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 are being 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, novel EGFR-TKIs that are potently effective against EGFR triple / double mutations are urgently needed.

[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 and R2 are each independently hydrogen or C optionally substituted with one or more halogens. 1-6 is alkyl, A is a 5-10 membered heteroaryl; R3 and R4 are independently hydrogen; halogen; Halogen, hydroxy, and halogen, hydroxy, C1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C optionally substituted with one or more halogens 1-6 Alkoxy, -CH2-S(O)2-C 1-6 C optionally substituted with alkyl, oxo, and one or more OH 3-6 C optionally substituted with one or more substituents selected from the group consisting of 4- to 8-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 alkyl; C optionally substituted with one or more halogens 1-6 Alkoxy; -S(O)2-C 1-6 alkyl; Halogen, C optionally substituted with one or more halogens 1-6 Alkyl, and mono- or di-(C 1-6 4-8 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of (alkyl)amino; Halogen, C 1-6 Alkyl, and halo-C 1-6 -O-4 to 8 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl; or Halogen and C optionally substituted with one or more halogens 1-6 -NHC optionally substituted with one or more substituents selected from the group consisting of alkoxy 3-6 is cycloalkyl, L is a linear or branched C 2-6 alkylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene; R5 is hydrogen or C 1-6 is alkyl, R6 and R7 are, independently of each other, hydrogen, halogen, or halo-C 1-6is alkyl, X1 is CH or N.

[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, C1-6 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, "alkenyl" refers to an aliphatic hydrocarbon radical containing at least one carbon-carbon double bond, and includes both straight-chain and branched-chain hydrocarbon radicals. Non-limiting examples of "alkenyl" are vinyl, allyl, but-1-enyl, or but-2-enyl.

[0020] As used herein, "alkynyl" refers to an aliphatic hydrocarbon radical containing at least one carbon-carbon triple bond, and includes both straight-chain and branched-chain hydrocarbon radicals. Non-limiting examples of "alkynyl" are ethynyl, propargyl, but-1-ynyl, or but-2-ynyl.

[0021] 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.

[0022] 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.

[0023] As used herein, the terms "hydroxy" or "hydroxyl," alone or in combination with other terms, mean --OH.

[0024] 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.

[0025] As used herein, "amino" refers to --NH.sub.2.

[0026] 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.

[0027] 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).

[0028] As used herein, "heteroaryl" refers to a monovalent or divalent substituent derived from a mono- or polyheterocyclic aromatic hydrocarbon having 1 to 10 carbon ring members and containing one or more, preferably 1 to 3, heteroatoms selected from N, O, and S. Examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furopyridinyl, and the like. Unless otherwise defined, heteroaryl is a 4- to 12-membered heteroaryl, preferably a 4- to 10-membered heteroaryl, and more preferably a 4- to 7-membered heteroaryl.

[0029] 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.

[0030] 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.

[0031] The present invention also provides pharmaceutical compositions comprising at least one compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.

[0032] 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.

[0033] 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 and R2 are each independently hydrogen or C optionally substituted with one or more halogens. 1-6 is alkyl, A is a 5-10 membered heteroaryl; R3 and R4 are independently hydrogen; halogen; Halogen, hydroxy, and halogen, hydroxy, C1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C optionally substituted with one or more halogens 1-6 Alkoxy, -CH2-S(O)2-C 1-6 C optionally substituted with alkyl, oxo, and one or more OH 3-6 C optionally substituted with one or more substituents selected from the group consisting of 4- to 8-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 alkyl; C optionally substituted with one or more halogens 1-6 Alkoxy; -S(O)2-C 1-6 alkyl; Halogen, C optionally substituted with one or more halogens 1-6 Alkyl, and mono- or di-(C 1-6 4-8 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of (alkyl)amino; Halogen, C 1-6 Alkyl, and halo-C 1-6 -O-4 to 8 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl; or Halogen and C optionally substituted with one or more halogens 1-6 -NHC optionally substituted with one or more substituents selected from the group consisting of alkoxy 3-6 is cycloalkyl, L is a linear or branched C 2-6 alkylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene; R5 is hydrogen or C 1-6 is alkyl, R6 and R7 are, independently of each other, hydrogen, halogen, or halo-C 1-6is alkyl, X1 is CH or N.

[0034] In certain embodiments, R1 may be hydrogen or methyl. Preferably, R1 may be methyl.

[0035] In certain embodiments, R2 is C optionally substituted with one or more halogens. 1-6 It may also be alkyl.

[0036] In certain embodiments, A can be pyrazolyl, pyrazinyl, thiazolyl, pyridinyl, or pyrimidinyl.

[0037] In certain embodiments, the 4-8 membered heterocyclyl can be azetidinyl, oxetanyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[2.3]hexanyl, pyrrolidinyl, 2-thio-6-azaspiro[3.3]heptanyl, hexahydro-1H-thieno[3,4-c]pyrrolyl, or 2-azaspiro[3.3]heptanyl.

[0038] In certain embodiments, L can be ethylene, n-propylene, 1-methylpropylene, 1-ethylpropylene, 3-methylpropylene, 2-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, n-butylene, 1-methylbutylene, 3-methylbutylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene.

