as a pale yellow solid (1.80 mg) in the same manner as in Step 6 of Example 1, except that cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutyl)amino)pyridin-3-yl)methanone (2.80 mg, 0.007 mmol) prepared in Step 5 was used instead of (S)-cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone. 1H-NMR (CDCl3, 400MHz) δ 9.54 (brs, 1H), 8.81 (s, 1H), 8.38 (d, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.68 (brs, 1H), 6.44 (d, 1H), 4.90-4.81 (m, 2H), 4.26 (s, 2H), 3.78 (s, 3H), 3.74 (s, 2H), 2.63-2.60 (m, 1H), 1.21-1.18 (m, 2H), 1.02-0.93 (m, 4H); MS (ESI) m / z=406.2 (M + H) +

[0129] Example 3: ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (S)-1 prepared in Preparation Example 1 in DMF (3 mL) 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 A mixture of ((S)-1-carboxylic acid (30.00 mg, 0.079 mmol), (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (47.12 mg, 0.236 mmol), HATU (59.82 mg, 0.157 mmol), and DIPEA (0.04 mL, 0.236 mmol) was stirred at 80 °C for 12 h. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give ((S)-1-carboxylic acid (30.00 mg, 0.079 mmol), (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (47.12 mg, 0.236 mmol), HATU (59.82 mg, 0.157 mmol), and DIPEA (0.04 mL, 0.236 mmol). ... 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5-yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone was prepared (2.70 mg, 0.005 mmol, yield: 6.52%). 1 H-NMR (CD3OD, 400MHz) δ 8.30 (s, 3H), 8.28-8.26 (d, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 6.71 (d, 1H), 4.72-4.69 (m, 1H), 4.68-4.56 MS (ESI) m / z=527.1 (M + H) +

[0130] Example 4: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone The title compound was prepared as in Example 3, except that 3-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (15.71 mg, 0.079 mmol) was used instead of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride, to give a white solid (3.50 mg). 1 H-NMR (DMSO-d6, 400MHz) δ 8.30 (d, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 6.80 (d, 1H), 4.52-4.48 (m, 1H), 4.32-4.29 (m, 2H), 4.01-3.96 (m, 2H), 3.78 (s, 3H), 3.02 (s, 3H), 2.13-1.99 (m, 3H), 1.53 (s, 3H), 1.37 (d, 3H); MS (ESI) m / z=527.3 (M + H) +

[0131] Example 5: (S)-1-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 (-carbonyl)azetidin-3-yl)-N,N-dimethylmethanesulfonamide formate The title compound was prepared as a white solid (4.00 mg) in the same manner as in Example 3, except that azetidin-3-ylmethanesulfonyl fluoride hydrochloride (14.92 mg, 0.079 mmol) was used instead of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride. 1 H-NMR (DMSO-d6, 400MHz) δ 10.06 (s, 1H), 8.30 (d, 1H), 8.21 (s, 1H), 8.13 (d, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 6.80 (d, 1H), 4.51-4.47 (m, 1H), 4.33-4.29 (m, 2H), 4.02-3.96 (m, 2H), 3.48 (d, 2H), 3.11-3.06 (m, 1H), 2.13-1.98 (m, 2H), 1.37 (d, 3H); MS (ESI) m / z=542.2 (M + H) +

[0132] Example 6: ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (S)-1 prepared in Preparation Example 1 in DMF (2 mL) 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5A reaction mixture of (S)-1-carboxylic acid (30.0 mg, 0.079 mmol), (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol), HATU (59.82 mg, 0.157 mmol), and DIPEA (0.04 mL, 0.236 mmol) was stirred at 80 °C for 3 h. The crude reaction mixture was concentrated under reduced pressure, purified by column chromatography (MeOH / EA = 0-30%), and recrystallized (EA / IPE) to give ((S)-1-carboxylic acid (30.0 mg, 0.079 mmol), (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol), HATU (59.82 mg, 0.157 mmol), and DIPEA (0.04 mL, 0.236 mmol). The crude reaction mixture was concentrated under reduced pressure, purified by column chromatography (MeOH / EA = 0-30%), and recrystallized (EA / IPE) to give ((S)-1-carboxylic acid (30.0 mg, 0.079 mmol). 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone was prepared as a white solid (6 mg, 0.011 mmol, yield: 14.48%). 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (d, 1H), 8.34 (s, 1H), 8.20 (d, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.63 (brs, 1H), 6.43 (d, 1H), 4.99-4.95 (m, 1H), 4.77-4.72 (m, 1H), 4.47-4.41 (m, 1H), 4.26-4.24 (m, 1H), 4.12-4.09 (m, 1H), 3.82 (s, 3H), 3.44-3.31 (m, 2H), 2.98 (s, 2H), 2.17-2.13 (m, 2H), 1.49-1.45 (m, 6H); MS (ESI) m / z=527.2 (M + H) +

[0133] Example 7: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone The title compound was prepared as in Example 6, except that 2-(azetidin-3-yl)propan-2-ol hydrochloride (15.9 mg, 0.105 mmol) was used instead of (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give a white solid (2 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.30 (s, 1H), 8.22 (d, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.49 (s, 1H), 6.38 (d, 1H), 4.77-4.73 (m, 1H), 4.26-4.22 (m, 4H), 4.10-4.06 (m, 1H), 2.73-2.18 (m, 2H), 1.45 (d, 3H), 1.28 (t, 1H), 1.24 (s, 6H); MS (ESI) m / z=479.3 (M + H) +

[0134] Example 8: ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone formate The title compound was prepared as in Example 6, except that (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride was replaced with (2S,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol), to give a white solid (11.9 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.49-8.47 (m, 2H), 8.42 (s, 1H), 8.38 (d, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 6.67 (d, 1H), 4.70-4.64 (m, 2H), 4.57-4.55 (m, 1H), 4.27-4.25 (m, 1H), 4.12-4.10 (m, 1H), 4.06-4.02 (m, 1H), 3.81 (s, 3H), 3.40-3.32 (m, 2H), 2.97 (s, 3H), 2.88-2.86 (m, 1H), 2.18-2.14 (m, 2H), 1.57 (d, 3H), 1.49 (d, 3H); MS (ESI) m / z=526.9 (M + H) +

[0135] Example 9: (S)-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl) (1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as a white solid (18.1 mg) in the same manner as in Example 6, except that 2,2-difluoro-5-azaspiro[2.3]hexane hydrochloride (17.95 mg, 0.115 mmol) was used instead of (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H), 8.46-8.41 (m, 3H), 8.16 (s, 1H), 7.92 (s, 1H), 6.73 (d, 1H), 4.71-4.68 (d, 1H), 4.50-4.48 (m, 2H), 4.36-4.30 (m, 3H), 4.15-4.11 (m, 1H), 3.83 (s, 3H), 2.24-2.16 (m, 2H), 1.58 (t, 2H), 1.51 (d, 3H); MS (ESI) m / z=482.9 (M + H) +

[0136] Example 10: (S)-(11 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2,2,2-trifluoroethyl)azetidin-1-yl)methanone The title compound was prepared as a white solid (4.5 mg) in the same manner as in Example 6, except that 3-(2,2,2-trifluoroethyl)azetidine hydrochloride (17.72 mg, 0.101 mmol) was used instead of (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.34 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 6.43 (d, 1H), 4.74-4.72 (d, 1H), 4.51-4.49 (m, 2H), 4.27-4.24 (m, 1H), 4.12-4.07 (m, 3H), 3.82 (s, 3H), 3.09-3.05 (m, 1H), 2.53-2.46 (m, 2H), 2.20-2.14 (m, 2H), 1.47 (d, 3H); MS (ESI) m / z=503.2 (M + H) +

[0137] Example 11: Cyclopropyl (1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone 2,2,2-trifluoroacetate Step 1: 4-(4-((4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-5-(cyclopropanecarbonyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one To a solution of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (20.0 mg, 0.06 mmol) prepared in Preparation 6 in 1,4-dioxane (1.5 mL) was added (4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (29.84 mg, 0.08 mmol) prepared in Preparation 7, Pd(dba) (11.39 mg, 0.01 mmol), XPhos (11.86 mg, 0.02 mmol), and cesium carbonate (60.82 mg, 0.19 mmol). The reaction mixture was purged with N for 30 minutes and stirred at 100 °C for 2 hours. The reaction mixture was diluted with DCM and water. The aqueous phase was extracted with DCM. The combined organic phase was washed with saturated brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM=5-10%) to produce 4-(4-((4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-5-(cyclopropanecarbonyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (12.0 mg, 0.02 mmol, yield: 29.5%). MS (ESI) m / z=654.3 (M+H). +