[0039] Representative compounds of formula (I) are listed below. (1) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (2) (S)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (3) (R)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (4) 1 1 -methyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (5) (R)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (6) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (7) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,5-dimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (8) (S)-2-(6-(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)-5-fluoropyridin-3-yl)propan-2-ol; (9) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (10) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (11) (6 1 S,6 3 R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane; (12) (R)-4 5 -(3-fluoropyridin-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; (13) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1,7-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (14) 4 5 -(3-methoxypyridin-2-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (15) (S)-4 5 -(3-methoxypyridin-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; (16) 4 5 -(3-methoxypyridin-2-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (17) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,8-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (18) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (19) (S)-4 5 -(3-(difluoromethoxy)pyridin-2-yl)-1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (20) (S)-1 1 ,6-dimethyl-4 5 -(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (21) (S)-4 5 -(5-fluoro-3-methoxypyridin-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; (22) (S)-4 5 -(3-(2,2-difluoroethoxy)pyridin-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; (23) (S)-1 1 ,6-dimethyl-4 5 -(pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (24) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-7-(trifluoromethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (25) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane; (26) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (27) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (28) (S)-1 1 ,6-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (29) (6S)-1 1 ,6-dimethyl-4 5 -(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (30) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (31) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (32) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (33) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (34) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -isopropyl-6-methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (35) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (36) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (37) 1 1 ,7,7-trimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (38) 1 1 ,7,7-trimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (39) (S)-1 1 ,8-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (40) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-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; (41) (S)-1 1 ,6-dimethyl-4 5 -(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (42) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (43) (S)-N-(3,3-difluorocyclobutyl)-2-(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)pyridin-4-amine; (44) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-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; (45) (S)-4 5 -(3-fluoro-5-(piperidin-1-ylmethyl)pyridin-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; (46) 2-((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)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine; (47) 2-((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)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine; (48) (3-fluoro-2-(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)pyridin-4-yl)methanol; (49) (S)-(1-((6-(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)-5-fluoropyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methanol; (50) (S)-4 5 -(3-fluoro-5-((4-fluoropiperidin-1-yl)methyl)pyridin-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; (51) 4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (52) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (53) 4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (54) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,8-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (55) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (56) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-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; (57) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-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; (58) (S)-4 5 -(5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridin-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; (59) (S)-4 5 -(5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (60) (S)-4 5 -(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-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; (61) (S)-4 5 -(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-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; (62) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[oxetane-3,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (63) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[cyclopropane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (64) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[cyclobutane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (65) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[cyclopentane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (66) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (67) (S)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (68) (S)-1 1 ,8-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (69) (S)-7-Fluoro-1 1 -methyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (70) (R)-7-Fluoro-1 1 -methyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (71) 1 1 ,7,7-trimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (72) (R)-1 1 ,8-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (73) (S)-1 1 ,8-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (74) (S)-1 1 ,6-dimethyl-4 5 -(2-(trifluoromethyl)thiazol-4-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (75) (R)-1 1 ,6-dimethyl-4 5 -(2-(trifluoromethyl)thiazol-4-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (76) (S)-4 5 -(1,4-dimethyl-1H-pyrazol-3-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; (77) (S)-4 5 -(1,4-dimethyl-1H-pyrazol-3-yl)-1 1 ,8-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (78) (S)-4 5 -(5-(difluoromethoxy)pyrazin-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; (79) (S)-2-(6-(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)pyridin-3-yl)propan-2-ol; (80) (S)-2-(6-(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)pyridin-3-yl)propan-2-ol; (81) (S)-4 5 -(4-(difluoromethoxy)pyridin-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; (82) (S)-4 5 -(4-(difluoromethoxy)pyridin-2-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; (83) (S)-4 5 -(4-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (84) 4 5 -(4-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (85) (S)-4 5 -(5-(difluoromethoxy)pyridin-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; (86) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-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; (87) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (88) (R)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (89) 4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,7,7-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (90) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-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; (91) 4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (92) (S)-4 5 -(4-(difluoromethoxy)-3-fluoropyridin-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; (93) (S)-1 1 ,6-dimethyl-4 5 -(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (94) (S)-4 5 -(3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-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; (95) 2-(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)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol; (96) 2-(6-((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)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol; (97) 1,1,1-trifluoro-2-(6-(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)pyridin-3-yl)propan-2-ol; (98) 1,1,1-trifluoro-2-(6-((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 -yl)pyridin-3-yl)propan-2-ol; (99) (S)-4 5 -(4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridin-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; (100) (S)-4 5 -(4-(3-(2,2-difluoropropyl)azetidin-1-yl)pyridin-2-yl)-1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (101) (S)-1 1 ,6-dimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (102) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (103) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (104) 1 1 ,1 3 ,7,7-tetramethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (105) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (106) (S)-4 5 -(5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-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; (107) (S)-4 5 -(5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-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; (108) (S)-4 5 -(5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-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; (109) (S)-4 5 -(5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (110) (S)-4 5 -(5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (111) (S)-4 5-(5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (112) (S)-4 6 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4),4(3,5)-dipyrimidina-1(4,5)-pyrazolacyclononaphane; (113) (S)-2-(5-fluoro-6-(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)pyridin-3-yl)propan-2-ol; (114) (S)-2-(5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (115) (S)-4 5 -(3-fluoro-5-(methylsulfonyl)pyridin-2-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; (116) (S)-4 5 -(3-fluoro-5-(methylsulfonyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (117) 1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol; (118) 1-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol; (119) (S)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (120) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-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; (121) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,13 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (122) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-2-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; (123) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (124) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (125) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-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; (126) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (127) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(morpholinomethyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (128) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-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; (129) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-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; (130) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (131) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (132) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (133) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (134) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (135) (S)-2-(5-(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)pyrazin-2-yl)propan-2-ol; (136) (S)-4 5 -(3-fluoro-5-(((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (137) (S)-4 5 -(3-fluoro-5-(((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (138) (S)-4 5 -(3-fluoro-5-(((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (139) (S)-2-(5-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyrazin-2-yl)propan-2-ol; (140) (S)-6-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (141) (S)-6-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (142) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (143) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (144) 5-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide; (145) 5-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide; (146) (S)-4 5 -(3-fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (147) (S)-4 5 -(3-fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (148) (S)-4 5 -(3-fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (149) (S)-4 5 -(3-fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (150) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyrimidin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (151) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyrimidin-2-yl)-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (152) (R)-2-(5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (153) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (154) (R)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (155) (S)-2-(2-(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)pyrimidin-5-yl)propan-2-ol; (156) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (157) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (158) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (159) (S)-1-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (160) (S)-2-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-ol; (161) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (162) (S)-1-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (163) (S)-2-(2-(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)pyridin-4-yl)propan-2-ol; (164) (S)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-4-yl)propan-2-ol; (165) (S)-2-(6-(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)pyridin-2-yl)propan-2-ol; (166) (S)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-2-yl)propan-2-ol; (167) (R)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (168) (R)-1-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (169) (S)-1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-ol; (170) (S)-1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-ol; (171) (S)-1-((5-fluoro-6-(1 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)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol; (172) (S)-1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol; (173) (R)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)piperidin-3-ol; (174) (S)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)piperidin-3-ol; (175) (S)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (176) (R)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (177) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-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; (178) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (179) (R)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (180) (S)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyrimidin-5-yl)propan-2-ol; (181) (R)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5-yl)pyrimidin-5-yl)propan-2-ol; (182) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyrimidin-2-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; (183) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyrimidin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (184) (S)-N,N-dimethyl-1-(6-(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)pyridin-3-yl)piperidin-4-amine; (185) (S)-N,N-dimethyl-1-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)piperidin-4-amine; (186) (S)-4 5 -(5-(difluoromethyl)pyridin-2-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; (187) (S)-4 5-(5-(difluoromethyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (188) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(trifluoromethyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (189) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(trifluoromethyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (190) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and (191) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.