[0138] Step 2: 4-(4-((5-(cyclopropanecarbonyl)-4-((3-hydroxypropyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one To a solution of 4-(4-((4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-5-(cyclopropanecarbonyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (12.0 mg, 0.02 mmol) prepared in step 1 in THF (1.0 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 0.04 mL, 0.04 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (EA / n-Hex=0-100%) & (MeOH / DCM=0-30%) to produce 4-(4-((5-(cyclopropanecarbonyl)-4-((3-hydroxypropyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one as a white foam (3.50 mg, 0.009 mmol, yield: 46.6%). MS (ESI) m / z=410.2 (M+H). +

[0139] Step 3: Cyclopropyl (1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone To a solution of 4-(4-((5-(cyclopropanecarbonyl)-4-((3-hydroxypropyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one (2.22 mg, 0.01 mmol) in toluene (1.08 mL) was added (tributylphosphoranylidene)acetonitrile solution (1.0 M in toluene, 0.04 mL, 0.04 mmol). The reaction mixture was stirred at 130 °C for 12 h, concentrated, and purified by silica gel column chromatography (MeOH / DCM = 0-30%) to give cyclopropyl (1H-pyrazol-3-one). 1 -methyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone was prepared in the form of a TFA salt (0.80 mg, 0.002 mmol, yield: 29.1%). 1 H-NMR (CDCl3, 400 MHz) δ 11.44 (s, 1H), 9.95 (t, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.43 (d, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 6.79 (d, 1H), 4.39 (s, 2H), 3.79 (s, 3H), 3.76 (s, 2H), 2.24-2.23 (m, 3H), 1.23 (t, 2H), 1.07 (t, 2H); MS (ESI) m / z=392.1 (M+H) +

[0140] Example 12: Methyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate Step 1: Methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate To a solution of methyl 4,6-dichloronicotinate (3.70 g, 17.96 mmol) in DMA (29.12 mL) was added (S)-3-aminobutan-1-ol (1.60 g, 17.96 mmol) and DIPEA (5.02 mL, 35.92 mmol). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with DCM. The combined organic layer was washed with saturated brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / n-Hex = 0-30%) to prepare methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (2.93 g, 11.3 mmol, yield: 63.2%). 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.15 (d, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.83-3.67 (m, 3H), 2.69-2.51 (m, 1H), 1.90-1.75 (m, 2H), 1.28 (d, 3H); MS (ESI) m / z=259.0 (M+H) +

[0141] Step 2: Methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate To a solution of methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (105.0 mg, 0.41 mmol) in toluene (1.78 mL) was added 4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (77.60 mg, 0.41 mmol) prepared in Preparation 8 and (tributylphosphoranylidene)acetonitrile (1.0 M in toluene, 305.76 mg, 1.01 mmol). The reaction mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (EA / n-Hex=0-100%) & (MeOH / DCM=0-30%) to prepare methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (121.60 mg, 0.28 mmol, yield: 69.4%). 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.19 (d, 1H), 8.14 (d, 1H), 7.96 (s, 1H), 6.64 (s, 1H), 6.17 (d, 1H), 5.03 (s, 2H), 4.54-4.36 (m, 2H), 3.93 (quin, 1H), 3.84 (s, 3H), 3.68 (s, 3H), 2.09 (sep, 2H), 1.35 (d, 3H)

[0142] Step 3: Methyl (S)-1 1,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate To a solution of methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (120.0 mg, 0.28 mmol) in 1,4-dioxane (5.56 mL), cesium carbonate (271.59 mg, 0.83 mmol), Pd(dba) (50.89 mg, 0.06 mmol), and XPhos (52.98 mg, 0.11 mmol) were added. The reaction mixture was stirred at 130 °C for 3 h. The reaction mixture was added to water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over MgSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / n-Hex=0-100%) and (MeOH / DCM=0-30%) to give methyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate was prepared (63.0 mg, 0.16 mmol, yield: 57.34%). 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.45 (s, 1H), 8.34 (d, 1H), 8.31 (s, 1H), 8.26 (d, 1H), 8.12 (s, 1H), 6.42 (d, 1H), 4.73 (q, 1H), 4.29 (t, 1H), 4.09-4.06 (m, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.17 (d, 2H), 1.48 (d, 3H); MS (ESI) m / z=396.2 (M+H) +

[0143] Example 13: (S)-(1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(pyrrolidin-1-yl)methanone Step 1: (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Methyl (S)-1 prepared in Example 12 in THF (2.0 mL) and water (2.0 mL) 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 To a solution of (S)-1, 2,4-dimethyl-1,4-trimethyl ... 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The -carboxylic acid was prepared as a pale yellow solid (56.0 mg, 0.15 mmol, yield: 79.5%). 1 H-NMR (DMSO-d6, 400 MHz) δ 10.06 (s, 1H), 8.51 (s, 1H), 8.30-8.27 (m, 2H), 8.20 (s, 1H), 7.91 (s, 1H), 6.78 (d, 1H), 4.49 (t, 1H), 4.30 (s, 1H), 4.02 (s, 1H), 3.77 (s, 4H), 2.14-2.03 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z=382.1 (M+H) +

[0144] Step 2: (S)-(1 1 ,6-dimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(pyrrolidin-1-yl)methanone (S)-1 prepared in step 1 in DMF (4.28 mL) 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 To a solution of (S)-(1)-carboxylic acid (15.0 mg, 0.04 mmol), HATU (29.91 mg, 0.08 mmol) and DIPEA (20.55 μL, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 20 minutes, and then pyrrolidine (5.59 mg, 0.08 mmol) was added. The reaction mixture was stirred at 80° C. for 6 hours and extracted with DCM / water. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by C18 column chromatography (MeCN / water = 0-100%) to give (S)-(1)-carboxylic acid. 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(pyrrolidin-1-yl)methanone was prepared (8.40 mg, 0.02 mmol, yield: 49.2%). 1 H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.30 (d, 1H), 6.39 (d, 1H), 4.73 (t, 1H), 4.23 (s, 1H), 4.09 (d, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 2.15-1.96 (m, 8H), 1.43 (d, 3H); MS (ESI) m / z=435.2 (M+H) +

[0145] Example 14: (S)-(1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-((methylsulfonyl)methyl)azetidin-1-yl) methanone The title compound was prepared as a solid (26.0 mg) in a manner similar to Step 2 of Example 13, except 3-(methylsulfonylmethyl)azetidine hydrochloride (29.21 mg, 0.16 mmol) was used instead of pyrrolidine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.19 (s, 1H), 8.28 (d, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 6.78 (d, 1H), 4.49 (t, 1H), 4.30-3.95 (m, 6H), 3.76 (s, 3H), 3.55 (d, 2H), 3.18-3.16 (m, 1H), 2.96 (s, 3H), 2.11-2.00 (m, 2H), 1.35 (d, 3H); MS (ESI) m / z=513.2 (M+H) +

[0146] Example 15: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone The title compound was prepared as a solid (2.10 mg) in a manner similar to Step 2 of Example 13, except 2-oxa-6-azaspiro[3.3]heptane (3.90 mg, 0.04 mmol) was used instead of pyrrolidine. 1H-NMR (CD3OD, 400 MHz) δ 8.28 (s, 1H), 8.28 (d, 1H), 8.12 (s, 3H), 8.02 (s, 1H), 6.72 (d, 1H), 4.82 (s, 4H), 4.67 (t, 1H), 4.46 (s, 4H), 4.23-4.17 (m, 2H), 3.81 (s, 3H), 2.23-2.08 (m, 2H), 1.41 (d, 3H); MS (ESI) m / z=463.2 (M+H) +

[0147] Example 16: (S)-N,N,1 1 ,6-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as a solid (9.80 mg) in a manner similar to Step 2 of Example 13, except methyl 1H-pyrrole-3-carboxylate (4.92 mg, 0.04 mmol) was used instead of pyrrolidine. 1 H-NMR (CD3OD, 400 MHz) δ 8.31 (s, 1H), 8.27 (d, 1H), 8.14 (s, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 6.70 (d, 1H), 4.64 (t, 1H), 4.22-4.19 (m, 2H), 3.79 (s, 3H), 3.11 (s, 6H), 2.18-2.11 (m, 2H), 1.41 (d, 3H); MS (ESI) m / z=409.2 (M+H) +

[0148] Example 17: ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-hydroxypyrrolidin-1-yl)methanone The title compound was prepared as a solid (1.80 mg) in a manner similar to Step 2 of Example 13, except 3-pyrrolidinol (3.43 mg, 0.04 mmol) was used instead of pyrrolidine. 1 H-NMR (CD3OD, 400 MHz) δ 8.33(s, 1H), 8.29 (d, 1H), 8.11 (s, 2H), 8.03 (s, 1H), 8.01 (s, 1H), 6.73 (d, 1H), 4.66 (t, 1H), 4.45 (s, 1H), 4.25-4.22 (m, 2H), 3.83-3.49 (m, 8H), 2.20-2.00 (m, 4H), 1.42 (d, 3H); MS (ESI) m / z=451.2 (M+H) +