[0040] Further representative compounds of formula (I) are listed below. (51) 4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (52) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (55) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (57) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-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; (61) (S)-4 5 -(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-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; (80) (S)-2-(6-(1 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)pyridin-3-yl)propan-2-ol; (90) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-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; (91) 4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (98) 1,1,1-trifluoro-2-(6-((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 -yl)pyridin-3-yl)propan-2-ol; (102) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (103) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (104) 1 1 ,1 3 ,7,7-tetramethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (105) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (109) (S)-4 5 -(5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (110) (S)-4 5 -(5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (111) (S)-4 5 -(5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane. (113) (S)-2-(5-fluoro-6-(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)pyridin-3-yl)propan-2-ol; (114) (S)-2-(5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (117) 1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol; (118) 1-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol; (119) (S)-1-((5-fluoro-6-((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-45 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (120) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-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; (121) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (122) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-2-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; (123) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (124) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (125) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-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; (126) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (127) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(morpholinomethyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (128) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-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; (129) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (130) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (131) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (132) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (133) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (134) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (135) (S)-2-(5-(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)pyrazin-2-yl)propan-2-ol; (136) (S)-4 5 -(3-fluoro-5-(((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (137) (S)-4 5 -(3-fluoro-5-(((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (138) (S)-4 5 -(3-fluoro-5-(((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (139) (S)-2-(5-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5-yl)pyrazin-2-yl)propan-2-ol; (140) (S)-6-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (141) (S)-6-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (143) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (144) 5-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide; (145) 5-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45 -yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide; (146) (S)-4 5 -(3-fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (147) (S)-4 5 -(3-fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (148) (S)-4 5 -(3-fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (149) (S)-4 5 -(3-fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (150) (S)-1 1 ,1 3 ,8-trimethyl-4 5-(5-(methylsulfonyl)pyrimidin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (152) (R)-2-(5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (153) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (154) (R)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (155) (S)-2-(2-(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)pyrimidin-5-yl)propan-2-ol; (156) (S)-2-(1-((5-fluoro-6-(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-45 -yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (157) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (158) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (159) (S)-1-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (160) (S)-2-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-ol; (161) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (162) (S)-1-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (163) (S)-2-(2-(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)pyridin-4-yl)propan-2-ol; (164) (S)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-4-yl)propan-2-ol; (165) (S)-2-(6-(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)pyridin-2-yl)propan-2-ol; (166) (S)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-2-yl)propan-2-ol; (167) (R)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (168) (R)-1-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (169) (S)-1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-ol; (170) (S)-1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-ol; (171) (S)-1-((5-fluoro-6-(1 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)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol; (172) (S)-1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol; (173) (R)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)piperidin-3-ol; (174) (S)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)piperidin-3-ol; (175) (S)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (176) (R)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (177) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-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; (178) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (179) (R)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (180) (S)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyrimidin-5-yl)propan-2-ol; (181) (R)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5-yl)pyrimidin-5-yl)propan-2-ol; (182) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyrimidin-2-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; (183) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyrimidin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (184) (S)-N,N-dimethyl-1-(6-(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)pyridin-3-yl)piperidin-4-amine; (185) (S)-N,N-dimethyl-1-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)piperidin-4-amine; (186) (S)-4 5 -(5-(difluoromethyl)pyridin-2-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; (187) (S)-4 5-(5-(difluoromethyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (188) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(trifluoromethyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (189) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(trifluoromethyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (190) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and (191) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.

[0041] More preferred representative compounds of formula (I) are listed below. (52) (S)-4 5-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (55) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (57) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-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; (80) (S)-2-(6-(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)pyridin-3-yl)propan-2-ol; (98) 1,1,1-trifluoro-2-(6-((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 -yl)pyridin-3-yl)propan-2-ol; (102) (S)-1 1 ,1 3 ,6-trimethyl-4 5-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (103) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (104) 1 1 ,1 3 ,7,7-tetramethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (105) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (109) (S)-4 5 -(5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (110) (S)-4 5 -(5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (120) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-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; (121) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (127) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(morpholinomethyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (128) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-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; (130) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (131) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (133) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (134) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (135) (S)-2-(5-(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)pyrazin-2-yl)propan-2-ol; (140) (S)-6-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (150) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyrimidin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (153) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (154) (R)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (155) (S)-2-(2-(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)pyrimidin-5-yl)propan-2-ol; (156) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (157) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (158) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (159) (S)-1-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (161) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (176) (R)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (184) (S)-N,N-dimethyl-1-(6-(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)pyridin-3-yl)piperidin-4-amine; (185) (S)-N,N-dimethyl-1-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)piperidin-4-amine; (190) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and (191) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane or a pharmaceutically acceptable salt thereof.

[0042] 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.

[0043] 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 carboxylic acid, trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid.

[0044] 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 1-4 Examples include, but are not limited to, salts of alkyl).

[0045] 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.

[0046] The compounds of the present invention can be synthesized by methods known in the art or by the methods illustrated in Examples 1-191 below.

[0047] 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.

[0048] 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).

[0049] In one embodiment, the methods disclosed herein relate to the treatment of cancer caused by at least one mutation in EGFR.

[0050] 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.

[0051] 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.

[0052] In one embodiment, the at least one variant is at least one single variant selected from Table 1 shown below.

[0053] [Table 1]

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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]

[0066] In Reaction Scheme 1, R1, R2, R3, R4, R5, R6, R7, X1, L, and A are the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0067] Specifically, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared using a process comprising the steps of: reacting a compound of formula (IIa) with AR3R4-M to obtain a compound of formula (IIIa), reacting the compound of formula (IIIa) with NHR5-LR6R7-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (V) to obtain a compound of formula (VI), and cyclizing the compound of formula (VI) to obtain a compound of formula (I).

[0068] In the process of Scheme 1, compounds of formula (IIa), AR3R4-M, and NHR5-LR6R7-OH are commercially available. The reaction of compounds of formula (IIa) with AR3R4-M 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 DME, THF, or 1,4-dioxane under heating, for example, at a temperature of 40 to 120°C.

[0069] The reaction of the compound of formula (IIIa) with NHR5-LR6R7-OH may be carried out in the presence of a base such as potassium carbonate, cesium carbonate, TEA, DIPEA, etc. The reaction may also be carried out in an organic solvent such as anhydrous THF, DMF, DMA, etc., at room temperature or under heating, for example, at a temperature of 40 to 120°C.

[0070] A compound of formula (IV) is coupled with a compound of formula (V) via the Mitsunobu reaction to give a compound of formula (VI). The reaction of compounds of formulas (IV) and (V) may be carried out in the presence of a phosphorane ylide, such as (trimethylphosphoranylidene)acetonitrile or (tributylphosphoranylidene)acetonitrile. 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.

[0071] The compound of formula (VI) is cyclized to obtain the compound of formula (I) by the Buchwald-Hartwig reaction. The cyclization reaction of the compound of formula (VI) 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.

[0072] Alternatively, the compound of formula (IV) may be prepared by reacting a compound of formula (IIa) with NHR5-LR6R7-OH to give a compound of formula (IIIb), and reacting the compound of formula (IIIb) with AR3R4-M.

[0073] The reaction of the compound of formula (IIa) with NHR5-LR6R7-OH may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. The reaction may also be carried out in an organic solvent such as anhydrous THF, DMF, DMA, etc., at room temperature or under heating, for example, at a temperature of 40 to 120°C.

[0074] The reaction of the compound of formula (IIIb) with AR3R4-M can be carried out in the presence of a base such as sodium carbonate, 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 DME, THF, or 1,4-dioxane under heating, for example, at a temperature of 40 to 120°C.

[0075] Alternatively, compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared according to the following Reaction Scheme 2: [ka]

[0076] In Reaction Scheme 2, R1, R2, R3, R4, R5, R6, R7, X1, L, and A are the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0077] Specifically, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared using a process comprising the steps of: reacting a compound of formula (IIb) with AR3R4-X to obtain a compound of formula (IIIa), reacting the compound of formula (IIIa) with NHR5-LR6R7-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (V) to obtain a compound of formula (VI), and cyclizing the compound of formula (VI) to obtain a compound of formula (I).