[0149] Example 18: ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone The title compound was prepared as a solid (3.50 mg) in a manner similar to Step 2 of Example 13, except pyrrolidin-3-ylmethanol (3.98 mg, 0.04 mmol) was used instead of pyrrolidine. 1 H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 8.28 (d, 1H), 8.13 (s, 2H), 8.02 (s, 1H), 8.00 (s, 1H), 6.72 (d, 1H), 4.69 (t, 1H), 4.24-4.22 (m, 2H), 3.81 (s, 3H), 3.77-3.41 (m, 6H), 2.47 (s, 1H), 2.24-2.08 (m, 3H), 1.81-1.76 (m, 1H), 1.41 (d, 3H); MS (ESI) m / z=465.2 (M+H) +

[0150] Example 19: Methyl (S)-1 1 ,8-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate Step 1: Methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate A reaction mixture of methyl 4,6-dichloronicotinate (1000 mg, 4.854 mmol), (R)-4-aminobutan-2-ol (562.45 mg, 6.31 mmol), and DIPEA (2.11 mL, 12.134 mmol) in DMA (16.18 mL) was stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-40%) to produce methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate as a pale yellow solid (1010 mg, 3.904 mmol, yield: 80.44%). MS (ESI) m / z = 259.0 (M + H). +

[0151] Step 2: Methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate A reaction mixture of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (200 mg, 1.046 mmol) prepared in Preparation 8, (tributylphosphoranylidene)acetonitrile (0.686 mL, 2.615 mmol), and methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate (270.62 mg, 1.046 mmol) prepared in Step 1 in toluene (2 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and concentrated. The crude product was purified by flash column chromatography (EA / n-Hex=30-100%) to produce methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate as a pale yellow solid (171 mg, 0.396 mmol, yield: 37.85%). 1 H-NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.05 (s, 1H), 5.24-5.16 (m, 1H), 4.80 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.58 (q, 2H), 2.24-2.16 (m, 1H), 2.10-2.02 (m, 1H), 1.28 (d, 3H)

[0152] Step 3: Methyl (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate A suspension of tris(dibenzylideneacetone)dipalladium(0) (54.07 mg, 0.059 mmol), XPhos (56.3 mg, 0.118 mmol), cesium carbonate (384.77 mg, 1.181 mmol), and methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate (50 mg, 0.209 mmol) prepared in Step 2 in 1,4-dioxane (1.0 mL) was stirred at 90 °C for 2 h. The mixture was diluted with DCM, filtered through Celite, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-100%), slurried in EA / IPE for 0.5 h (room temperature), filtered, and purified to give methyl (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The -carboxylate was prepared as a pale yellow solid (64 mg, 0.162 mmol, yield: 41.12%). 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.50 (t, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.68 (brs, 1H), 6.39 (d, 1H), 5.48-5.41 (m, 1H), 4.07-4.00 (m, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.59-3.49 (m, 1H), 2.31-2.22 (m, 1H), 1.95-1.89 (m, 1H), 1.12 (d, 3H); MS (ESI) m / z=396.0 (M+H) +

[0153] Example 20: Methyl 1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate Step 1: Methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate The title compound was prepared as a white solid (1166 mg) in the same manner as in Step 1 of Example 19, except that 3-amino-2,2-dimethylpropan-1-ol (650.91 mg, 6.31 mmol) was used instead of (R)-4-aminobutan-2-ol. 1 H-NMR (CDCl3, 400 MHz) δ8.66 (s, 1H), 8.46 (s, 1H), 6.64 (s, 1H), 3.91 (s, 3H), 3.51 (d, 2H), 3.13 (d, 2H), 1.83 (t, 1H), 1.05 (s, 6H)

[0154] Step 2: Methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate The title compound was prepared as a white solid (382 mg) in the same manner as in Step 2 of Preparation 2, except that methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate (713.24 mg, 2.615 mmol) prepared in Step 1 was used instead of methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate. 1 H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.51 (s, 1H), 8.19 (d, 1H), 7.99 (s, 1H), 6.66 (s, 1H), 6.21 (d, 1H), 4.83 (s, 2H), 4.22 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.34 (d, 2H), 1.23 (s, 6H)

[0155] Step 3: Methyl 1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate The title compound was prepared as a white solid (49 mg) in the same manner as in Step 3 of Example 19, except that methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate (380 mg, 0.852 mmol) prepared in Step 2 was used instead of methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate. 1 H-NMR (CDCl3, 400 MHz) δ8.66 (s, 1H), 8.48 (t, 1H), 8.37 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 6.39 (d, 1H), 4.79 (brs, 1H), 4.21 (brs, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.54 (brs, 1H), 2.94 (brs, 1H), 1.41 (brs, 3H), 1.00 (brs, 3H); MS (ESI) m / z=410.0 (M + H) +

[0156] Example 21: ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (S)-1 prepared in Preparation Example 1 in DMF (1 mL) 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5A reaction mixture of (S)-1 carboxylic acid (30 mg, 0.0079 mmol), HATU (59.82 mg, 0.157 mmol), and DIPEA (30.5 mg, 0.236 mmol) was stirred at room temperature for 20 minutes, after which (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to give ((S)-1 carboxylic acid (30 mg, 0.0079 mmol). 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone was prepared as an off-white solid (7.2 mg, 0.014 mmol, 24% yield). 1 H-NMR (CDCl3, 400 MHz) δ 9.93 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 8.00 (brs, 1H), 7.92 (s, 1H), 6.80 (d, 1H), 4.79 (brs, 1H), 4.51-4.46 (m, 1H), 4.34-4.30 (m, 3H), 4.02-3.96 (m, 1H), 3.78 (s, 3H), 3.65-3.59 (m, 1H), 3.48-3.44 (m, 1H), 3.00 (s, 3H), 2.16-1.95 (m, 1H), 1.35 (d, 3H), 1.31 (d, 3H); MS (ESI) m / z=526.9 (M + H) +

[0157] Example 22: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methanone The title compound was prepared as an off-white solid (6.6 mg) in the same manner as in Example 21, except that 2-azaspiro[3.3]heptan-6-ol hydrochloride (15.69 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.30 (s, 1H), 8.26 (d, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.49 (s 1H), 6.38 (d, 1H), 4.78-4.73 (m, 1H), 4.29-4.22 (m, 5H), 4.11-4.06 (m, 1H), 3.82 (s, 3H), 2.67-2.62 (m, 2H), 2.21-2.16 (m, 3H), 1.46 (d, 3H); MS (ESI) m / z=476.9 (M + H) +

[0158] Example 23: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-fluoro-2-azaspiro[3.3]heptan-2-yl)methanone The title compound was prepared as an off-white solid (3.1 mg) in the same manner as in Example 21, except that 6-fluoro-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (24.04 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.31 (s, 1H), 8.25 (d, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.70 (s 1H), 6.38 (d, 1H), 5.08-4.88 (m, 1H), 4.78-4.72 (m, 1H), 4.32-4.21 (m, 4H), 4.08 (dd, 1H), 3.82 (s, 3H), 2.73-2.66 (m, 2H), 2.52-2.42 (m, 2H), 2.19-2.13 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=479.0 (M + H) +

[0159] Example 24: (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as an off-white solid (29 mg) in the same manner as in Example 21, except that 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (24.66 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 8.32 (s, 1H), 8.31 (d, 1H), 8.23 ​​(d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 6.38 (d, 1H), 5.89 (tt, 1H), 4.78-4.73 MS (ESI) m / z=485.0 (M + H) +

[0160] Example 25: (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as in Example 21, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (18 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give an off-white solid (27 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.32 (s, 1H), 8.31 (d, 1H), 8.24 (d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 6.38 (d, 1H), 4.79-4.73 (m, 1H), 4.47 (brs, 2H), 4.28-4.21 (m, 1H), 4.10-4.06 (m, 3H), 3.81 (s, 3H), 3.09-3.02 (m, 1H), 2.29-2.15 (m, 4H), 1.63 (t, 3H), 1.46 (d, 3H); MS (ESI) m / z=498.9 (M + H) +

[0161] Example 26: (S)-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl) (1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as in Example 21, except that 3-(2,2-difluoroethyl)-3-methylazetidine hydrochloride (18 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give an off-white solid (28 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.32 (s, 1H), 8.31 (d, 1H), 8.25 (d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 6.38 (d, 1H), 5.94 (tt, 1H), 4.76 (td, 1H), 4.28-4.01 (m, 6H), 3.81 (s, 3H), 2.27-2.14 (m, 4H), 1.47 (s, 3H), 1.46 (d, 3H); MS (ESI) m / z=498.9 (M + H) +