[0078] In the process of Reaction Scheme 2, compounds of formula (IIb), AR3R4-X, and NHR5-LR6R7-OH are commercially available. The reaction of compounds of formula (IIb) with AR3R4-X 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 DME, THF, or 1,4-dioxane under heating, for example, at a temperature of 40 to 120°C.

[0079] The reaction of the compound of formula (IIIa) with NHR5-LR6R7-OH may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. The reaction may also be carried out in an organic solvent such as anhydrous THF, DMF, DMA, etc., at room temperature or under heating, for example, at a temperature of 40 to 140°C.

[0080] A compound of formula (IV) is coupled with a compound of formula (V) via the Mitsunobu reaction to give a compound of formula (VI). The reaction of compounds of formulas (IV) and (V) may be carried out in the presence of a phosphorane ylide, such as (trimethylphosphoranylidene)acetonitrile or (tributylphosphoranylidene)acetonitrile. 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.

[0081] The compound of formula (VI) is cyclized to obtain the compound of formula (I) by the Buchwald-Hartwig reaction. The cyclization reaction of the compound of formula (VI) 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.

[0082] In one embodiment, a compound of formula (IV) may be prepared by reacting a compound of formula (IIb) with NHR5-LR6R7-OH to give a compound of formula (IIIc), and reacting the compound of formula (IIIc) with AR3R4-X.

[0083] The reaction of the compound of formula (IIb) with NHR5-LR6R7-OH may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. The reaction may also be carried out in an organic solvent such as anhydrous THF, DMF, DMA, etc., at room temperature or under heating, for example, at a temperature of 40 to 120°C.

[0084] The reaction of compounds of formula (IIIc) with AR3R4-X can be carried out in the presence of a base such as sodium carbonate, 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 DME, THF, or 1,4-dioxane under heating, for example, at a temperature of 40 to 120°C.

[0085] In another embodiment, compounds of formula (V) may be prepared according to the following Reaction Scheme 3: [ka]

[0086] In Reaction Scheme 3, R1 and R2 are the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0087] Specifically, the compound of formula (V) can be prepared using a process comprising the steps of reacting a compound of formula (VII) with a compound of formula (VIII) to obtain a compound of formula (IX), and hydrogenolysis of the compound of formula (IX) to obtain a compound of formula (V).

[0088] 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.

[0089] 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 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.

[0090] In yet another embodiment, compounds of formula (VIII) may be prepared according to the following Reaction Scheme 4: [ka]

[0091] In Reaction Scheme 4, R1 and R2 are the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0092] 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).

[0093] 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.

[0094] 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.

[0095] 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]

[0096] 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.

[0097] 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:

[0098] [Table 2] JPEG2026507655000009.jpg156170

[0099] Preparation Example 1: 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine A reaction mixture of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol), 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.14 g, 4.661 mmol), Pd(dppf)Cl (317.23 mg, 0.388 mmol), and 2 M KCO solution (3.88 mL, 11.66 mmol) in 1,4-dioxane (20 mL) was stirred at 90° C. for 3 hours. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-20%) to produce 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine as a white solid (910 mg, 3.675 mmol, yield: 94.61%). 1 H-NMR (CDCl3, 400 MHz) δ 9.02 (d, 1H), 7.93 (d, 1H), 7.29 (t, 1H), 7.20 (d, 1H), 6.88 (t, 1H); MS (ESI) m / z=248.0 (M + H) +

[0100] Preparation Example 2: 2-chloro-4-fluoro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine To a solution of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol) in 1,4-dioxane (20 mL) was added 1-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (1.29 g, 4.661 mmol), Pd(dppf)Cl (317.23 mg, 0.388 mmol), and 3M KCO solution (3.88 mL, 11.66 mmol). The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-30%) to produce 2-chloro-4-fluoro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine as a white solid (876 mg, 3.133 mmol, yield: 80.65%). 1 H-NMR (DMSO-d6, 400 MHz) δ 8.89 (d, 1H), 7.77 (d, 1H), 7.31 (s, 1H), 4.06 (s, 3H); MS (ESI) m / z 280.0=(M + H) +

[0101] Preparation Example 3: 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine To a solution of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol) in 1,4-dioxane (20 mL) was added (1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)boronic acid (903.95 mg, 4.661 mmol), Pd(dppf)Cl (317.23 mg, 0.388 mmol), and 3 M KCO solution (3.88 mL, 11.66 mmol). The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-30%) to produce 2-chloro-4-fluoro-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]pyridine as a white solid (886 mg, 3.169 mmol, yield: 81.57%). 1 H-NMR (DMSO-d6, 400 MHz) δ 8.89 (d, 1H), 7.77 (d, 1H), 7.31 (s, 1H), 4.06 (s, 3H); MS (ESI) m / z=280.0 (M + H) +

[0102] Preparation Example 4: 4-(6-chloro-4-fluoro-3-pyridyl)-2-(trifluoromethyl)-1H-thiazole The title compound was prepared as a white solid (809 mg) in the same manner as in Preparation 2, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)thiazole (1.41 g, 5.050 mmol) was used instead of 1-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole. 1 H-NMR (CDCl3, 400 MHz) δ 9.24 (d, 1H), 8.01 (s, 1H), 7.24 (d, 1H)

[0103] Preparation Example 5: 2-(6-chloro-4-fluoropyridin-3-yl)-5-(difluoromethoxy)pyrazine To a solution of 2-bromo-5-(difluoromethoxy)pyrazine (200 mg, 0.889 mmol) in 1,4-dioxane (4.53 mL) was added 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (228.9 mg, 0.889 mmol), Pd(dppf)Cl (72.59 mg, 0.089 mmol), and 3M KCO solution (0.89 mL, 2.667 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-40%) to produce 2-(6-chloro-4-fluoropyridin-3-yl)-5-(difluoromethoxy)pyrazine as a pale yellow solid (201 mg, 0.729 mmol, yield: 82.04%). 1 H-NMR (CDCl3, 400 MHz) δ 9.05 (d, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 47.47 (t, 1H), 7.25 (s, 1H)

[0104] Production Example 6: 2-(6'-chloro-4'-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol The title compound was prepared as a white solid (545 mg) in the same manner as in Preparation 5, except that 2-(6-bromo-3-pyridyl)propan-2-ol (700 mg, 3.24 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. 1 H-NMR (CDCl3, 400 MHz) δ 8.99 (d, 1H), 8.85 (d, 1H), 7.93 (dd, 1H), 7.70 (dd, 1H), 7.19 (d, 1H), 2.24 (s, 1H), 1.65 (s, 6H); MS (ESI) m / z=267.0 (M + H) +

[0105] Production Example 7: 6'-chloro-4-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine The title compound was prepared as a white solid (183 mg) in the same manner as in Preparation 5, except that 2-bromo-4-(difluoromethoxy)pyridine (200 mg, 0.893 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. 1 H-NMR (CDCl3, 400 MHz) δ 9.08 (d, 1H), 8.72 (d, 1H), 7.51 (s, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 6.70 (t, 1H); MS (ESI) m / z=343.9 (M + H) +

[0106] Production Example 8: 6'-chloro-5-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine The title compound was prepared as a white solid (467 mg) in the same manner as in Preparation 5, except that 2-bromo-5-(difluoromethoxy)pyridine (500 mg, 2.232 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. 1 MS (ESI) m / z=343.9 (M + H) +

[0107] Production Example 9: 6'-chloro-4-(difluoromethoxy)-3,4'-difluoro-2,3'-bipyridine The title compound was prepared as a white solid (272 mg) in the same manner as in Preparation 5, except that 2-bromo-4-(difluoromethoxy)-3-fluoro-pyridine (500 mg, 2.066 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (d, 1H), 8.52 (d, 1H), 7.31 9t, 1H), 7.25 (d, 1H), 6.75 (t, 1H)

[0108] Preparation Example 10: 2-(6'-chloro-4'-fluoro-[2,3'-bipyridin]-5-yl)-1,1,1-trifluoropropan-2-ol The title compound (185 mg) was prepared as an off-white solid in the same manner as in Preparation 5, except that 2-(6-bromo-3-pyridyl)-1,1,1-trifluoro-propan-2-ol (542 mg, 2.01 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=321.0 (M + H) +

[0109] Preparation Example 11: 6'-chloro-4'-fluoro-5-((1-methylpiperidin-4-yl)oxy)-2,3'-bipyridine The title compound was prepared as a white solid (468 mg) in the same manner as in Preparation 5, except that 2-bromo-5-((1-methylpiperidin-4-yl)oxy)pyridine (502.04 mg, 1.852 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=322.0 (M + H) +

[0110] Preparation Example 12: 6'-chloro-4'-fluoro-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-2,3'-bipyridine The title compound was prepared as a white solid (140 mg) in the same manner as in Preparation 5, except that 2-bromo-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine (188 mg, 0.554 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=390.1 (M + H) +

[0111] Preparation Example 13: 6'-chloro-4'-fluoro-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-2,3'-bipyridine Step 1: 2-Bromo-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine A reaction mixture of 1-(2,2,2-trifluoroethyl)piperidin-4-yl 4-methylbenzenesulfonate (750 mg, 2.223 mmol), K2CO3 (614.52 mg, 4.446 mmol), and 6-bromo-5-methoxy-pyridin-3-ol (498.92 mg, 2.445 mmol) in DMF (5 mL) was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-80%) to produce 2-bromo-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine as a colorless oil (382 mg, 1.035 mmol, yield: 46.54%). MS (ESI) m / z=370.0 (M + H) +

[0112] Step 2: 6'-chloro-4'-fluoro-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-2,3'-bipyridine The title compound was prepared as a white solid (301 mg) in the same manner as in Preparation 5, except that 2-bromo-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine (380 mg, 1.029 mmol) prepared in Step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=420.1 (M + H) +

[0113] Preparation Example 14: 6'-chloro-4-(3-(2,2-difluoroethyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine Step 1: 2-Bromo-4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridine A reaction mixture of 2-bromo-4-fluoropyridine (90 mg, 0.511 mmol), 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (156.33 mg, 0.665 mmol), and DIPEA (0.22 mL, 1.278 mmol) in DMA (1 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 MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-50%) to give 2-bromo-4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridine as a colorless oil (141 mg, 0.509 mmol, yield: 99.5%). MS (ESI) m / z = 277.9 (M + H). +