[0162] Example 27: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2-fluoropropan-2-yl)azetidin-1-yl)methanone The title compound was prepared as in Example 21, except that 3-(2-fluoropropan-2-yl)azetidine hydrochloride (16.11 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give an off-white solid (24 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.32 (s, 1H), 8.18 (d, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 6.38 (d, 1H), 4.77 (td, 1H), 4.27-4.21 (m, 5H), 4.11-4.06 (m, 1H), 3.82 (s, 3H), 2.87-2.73 (m, 1H), 2.22-2.11 (m, 2H), 1.46 (d, 3H), 1.39 (s, 3H), 1.33 (s, 3H); MS (ESI) m / z=481.0 (M + H) +

[0163] Example 28: (S)—N-(2-(3-fluoroazetidin-1-yl)ethyl)-1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as in Example 21, except that 2-(3-fluoroazetidin-1-yl)ethan-1-amine (12.39 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give a pale yellow solid (6.3 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.43 (d, 1H), 8.35 (d, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.64 (s, 1H), 6.71 (t, 1H), 6.38 (d, 1H), 5.25-5.05 (m, 1H), 4.74-4.69 (m, 1H), 4.26-4.20 (m, 1H), 4.07-4.03 (m, 1H), 3.81 (s, 3H), 3.79-70 (m, 2H), 3.45-3.40 (m, 2H), 3.31-3.22 (m, 2H), 2.81-2.74 (m, 2H), 2.15-2.11 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=481.9 (M + H) +

[0164] Example 29: (S)—N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as in Example 21, except that 2-(3,3-difluoroazetidin-1-yl)ethan-1-amine (14.28 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, as a pale yellow solid (8.8 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.42 (d, 1H), 8.34 (d, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 6.72 (t, 1H), 6.37 (d, 1H), 4.75-4.69 MS (ESI) m / z=500.0 (M + H) +

[0165] Example 30: (S)-N,1 1 ,6-trimethyl-N-((1-methylazetidin-3-yl)methyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as in Example 21, except that N-methyl-1-(1-methylazetidin-3-yl)methanamine dihydrochloride (19.62 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give a pale yellow solid (7.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.34 (d, 1H), 8.31 (s, 1H), 8.28 (d, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 6.38 (d, 1H), 4.79-4.74 (m, 1H), 4.40 (brs, 1H), 4.27-4.21 (m, 1H), 4.11-4.06 (m, 1H), 3.99 (brs, 1H), 3.82 (s, 3H), 2.93-2.82 (m, 1H), 2.59 (d, 2H), 2.45 (s, 6H), 2.19-2.14 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=478.0 (M + H) +

[0166] Example 31: (S)—N-(4-(dimethylamino)butyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide Instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, N 1 , N 1 The title compound was prepared as in Example 21, except that -dimethylbutane-1,4-diamine (9.14 mg, 0.079 mmol) was used, as a pale yellow solid (6.5 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.67 (d, 1H), 8.34 (d, 1H), 8.28 (s, 1H), 8.20-8.14 (m, 3H), 7.47 (brs, 1H), 6.37 (d, 1H), 4.79-4.74 (m, 1H), 4.27-4.21 (m, 1H), 4.11-4.06 (m, 1H), 3.82 (s, 3H), 3.41 (q, 2H), 2.36 (t, 2H), 2.25 (s, 6H), 2.17-2.14 (m, 2H), 2.07-2.02 (m, 1H), 1.69-1.63 (m, 3H), 1.47 (d, 3H); MS (ESI) m / z=480.9 (M + H) +

[0167] Example 32: (S)—N-(3-(dimethylamino)propyl)-N,1 1 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide Instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, N 1 ,N 1 ,N 3The title compound was prepared as in Example 21, except that -trimethylpropane-1,3-diamine (12.19 mg, 0.105 mmol) was used, as a pale yellow solid (19 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.33 (d, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 6.38 (d, 1H), 6.31 (d, 1H), 4.80-4.74 (m, 1H), 4.27-4.20 (m, 1H), 4.11-4.06 (m, 1H), 3.81 (s, 3H), 3.60-3.52 (m, 2H), 3.13 (s, 3H), 2.31-2.27 (m, 2H), 2.23 (s, 6H), 2.17-2.13 (m, 2H), 1.86-1.81 (m, 2H), 1.42 (d, 3H); MS (ESI) m / z=480.0 (M + H) +

[0168] Example 33: (S)—N-(3-(dimethylamino)-2,2-dimethylpropyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide Instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, N 1 ,N 1 The title compound was prepared as in Example 21, except that 1,2,2-tetramethylpropane-1,3-diamine (13.66 mg, 0.105 mmol) was used, to give the title compound as a pale yellow solid (33 mg). 1H-NMR (CDCl3, 400 MHz) δ 9.47 (s, 1H), 8.99 (d, 1H), 8.33 (d, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 6.37 (d, 1H), 4.81-4.75 MS (ESI) m / z=494.0 (M + H) +

[0169] Example 34: (S)-1 1 ,6-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as in Example 21, except that 2-(4-methylpiperazin-1-yl)ethan-1-amine (15.02 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, as a pale yellow solid (11.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.55 (d, 1H), 8.36 (d, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.55 (s, 1H), 6.74 (s, 1H), 6.37 (d, 1H), 4.77-4.72 (m, 1H), 4.28-4.22 (m, 1H), 4.09-4.05 (m, 1H), 3.81 (s, 3H), 3.52-3.48 (m, 2H), 2.64 (t, 2H), 2.62-2.47 (m, 6H), 2.31 (s, 3H), 2.17-2.13 (m, 2H), 1.47 (d, 3H); MS (ESI) m / z=507.0 (M + H) +

[0170] Example 35: (S)-1 1 ,6-dimethyl-N-(2-morpholinoethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as in Example 21, except that 2-morpholinoethan-1-amine (13.65 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, as a pale yellow solid (25.5 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H), 8.35 (d, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.77 (s, 1H), 6.78 (s, 1H), 6.37 (d, 1H), 4.77-4.71 MS (ESI) m / z=495.0 (M + H) +

[0171] Example 36: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)methanone The title compound was prepared as a pale yellow solid (3.5 mg) in the same manner as in Example 21, except that 6-methyl-2,6-diazaspiro[3.4]octane 2,2,2-trifluoroacetate (37.15 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1H-NMR (CDCl3, 400 MHz) δ 8.35-8.31 (m, 3H), 8.14 (s, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 6.38 (d, 1H), 4.79-4.74 (m, 1H), 4.26-4.23 (m, 5H), 4.11-4.06 (m, 1H), 3.82 (s, 3H), 2.77 (s, 2H), 2.60 (t, 2H), 2.37 (s, 3H), 2.17-2.14 (m, 4H), 1.46 (d, 3H); MS (ESI) m / z=490.0 (M + H) +

[0172] Example 37: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)methanone The title compound was prepared as in Example 21, except that 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (22.36 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give a pale yellow solid (3.4 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.35-8.26 (m, 3H), 8.14 (s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 6.39 (d, 1H), 4.79-4.74 (m, 1H), 4.26-4.23 (m, 1H), 4.11-3.97 (m, 4H), 3.82 (s, 3H), 3.69-3.65 (m, 1H), 2.31 (brs, 2H), 2.27 (s, 3H), 2.18-2.14 (m, 2H), 2.04-2.01 (m, 1H), 1.87-1.83 (m, 4H), 1.46 (d, 3H); MS (ESI) m / z=504.3 (M + H) +

[0173] Example 38: (S)-N-(1-(1 1 ,6-dimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide The title compound was prepared as in Example 21, except that N-(azetidin-3-yl)-N-methylmethanesulfonamide (17.22 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give a pale yellow solid (2.4 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37-8.33 (m, 2H), 8.15 (d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.56 (s, 1H), 6.39 (d, 1H), 4.78-4.71 (m, 2H), 4.54-4.38 (m, 4H), 4.29-4.23 (m, 1H), 4.12-4.08 (m, 1H), 3.82 (s, 3H), 3.01 (s, 3H), 2.85 (s, 3H), 2.19-2.14 (m, 2H), 1.47 (s, 3H); MS (ESI) m / z=528.2 (M + H) +

[0174] Example 39: (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as a pale yellow solid (38 mg) in the same manner as in Example 21, except that 3-(difluoromethoxy)azetidine hydrochloride (16.73 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.58 (s, 1H), 6.38 (d, 1H), 6.30 (t, 1H), 5.10-5.04 MS (ESI) m / z=486.9 (M + H) +

[0175] Example 40: (S)-(6-(difluoromethyl)-2-azaspiro[3.3]heptan-2-yl) (1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as a pale yellow solid (40.7 mg) in the same manner as in Example 21, except that 6-(difluoromethyl)-2-azaspiro[3.3]heptane hydrochloride (19.26 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.31 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 6.38 (d, 1H), 5.80 (td, 1H), 4.76 MS (ESI) m / z=510.9 (M + H) +