[0114] Step 2: 6'-chloro-4-(3-(2,2-difluoroethyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine The title compound was prepared as a white solid (65 mg) in the same manner as in Preparation 5, except that 2-bromo-4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridine (129.14 mg, 0.466 mmol) prepared in Step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=327.9 (M + H) +

[0115] Preparation Example 15: 6'-chloro-4-(3-(2,2-difluoropropyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine Step 1: 2-Bromo-4-(3-(2,2-difluoropropyl)azetidin-1-yl)pyridine The title compound was prepared as a white solid (145 mg) in the same manner as in Step 1 of Preparation 14, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (114.09 mg, 0.665 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate. MS (ESI) m / z=292.9 (M + H). +

[0116] Step 2: 6'-chloro-4-(3-(2,2-difluoropropyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine The title compound was prepared as a white solid (68 mg) in the same manner as in Preparation 5, except that 2-bromo-4-(3-(2,2-difluoropropyl)azetidin-1-yl)pyridine (135.68 mg, 0.466 mmol) prepared in Step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=341.9 (M + H) +

[0117] Preparation Example 16: 6'-chloro-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine Step 1: 2-Bromo-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridine A reaction mixture of 6-bromo-5-fluoronicotinaldehyde (200 mg, 0.98 mmol), 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (230.54 mg, 0.98 mmol), and sodium triacetoxyborohydride (623.35 mg, 2.941 mmol) in DCM (5 mL) was stirred at room temperature for 20 hours. The reaction mixture was diluted with DCM, quenched with NaHCO solution, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-70%) to give 2-bromo-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridine as a pale yellow solid (168 mg, 0.543 mmol, yield: 55.43%). MS (ESI) m / z=310.8 (M + H) +

[0118] Step 2: 6'-chloro-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine The title compound was prepared as a white solid (151 mg) in the same manner as in Preparation 5, except that 2-bromo-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridine (150 mg, 0.485 mmol) prepared in Step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=359.9 (M + H) +

[0119] Preparation Example 17: 6'-chloro-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine Step 1: 2-Bromo-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridine The title compound was prepared as a white solid (214 mg) in the same manner as in Step 1 of Preparation 16, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (168.25 mg, 0.98 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate. 1 H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.43 (dd, 1H), 3.58 (s, 2H), 3.54 (t, 2H), 2.87 (t, 2H), 2.83-2.76 (m, 1H), 2.12 (td, 2H), 1.58 (t, 3H)

[0120] Step 2: 6'-chloro-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine The title compound was prepared as a white solid (151 mg) in the same manner as in Preparation 5, except that 2-bromo-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridine (156.8 mg, 0.485 mmol) prepared in Step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=374.0 (M + H) +

[0121] Preparation Example 18: 6'-chloro-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine Step 1: 2-Bromo-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridine The title compound was prepared as a white solid (159 mg) in the same manner as in Step 1 of Preparation 16, except that 3-(difluoromethoxy)azetidine hydrochloride (156.43 mg, 0.98 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate. 1 H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.43 (dd, 1H), 6.20 (t, 1H), 4.84-4.78 (m, 1H), 3.70 (td, 2H), 3.66 (s, 3H), 3.14 (td, 2H)

[0122] Step 2: 6'-chloro-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine The title compound was prepared as a white solid (152 mg) in the same manner as in Preparation 5, except that 2-bromo-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridine (150.96 mg, 0.485 mmol) prepared in Step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z=361.9 (M + H) +

[0123] Preparation Example 19: (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol A suspension of 2-chloro-4-fluoro-5-iodopyridine (350 mg, 1.36 mmol), (S)-3-aminobutan-1-ol (145.43 mg, 1.632 mmol), and DIPEA (0.59 mL, 3.399 mmol) in DMA (6.06 mL) was stirred at 90 °C for 3 h. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / Hex = 0-50%) to produce (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol as an off-white solid (399 mg, 1.222 mmol, yield: 89.87%). 1 H-NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 6.44 (s, 1H), 5.14 (d, 1H), 3.88-3.79 (m, 3H), 3.02 (s, 1H), 1.96-1.75 (m, 2H), 1.29 (d, 3H)

[0124] Preparation Example 20: (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol The title compound was prepared as an off-white solid (406 mg) in the same manner as in Preparation 19, except that (R)-4-aminobutan-2-ol (89.14 mg, 1.36 mmol) was used instead of (S)-3-aminobutan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 6.42 (s, 1H), 5.57 (brs, 1H), 4.08-4.05 (m, 1H), 3.44-3.28 (m, 2H), 1.98 (s, 1H), 1.93-1.76 (m, 2H), 1.33 (d, 3H)

[0125] Preparation 21: (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol To a solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (500.00 mg, 2.019 mmol) prepared in Preparation 1 in DMA (6 mL) was added (S)-3-aminobutan-1-ol (216.01 mg, 2.423 mmol) and DIPEA (564.48 μL, 4.039 mmol). The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by column chromatography (EA / n-Hex=30-100%) to produce (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol as a white solid (500 mg, 1.759 mmol, yield: 78.17%). 1 H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 7.91-8.68 (m, 2H), 7.20 (t, 1H), 6.81 (d, 1H), 6.68 (s, 1H), 3.90-3.83 (t, 3H), 1.89 (q, 2H), 1.67 (s, 1H), 1.33 (d, 3H)