[0176] Example 41: (S)-1-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-3-methylbutan-2-one The title compound was prepared as in Example 21, except that 1-(azetidin-3-yl)-3-methylbutan-2-one (14.81 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, as a pale yellow solid (3.1 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.31 (s, 1H), 8.27 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.68 (s,1 H), 6.38 (d, 1H), 4.79-4.73 (m, 1H), 4.50 (brs, 2H), 4.27-4.21 (m, 1H), 4.11-4.06 (m, 1H), 3.91 (brs, 2H), 3.82 (s, 3H), 3.10-3.03 (m, 1H), 2.90 (d, 2H), 2.65-2.58 (m, 1H), 2.19-2.14 (m, 2H), 1.46 (d, 3H), 1.15 (d, 6H); MS (ESI) m / z=505.0 (M + H) +

[0177] Example 42: (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone The title compound was prepared as a pale yellow solid (0.9 mg) in the same manner as in Example 21, except that 1-(azetidin-3-yl)-N,N-dimethylmethanamine dihydrochloride (14.72 mg, 0.079 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.31 (s, 1H), 8.29 (d, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.46 (s,1 H), 6.38 (d, 1H), 4.79-4.74 (m, 1H), 441 (brs, 2H), 4.28-4.21 (m, 1H), 4.11-4.07 (m, 1H), 3.99 (brs, 2H), 3.82 (s, 3H), 2.91-2.85 (m, 1H), 2.59 (d, 2H), 2.26 (s, 6H), 2.19-2.14 (m, 2H), 2.06-2.01 (m, 1H), 1.46 (d, 3H); MS (ESI) m / z=478.0 (M + H) +

[0178] Example 43: ((S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (S)-1 prepared in Preparation Example 2 in DMF (1 mL) 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5A reaction mixture of (S)-1 carboxylic acid (30 mg, 0.079 mmol), HATU (59.82 mg, 0.157 mmol), and DIPEA (30.5 mg, 0.236 mmol) was stirred at room temperature for 20 minutes, after which (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to give ((S)-1 carboxylic acid (30 mg, 0.079 mmol). 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone was prepared as an off-white solid (20.4 mg, 0.039 mmol, yield: 49.25%). 1 H-NMR (CDCl3, 400 MHz) δ 8.36-8.31 (m, 3H), 8.24 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 6.37 (d, 1H), 5.45-5.42 (m, 1H), 4.99-4.92 (m, 1H), 4.46-4.35 (m, 2H), 4.03-3.95 (m, 1H), 3.75 (s, 3H), 3.48-3.31 (m, 4H), 2.99 (s, 3H), 2.27-2.19 (m, 1H), 1.97-1.1.91 (m, 1H), 1.45 (d, 3H), 1.11 (d, 3H); MS (ESI) m / z=526.9 (M + H) +

[0179] Example 44: (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as an off-white solid (13.1 mg) in the same manner as in Example 43, except that 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (9.25 mg, 0.039 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 8.42 (t, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 6.37 (d, 1H), 5.89 (tt, 1H), 5.44-5.37 (m, 1H), 4.48-4.46 (m, 2H), 4.05-3.94 (m, 2H), 3.76 (s, 3H), 3.51-3.45 (m, 1H), 3.04-2.97 (m, 1H), 2.31-2.20 (m, 3H), 1.96-1.90 (m, 1H), 1.11 (d, 3H); MS (ESI) m / z=484.9 (M + H) +

[0180] Example 45: (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as in Example 43, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (6.75 mg, 0.039 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give an off-white solid (13.4 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.42 (t, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 6.37 (d, 1H), 5.45-5.37 (m, 1H), 4.46 (brs, 2H), 4.02-3.94 (m, 3H), 3.76 (s, 3H), 3.51-3.44 (m, 1H), 3.09-3.02 (m, 1H), 2.29-2.19 (m, 3H), 1.96-1.90 (m, 1H), 1.63 (t, 3H), 1.11 (d, 3H); MS (ESI) m / z=498.9 (M + H) +

[0181] Example 46: ((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl) (1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone 1 prepared in Preparation Example 3 in DMF (1 mL) 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 A reaction mixture of 1-methyl-3-(methylsulfonylmethyl)azetidin-1-yl azetidine (19.61 mg, 0.152 mmol) and 1-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (20 mg, 0.051 mmol), HATU (38.46 mg, 0.101 mmol), and DIPEA (19.61 mg, 0.152 mmol) was stirred at room temperature for 20 minutes, and then (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (10.1 mg, 0.051 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to give ((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)azetidine (1 1 ,7,7-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone was prepared as an off-white solid (18.7 mg, 0.035 mmol, yield: 68.39%). 1 H-NMR (CDCl3, 400 MHz) δ 8.34-8.28 (m, 3H), 8.15 (s, 1H), 8.02 (s, 1H), 7.85 (brs, 1H), 6.37 (d, 1H), 4.97-4.90 (m, 1H), 4.77 (brs, 1H), 4.45-4.34 (m, 2H), 4.13 (brs, 1H), 3.83 (s, 3H), 3.51 (brs, 1H), 3.40-3.3.27 (m, 3H), 2.97 (s, 3H), 2.85 (brs, 1H), 1.43 (d, 3H), 1.35 (brs, 3H), 1.00 (brs, 3H); MS (ESI) m / z=540.9 (M + H) +

[0182] Example 47: (3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as an off-white solid (7.8 mg) in the same manner as in Example 46, except that 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (8.92 mg, 0.038 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. 1H-NMR (CDCl3, 400 MHz) δ 8.46 (t, 1H), 8.36 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.42 (s, 1H), 6.38 (d, 1H), 5.90 (tt, 1H), 4.77 (brs, 1H), 4.48 (brs, 2H), 4.13 (brs, 1H), 4.05 (brs, 2H), 3.86 (s, 3H), 3.54 (brs, 1H), 3.05-2.98 (m, 1H), 2.91 (brs, 1H), 2.31-2.20 (m, 2H), 1.37 (brs, 3H), 1.01 (brs, 3H); MS (ESI) m / z=498.9 (M + H) +

[0183] Example 48: (3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as in Example 46, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (6.51 mg, 0.038 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride, to give an off-white solid (6.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.46 (t, 1H), 8.36 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.43 (s, 1H), 6.38 (d, 1H), 4.78 (brs, 1H), 4.47 (brs, 2H), 4.14 (brs, 1H), 4.03 (brs, 2H), 3.86 (s, 3H), 3.53 (brs, 1H), 3.10-3.03 (m, 1H), 2.90 (brs, 1H), 2.30-2.20 (m, 2H), 1.64 (t, 3H), 1.37 (brs, 3H), 1.01 (brs, 3H); MS (ESI) m / z=512.9 (M + H) +

[0184] Example 49: (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone Step 1: Methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate The title compound was prepared as an off-white solid (927 mg) in the same manner as in Step 1 of Preparation 1, except that methyl 4,6-dichloronicotinate (1000 mg, 4.854 mmol) prepared in Step 1 was used instead of ethyl 4,6-dichloronicotinate. MS (ESI) m / z=258.9 (M + H)+

[0185] Step 2: Methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate The title compound was prepared as an off-white solid (290 mg) in the same manner as in Step 2 of Preparation 1, except that methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (252.12 mg, 0.975 mmol) and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (200 mg, 0.975 mmol) prepared in Step 1 were used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.21 (d, 1H), 8.17 (d, 1H), 6.65 (s, 1H), 6.21 (d, 1H), 4.84 (s, 2H), 4.38-4.25 (m, 2H), 3.95-3.90 (m, 1H), 3.88 (s, 3H), 3.66 (s, 3H), 2.48 (3H), 2.12-2.02 (m, 2H), 1.35 (d, 3H)

[0186] Step 3: Methyl (S)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate The title compound was prepared as an off-white solid (927 mg) in the same manner as in Step 3 of Preparation 1, except that methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (290 mg, 0.65 mmol) prepared in Step 2 was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate. MS (ESI) m / z=410.0 (M + H)+

[0187] Step 4: (S)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Ethyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5Instead of the -carboxylate, the methyl (S)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The title compound was prepared as in Step 4 of Preparation 1, except that 1,4-dicarboxylate (55 mg, 0.134 mmol) was used, as an off-white solid (42 mg). MS (ESI) m / z=396.0 (M + H)+

[0188] Step 5: (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone (S)-1 prepared in step 4 in DMF (1 mL) 1 ,1 3, 6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 A reaction mixture of (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)-azetidine (1,2,2-trifluoroacetate) (11.89 mg, 0.051 mmol), HATU (38.46 mg, 0.101 mmol), and N,N-diisopropylethylamine (19.61 mg, 0.152 mmol) was stirred at room temperature for 20 minutes, and then 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (11.89 mg, 0.051 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to give (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)azetidine (1,2,2-trifluoroacetate). 1 ,1 3 ,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone was prepared as an off-white solid (10 mg, 0.02 mmol, 39.66%). 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (d, 1H), 8.24 (s, 1H), 8.23 ​​(d, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 6.36 (d, 1H), 5.89 (tt, 1H), 4.76 (t, 1H), 4.48 (brs, 2H), 4.26-4.20 (m, 1H), 4.03-3.99 (m, 3H), 3.75 (s, 3H), 3.04-2.97 (m, 1H), 2.59 (s, 3H), 2.31-2.18 (m, 3H), 2.12-2.09 (m, 1H), 1.45 (d, 3H); MS (ESI) m / z=499.0 (M + H)+

[0189] Example 50: (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as in Example 49, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (8.68 mg, 0.051 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate, to give an off-white solid (12.9 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (d, 1H), 8.25 (d, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.77-7.70 (m, 1H), 6.36 (d, 1H), 4.77 (t, 1H), 4.47 (brs, 2H), 4.25-4.20 (m, 1H), 4.03-3.99 (m, 3H), 3.75 (s, 3H), 3.09-3.02 (m, 1H), 2.59 (s, 3H), 2.30-2.18 (m, 3H), 2.12-2.07 (m, 1H), 1.63 (t, 3H), 1.45 (d, 3H); MS (ESI) m / z=513.0 (M + H) +

[0190] Example 51: (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone Step 1: (6-chloro-4-fluoropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone A reaction mixture of 4,6-dichloronicotinic acid (150 mg, 0.0781 mmol), HATU (594.12 mg, 1.562 mmol), and DIPEA (0.41 mL, 2.344 mmol) in DMF (1.57 mL) was stirred at room temperature for 20 minutes, after which 3-(difluoromethoxy)azetidine hydrochloride (124.66 mg, 0.781 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-60%) to produce (6-chloro-4-fluoropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone as a yellow liquid (58 mg, 0.195 mmol, yield: 24.99%). 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 7.45 (s, 1H), 6.27 (t, 1H), 5.10-5.04 (m, 1H), 4.55-4.51 (m, 1H), 4.28-4.23 (m, 2H), 4.12-4.09 (m, 1H)

[0191] Step 2: (S)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone The title compound was prepared as an off-white solid (39 mg) in the same manner as in Step 1 of Preparation 1, except that (6-chloro-4-fluoropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone (56 mg, 0.188 mmol) prepared in Step 1 was used instead of 4,6-dichloronicotinate. MS (ESI) m / z=349.9 (M + H) +

[0192] Step 3: (S)-(4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone The title compound was prepared as an off-white solid (42 mg) in the same manner as in Step 2 of Preparation 1, except that (S)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone (37.49 mg, 0.107 mmol) prepared in Step 2 and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (22 mg, 0.107 mmol) prepared in Preparation 9 were used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.23 ​​(d, 1H), 8.05 (s, 1H), 7.98 (d, 1H), 6.64 (s, 1H), 6.28 (t, 1H), 6.22 (d, 1H), 5.02-5.01 (m, 1H), 4.80 (s, 2H), 4.52-4.48 (m, 2H), 4.40-4.25 (m, 4H), 3.86-3.82 (m, 1), 3.67 (s, 3H), 2.49 (s, 3H), 2.11-2.03 (m, 2H), 1.35 (d, 3H)

[0193] Step 4: (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone The title compound was prepared as an off-white solid (14.6 mg) in the same manner as in Step 3 of Preparation 1, except that (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone (40 mg, 0.074 mmol) prepared in Step 3 was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 6.36 (d, 1H), 6.30 (t, 1H), 5.09-5.04 (m, 1H), 4.76 MS (ESI) m / z=500.9 (M + H) +

[0194] Example 52: (S)—N-(2,2-difluoroethyl)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide Step 1: 4-amino-6-chloro-N-(2,2-difluoroethyl)nicotinamide To a solution of 4,6-dichloronicotinic acid (200 mg, 1.04 mmol) in DMA (5 mL) was added HATU (594.1 mg, 1.56 mmol), and the reaction mixture was stirred at room temperature for 15 minutes. 2,2-Difluoroethylamine (103.7 mg, 1.04 mmol) and DIPEA (0.54 mL, 3.13 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (EA / n-Hex = 10-60%) to produce 4-amino-6-chloro-N-(2,2-difluoroethyl)nicotinamide as a white solid (139.1 mg, 0.55 mmol, yield: 52.4%). 1 H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 7.47 (s, 1H), 6.61 (brs, NH), 6.02 (td, 1H), 3.93-3.85 (m, 2H)

[0195] Step 2: (S)-6-chloro-N-(2,2-difluoroethyl)-4-((4-hydroxybutan-2-yl)amino)nicotinamide The title compound was prepared as a white solid (97 mg) in the same manner as in Step 1 of Example 19, except that 4-amino-6-chloro-N-(2,2-difluoroethyl)nicotinamide (139.1 mg, 0.55 mmol) prepared in Step 1 and (S)-3-aminobutan-1-ol (58.3 mg, 0.65 mmol) were used instead of methyl-4,6-dichloronicotinate and (R)-4-aminobutan-2-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.21-8.19 (m, 2H), 7.29 (brs, 1H), 6.62 (s, 1H), 5.97 (td, 1H), 3.79 (m, 5H), 2.46 (s, 1H), 1.86-1.81 (m, 2H), 1.29 (d, 3H); MS (ESI) m / z=308.1 (M + H) +

[0196] Step 3: (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloro-N-(2,2-difluoroethyl)nicotinamide The title compound was prepared as an off-white solid (126 mg) in the same manner as in Step 2 of Example 19, except that (S)-6-chloro-N-(2,2-difluoroethyl)-4-((4-hydroxybutan-2-yl)amino)nicotinamide (96.8 mg, 0.31 mmol) and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (64.6 mg, 0.31 mmol) prepared in Step 2 were used instead of methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol prepared in Preparation Example 8. 1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 8.20 (d, 2H), 6.65 (s, 1H), 6.57 (m, 1H), 6.21 (d, 1H), 5.81 (td, 1H), 4.78 (brs, 2NH), 4.36-4.29 (m, 2H), 3.88-3.75 (m, 3H), 3.67 (s, 3H), 2.49 (s, 3H), 2.07 (m, 2H), 1.34 (d, 3H); MS (ESI) m / z=495.2 (M + H) +

[0197] Step 4: (S)-N-(2,2-difluoroethyl)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide The title compound was prepared as an off-white solid (28 mg) in the same manner as in Step 3 of Example 19, except that (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloro-N-(2,2-difluoroethyl)nicotinamide (126.2 mg, 0.25 mmol) prepared in Step 3 was used instead of methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate. 1 H-NMR (CDCl3, 400 MHz) δ 8.42-8.40 (m, 2H), 8.23 ​​(d, 2H), 7.25 (s, 1H), 6.36 (d, 1H), 6.26-6.23 (m, 1H), 5.99 (td, 1H), 4.75 (t, 1H), 4.26-4.25 (m, 1H), 4.04-4.01 (m, 1H), 3.87 (m, 2H), 3.76 (s, 3H), 2.60 (s, 3H), 2.22-2.07 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=459.2 (M + H) +

[0198] Example 53: (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone Step 1: (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol To a solution of (3R)-butane-1,3-diol (10.0 g, 110.96 mmol) and imidazole (9.8 g, 144.25 mmol) in DCM (100 mL) was added tert-butyldimethylchlorosilane (18.4 g, 122.06 mmol) at 0 °C, and the reaction mixture was stirred overnight while gradually warming to room temperature. The reaction mixture was diluted with DCM and washed with saturated brine. The organic layer was collected, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-40%) to produce (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol as a colorless oil (21.25 g, 103.97 mmol, yield: 93.7%). 1 H-NMR (CDCl3, 400 MHz) δ 4.07-4.03 (m, 1H), 3.93-3.89 (m, 1H), 3.87-3.83 (m, 1H), 3.39 (s, OH), 1.68-1.66 (m, 2H), 1.22 (d, 3H), 0.93 (s, 9H), 0.11 (s, 6H)

[0199] Step 2: Methyl (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-chloronicotinate To a mixture of methyl 6-chloro-4-hydroxypyridine-3-carboxylate (2.0 g, 10.66 mmol), (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (2.6 g, 12.79 mmol) prepared in Step 1, and triphenylphosphine (4.2 g, 15.99 mmol) in THF (45 mL), diisopropyl azodicarboxylate (40% in toluene, 8.98 mL, 17.06 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and then purified by column chromatography (EA / n-Hex = 0-10%) to produce methyl (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-chloronicotinate as a colorless oil (3.9 g, 10.40 mmol, yield: 97.6%). 1 H-NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 7.01 (s, 1H), 4.83-4.78 (m, 1H), 3.91 (s, 3H), 3.83-3.72 (m, 2H), 2.07-2.01 (m, 1H), 1.87-1.82 (m, 1H), 1.44 (d, 3H), 0.89 (s, 9H), 0.02 (s, 6H); MS (ESI) m / z=374.2 (M + H) +

[0200] Step 3: Methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)oxy)nicotinate To a solution of methyl (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-chloronicotinate (3.8 g, 10.03 mmol) prepared in Step 2 in THF (60 mL) was added tetrabutylammonium fluoride (1 M in THF, 20.06 mL, 20.06 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DMC, washed with water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-70%) to produce methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)oxy)nicotinate as a colorless oil (1.8 g, 6.96 mmol, yield: 69.4%). 1 H-NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 6.94 (s, 1H), 4.82-4.80 (m, 1H), 3.89 (s, 3H), 3.78-3.77 (m, 1H), 3.60-3.58 (m, 1H), 2.05-2.03 (m, 2H), 1.43 (d, 3H); MS (ESI) m / z=260.1 (M + H) +

[0201] Step 4: Methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)oxy)-6-chloronicotinate The title compound was prepared as a light brown foam (587 mg) in the same manner as in Step 2 of Preparation 1, except that methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)oxy)nicotinate (500 mg, 1.93 mmol) prepared in Step 3 and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (200 mg, 0.98 mmol) prepared in Preparation 9 were used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 8.13 (d, 1H), 6.92 (s, 1H), 6.16 (d, 1H), 5.09 (brs, 2NH), 4.83-4.82 (m, 1H), 4.35-4.34 (m, 2H), 3.81 (s, 3H), 3.58 (s, 3H), 2.41 (s, 3H), 2.20-2.16 (m, 2H), 1.42 (d, 3H); MS (ESI) m / z=447.1 (M + H) +

[0202] Step 5: Methyl (S)-1 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate To a solution of methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)oxy)-6-chloronicotinate (587 mg, 1.31 mmol) prepared in step 4 in 1,4-dioxane (6 mL) was added tris(dibenzylideneacetone)dipalladium(0) (241 mg, 0.26 mmol), XPhos (250 mg, 0.53 mmol), and cesium carbonate (1.3 g, 3.94 mmol). The reaction mixture was stirred at 120°C for 2 h. The reaction mixture was diluted with DCM, filtered through Celite, and then concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=40-100%) and triturated with EA / isopropyl ether to give methyl (S)-1 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The -carboxylate was prepared as a white solid (168 mg, 0.41 mmol, yield: 31.2%). 1H-NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.70 (s, 1H), 8.44 (d, 1H), 7.51 (s, 1H), 6.41 (d, 1H), 5.18-5.20 (m, 1H), 4.77 (t, 1H), 4.08-4.06 (m, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 2.61 (s, 3H), 2.40-2.30 (m, 2H), 1.58 (d, 3H); MS (ESI) m / z=411.2 (M + H) +

[0203] Step 6: (S)-1 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylic acid Methyl (S)-1 prepared in step 5 in THF (2 mL), water (0.5 mL), and methanol (0.5 mL) 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 To a solution of (S)-1, 2-carboxylate (55 mg, 0.13 mmol) was added 3N NaOH (447.8 μL, 1.34 mmol). The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled, concentrated, dissolved in water, acidified to pH 1-2 with 9N HCl, and stirred for 30 min. The resulting solid was filtered and dried in vacuo to give (S)-1. 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The -carboxylic acid was prepared as a pale yellow solid (35 mg, 0.09 mmol, yield: 72.7%). 1H-NMR (DMSO-d6, 400 MHz) δ 10.5 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.40 (d, 1H), 6.84 (d, 1H), 5.01-4.99 (m, 1H), 4.52 (m, 1H), 4.27-4.25 (m, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 2.25-2.24 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=397.2 (M + H) +

[0204] Step 7: (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Il)methanone (S)-1 prepared in step 6 in DMF (1 mL) 1 ,1 3 ,6-trimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 To a solution of (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)-(1-methyl-2-propanol)-carboxylic acid (35 mg, 0.09 mmol), HATU (67 mg, 0.18 mmol) and N,N-diisopropylethylamine (46.3 μL, 0.27 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, and then 3-(2,2-difluoropropyl)azetidine hydrochloride (15 mg, 0.09 mmol) was added. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (MeOH / EA=0-10%) and stirred in EA / n-Hex for 1 hour to give (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)-(1-methyl-2-propanol). 1 ,1 3 ,6-trimethyl-1 1H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone was prepared as an off-white solid (18.8 mg, 0.04 mmol, yield: 41.3%). 1 H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.43 (d, 1H), 8.21 (d, 1H), 7.74 (s, 1H), 6.44 (d, 1H), 5.22-5.20 (m, 1H), 4.76 (t, 1H), 4.40-4.38 (m, 1H), 4.23-4.17 (m, 1H), 4.08-4.05 (m, 1H), 3.91-3.90 (m, 2H), 3.77 (s, 3H), 3.00-2.95 (m, 1H), 2.61 (s, 3H), 2.29-2.21 (m, 4H), 1.67-1.57 (m, 6H); MS (ESI) m / z=514.2 (M + H) +

[0205] Biological assays 1. Biochemical EGFR Inhibition Assay Biochemical EGFR kinase assays were performed using Perkin-Elmer's Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology. Compounds of the present invention were first diluted to 20 mM in 100% DMSO for storage and then added to kinase buffer to yield compound concentrations ranging from 0.003 μM to 10 μM.

[0206] Briefly, wild-type (EGFR WT), double mutants [del19 / C797S (EGFR D19CS) and L858R / C797S (EGFR LRCS)], triple mutants [del19 / T790M / C797S (EGFR D19TMCS) and L858R / T790M / C797S (EGFR LRTMCS)] of each EGFR enzyme, serially diluted EGFR inhibitors, ULight-poly-GT peptide substrate (PerkinElmer; TRF0100-M), and different concentrations of ATP (Km and final assay concentration of 100 μM) were mixed in kinase assay buffer (50 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, and 0.01% Tween-20) and plated in a 384-well plate (Optiplate TM 384, white, PerkinElmer; 6007290).

[0207] Each kinase reaction was incubated for 1 hour at room temperature and then stopped by adding 4 μL of stop solution (10 mM EDTA). A specific europium-labeled anti-phosphopeptide antibody (PerkinElmer, AD0069) diluted in LANCE detection buffer was then added to a final concentration of 2 nM. After 60 minutes of incubation at room temperature, the LANCE signal was measured using an EnVision Multilabel Reader (Perkin-Elmer). The excitation wavelength was set to 320 nm, and emission was monitored at 615 nm (donor) and 665 nm (acceptor). IC 50 Values ​​were determined using GraphPad Prism software (GraphPad Software, Inc., San Diego, CA, USA).

[0208] IC of compounds of formula (I) for the activity of each EGFR kinase assessed as above 50 The values ​​are shown in Tables 3 and 4 below. Legend: A=IC 50 < 10 nM B=10nM ≦ IC 50 < 100nM C=100nM ≦ IC 50 < 1000nM D= IC 50 ≧ 1000nM

[0209] [Table 3]

[0210] [Table 4]

[0211] As shown by the above results, the macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moiety or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against EGFR triple / double mutants.

[0212] 2. Kinase selectivity Biochemical selectivity kinase assays were performed using Perkin-Elmer's Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology. Compounds of the present invention were first diluted to 20 mM in 100% DMSO for storage and then added to kinase buffer to yield compound concentrations ranging from 0.003 μM to 10 μM.

[0213] Briefly, each EGFR enzyme (LCK, JAK2, FLT3, HGK (MAP4K4), IRAK4), serially diluted EGFR inhibitors, ULight peptide substrates (JAK1, TK, GT, and p70S6K, PerkinElmer), and different concentrations of ATP (Km and 1 mM final assay concentration) were mixed in kinase assay buffer (50 mM HEPES pH 7.4, 10 mM MgCl, 1 mM EGTA, 10 mM MnCl, 2 mM DTT, and 0.01% Tween-20) and plated in a 384-well plate (Optiplate TM 384, white, PerkinElmer; 6007290).

[0214] Each kinase reaction was incubated for 1 hour at room temperature and then stopped by adding 4 μL of stop solution (10 mM EDTA). A specific europium-labeled anti-phosphopeptide antibody (PerkinElmer, AD0069) diluted in LANCE detection buffer was then added to a final concentration of 2 nM. After 60 minutes of incubation at room temperature, the LANCE signal was measured using an EnVision Multilabel Reader (Perkin-Elmer). The excitation wavelength was set to 320 nm, and emission was monitored at 615 nm (donor) and 665 nm (acceptor). IC 50 Values ​​were determined using GraphPad Prism software (GraphPad Software, Inc., San Diego, CA, USA).

[0215] [Table 5]

[0216] As shown by the above results, the compounds of the present invention exhibit excellent kinase selectivity.

[0217] 3.Pharmacokinetic studies The pharmacokinetics and oral bioavailability of test compounds were evaluated in mice after single intravenous and oral administration. Test compounds were dissolved in 5% DMSO:5% solutol-ethanol (1:1) and 90% saline and administered intravenously at a dose of 1 mg / 5 mL / kg. Test compounds were suspended or dissolved in 0.5% methylcellulose containing 0.2% Tween 80 or 50% polyethylene glycol 400 and administered orally at a dose of 3 mg / 10 mL / kg. Blood samples were collected from mice at designated times using a composite sampling design (two times per animal, n = 3 per time point). Plasma was separated from the blood samples after centrifugation. The concentration of the test compound in each sample was analyzed to obtain a plasma concentration profile. Oral bioavailability was calculated using the following formula: JPEG2026507653000013.jpg15144

[0218] The compounds of the present invention exhibit excellent oral bioavailability along with improved pharmacokinetic properties.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R １ is hydrogen or C １－３ is alkyl, R ２ teeth, C １－６ Alkoxy; C optionally substituted with one or more substituents selected from the group consisting of OH and halogen ３－６ cycloalkyl; Hydroxy, halogen, C １－６ Alkyl, hydroxy-C １－６ Alkyl, C substituted with one or more halogens １－６ Alkyl, C １－６ Alkoxy, C substituted with one or more halogens １－６ Alkoxy, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C １－６ Alkylcarbonylmethyl, and mono- or di-C １－６ 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkylaminomethyl; and -NR ３ R ４ (where R ３ and R ４ are each independently hydrogen, C optionally substituted with one or more halogens １－６ Alkyl, mono- or di-(C １－６ Alkyl)amino-C １－６ alkyl, or 3- to 7-membered heterocyclyl-C １－３ alkyl (wherein 3- to 7-membered heterocyclyl is substituted with halogen and C １－６ and optionally substituted with one or more substituents selected from the group consisting of alkyl. is selected from the group consisting of L is a linear or branched C ３－６ It is alkylene.

2. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

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

4. R ２ But C １－６ Alkoxy; C ３－６ Cycloalkyl; hydroxy, halogen, C １－６ Alkyl, hydroxy-C １－６ Alkyl, C substituted with one or more halogens １－６ Alkyl, C substituted with one or more halogens １－６ Alkoxy, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C １－６ Alkylcarbonylmethyl, and mono- or di-C １－６ a 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkylaminomethyl; or -NR ３ R ４ 2. The compound of claim 1, wherein:

5. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the 3- to 7-membered heterocyclyl is selected from the group consisting of pyrrolidine, azetidine, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.3]hexane, 2,6-diazaspiro[3.4]octane, and 2,7-diazaspiro[3.5]nonane.

6. R ３ and R ４ are independently hydrogen, C １－６ Alkyl, halo-C １－６ Alkyl, or di-(C １－６ Alkyl)amino-C １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

7. R ３ is hydrogen or C １－６ alkyl, and R ４ but halogen and C １－６ 3- to 7-membered heterocyclyl-C optionally substituted with one or more substituents selected from the group consisting of alkyl １－３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

8. 3- to 7-membered heterocyclyl-C １－３ The alkyl is azetidinyl-C １－３ Alkyl, piperazinyl-C １－３ Alkyl, and morpholinyl-C １－３ 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is n-propylene, 1-methylpropylene, 3-methylpropylene, 2,2-dimethylpropylene, or n-butylene.

10. (1) (S)-Cyclopropyl(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (2) Cyclopropyl(1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4 5 -yl)methanone; (3) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (4) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (5) (S)-1-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-N,N-dimethylmethanesulfonamide; (6) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (7) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (8) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (9) (S)-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (10) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2,2,2-trifluoroethyl)azetidin-1-yl)methanone; (11) Cyclopropyl(1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (12) Methyl (S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate; (13) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(pyrrolidin-1-yl)methanone; (14) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (15) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (16) (S)-N,N,1 1 ,6-Tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (17) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-hydroxypyrrolidin-1-yl)methanone; (18) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone; (19) Methyl (S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate; (20) Methyl 1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxylate; (21) ((S)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (22) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methanone; (23) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-fluoro-2-azaspiro[3.3]heptan-2-yl)methanone; (24) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (25) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (26) (S)-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (27) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-(2-fluoropropan-2-yl)azetidin-1-yl)methanone; (28) (S)-N-(2-(3-fluoroazetidin-1-yl)ethyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (29) (S)-N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (30) (S)-N,1 1 ,6-trimethyl-N-((1-methylazetidin-3-yl)methyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (31) (S)-N-(4-(dimethylamino)butyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (32) (S)-N-(3-(dimethylamino)propyl)-N,1 1 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (33) (S)-N-(3-(dimethylamino)-2,2-dimethylpropyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (34) (S)-1 1 ,6-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (35) (S)-1 1 ,6-dimethyl-N-(2-morpholinoethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamides; (36) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)methanone; (37) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (38) (S)-N-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide; (39) (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (40) (S)-(6-(difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (41) (S)-1-(1-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carbonyl)azetidin-3-yl)-3-methylbutan-2-one; (42) (S)-(1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone; (43) ((S)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone; (44) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (45) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (46) ((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (47) (3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (48) (3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,7,7-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (49) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (50) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; (51) (S)-(3-(difluoromethoxy)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone; and (52) (S)-N-(2,2-difluoroethyl)-1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -Carboxamide 2. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone or a pharmaceutically acceptable salt thereof.

12. (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)methanone or a pharmaceutically acceptable salt thereof.

13. 13. A method of treating a protein kinase mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. 14. The method of claim 13, wherein the protein kinase-mediated disease is cancer or an immune disease.

15. 15. The method of claim 14, wherein the cancer is bladder cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, uterine cancer, heart cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, lymphoma, pancreatic cancer, head and neck cancer, thyroid cancer, prostate cancer, skin cancer, or a blood tumor.

16. 15. The method of claim 14, wherein the cancer is lung cancer.

17. 15. The method of claim 14, wherein the cancer is non-small cell lung cancer.

18. 13. A method of selectively inhibiting at least one mutant form of EGFR in a biological sample or in a patient, the method comprising contacting the biological sample with a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or administering to a patient a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

19. 19. The method of claim 18, wherein the at least one mutation is at least one single mutation selected from the group consisting of EGFR Del19 (Del E746-A750) and EGFR L858R.

20. 19. The method of claim 18, wherein the at least one mutant is at least one double mutant selected from the group consisting of EGFR Del19 / T790M, EGFR Del19 / C797S, EGFR Del19 / C797X (X=G, N), EGFR Del19 / L792X (X=F, H, P, R, V, Y), EGFR Del19 / L718X (X=Q, V), EGFR L858R / T790M, EGFR L858R / C797S, EGFR L858R / C797X (X=G, N), EGFR L858R / L792X (X=F, H, P, R, V, Y), and EGFR L858R / L718X (X=Q, V).

21. 19. The method of claim 18, wherein the at least one mutant is at least one double mutant selected from the group consisting of EGFR Del19 / C797S and EGFR L858R / C797S.

22. The at least one mutant is selected from the group consisting of EGFR Del19 / T790M / C797S, EGFR Del19 / T790M / C797X (X=G, N), EGFR Del19 / T790M / L792X (X=F, H, P, R, V, Y), EGFR Del19 / T790M / L718X (X=Q, V), EGFR L858R / T790M / C797S, EGFR L858R / T790M / C797X (X=G, N), EGFR L858R / T790M / L792X (X=F, H, P, R, V, Y), and EGFR 19. The method of claim 18, wherein the mutant is at least one triple mutant selected from the group consisting of L858R / T790M / L718X (X = Q, V).

23. 19. The method of claim 18, wherein the at least one mutant is at least one triple mutant selected from the group consisting of EGFR Del19 / T790M / C797S and EGFR L858R / T790M / C797S.

24. A pharmaceutical composition for treating a protein kinase-mediated disease, comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

25. 25. The pharmaceutical composition of claim 24, wherein the protein kinase-mediated disease is cancer or an immune disease.

26. 26. The pharmaceutical composition of claim 25, wherein the cancer is bladder cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, uterine cancer, heart cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, lymphoma, pancreatic cancer, head and neck cancer, thyroid cancer, prostate cancer, skin cancer, or blood tumor.

27. A pharmaceutical composition for selectively inhibiting at least one mutant of EGFR compared to wild-type EGFR, comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

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