[0126] Preparation Example 22: 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.00 g, 7.767 mmol), 2-bromo-3-methoxypyridine (1.46 g, 7.767 mmol), 1 M K2CO3 solution (23.30 mL, 23.301 mmol), and Pd(dppf)Cl2 (951.43 mg, 1.165 mmol) in 1,4-dioxane (30 mL) was stirred at 90 °C for 2 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (hexane / EA = 0-30%) to give 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (1000 mg, 4.190 mmol, yield: 53.95%). 1H-NMR (CD3OD, 400MHz) δ 8.47 (d, 1H), 8.26 (d, 1H), 7.64 (d, 1H), 7.51-4-7.46 (m, 2H), 3.89 (s, 3H); MS (ESI) m / z=239.1 (M + H) +

[0127] Preparation 23: 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) +

[0128] 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. 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 = 0-25%) to give 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) +

[0129] 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), a solution of iPrMgCl LiCl complex in THF (1.3 M, 112 mL, 145 mmol) was slowly added 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). 1H 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) +

[0130] 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. After completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4. 、 After filtration and concentration 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) +

[0131] 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. 1 H 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) +

[0132] Preparation 24: 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) +

[0133] 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. 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-1,3-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) +

[0134] 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), a solution of iPrMgCl LiCl complex in THF (1.3 M, 26 mL, 33.8 mmol) was slowly added 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) +

[0135] 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) +

[0136] 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 an atmosphere of H 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 gray 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) +

[0137] Preparation 25: (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-iodopyridine (3.0 g, 11.654 mmol) and (R)-3-amino-1-butanol (1.038 g, 11.654 mmol) was purged with nitrogen gas for 10 minutes. DMF (15 mL) and DIPEA (4.06 mL, 23.307 mmol, 2.0 eq) were added, and the reaction mixture was stirred at 80 °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 (EA / n-Hex = 0-40%) to give (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol as an off-white solid (2.56 g). 1 H-NMR (CDCl3, 400MHz) δ 8.20 (s, 1H), 6.44 (s, 1H), 5.13-5.11 (d, 1H), 3.85-3.80 (q, 2H), 1.91-1.88 (q, 1H), 1.82-1.78 (t, 1H), 1.29-1.25 (d, 3H); MS (ESI) m / z=327.0 (M + H) +

[0138] Preparation 26: 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine Step 1: 2-Bromo-5-(oxetan-3-yloxy)pyrazine To a solution of sodium hydride (15.13 mg, 0.631 mmol) in THF (2 mL) was added 3-hydroxyoxetane (26.69 μL, 0.42 mmol) at room temperature. The reaction mixture was stirred for 5 minutes, and 2,5-dibromopyrazine (100 mg, 0.42 mmol) was added to the mixture. The reaction mixture was stirred at 50°C for 4 hours and quenched with water. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EA / n-Hex = 0-40%) to produce 2-bromo-5-(oxetan-3-yloxy)pyrazine as a white solid (86 mg, 0.382 mmol, yield: 88.54%). 1 H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 8.10 (s, 1H), 5.58 (quin, 1H), 4.99 (t, 2H), 4.74 (t, 2H)

[0139] Step 2: 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (115.01 mg, 0.447 mmol), Pd(dppf)Cl (30.4 mg, 0.037 mmol), 2-bromo-5-(oxetan-3-yloxy)pyrazine (86 mg, 0.372 mmol) prepared in Step 1, and 3M KCO solution (0.37 mL, 1.117 mmol) in 1,4-dioxane (2.5 mL) was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, concentrated, and extracted with DCM / water. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by column chromatography (EA / n-Hex=0-50%) to produce 2-(6-chloro-4-fluoro-3-pyridyl)-5-(oxetan-3-yloxy)pyrazine as a white solid (60 mg, 0.213 mmol, yield: 57.23%). 1H-NMR (CDCl3, 400 MHz) δ 9.01 (d, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.23 (d, 1H), 5.69 (quin, 1H), 5.04 (t, 2H), 4.79 (t, 1H)

[0140] Preparation Example 27: 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine Step 1: 1-((6-bromo-5-fluoropyridin-3-yl)methyl)-4-methylpiperazine To a solution of 1-methylpiperazine (119.62 μL, 1.078 mmol) in DCM (5 mL) was added 6-bromo-5-fluoro-pyridine-3-carbaldehyde (200 mg, 0.980 mmol) and sodium triacetoxyborohydride (623.35 mg, 2.941 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and poured into saturated NaHCO3 solution. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / EA = 0-30%) to produce 1-((6-bromo-5-fluoropyridin-3-yl)methyl)-4-methylpiperazine as a white solid (232 mg, 0.805 mmol, yield: 82.12%). 1 H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 7.50 (dd, 1H), 3.52 (s, 2H), 2.43 (brs, 8H), 2.32 (s, 3H)

[0141] Step 2: 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine The title compound was prepared as a brown solid in the same manner as in Preparation 1, except that 1-((6-bromo-5-fluoropyridin-3-yl)methyl)-4-methylpiperazine (230 mg, 0.798 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (246.63 mg, 0.958 mmol) prepared in Step 1 were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (190 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.51 (s, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 3.63 (s, 2H), 2.56-2.49 (m, 8H), 2.32 (s, 3H)

[0142] Preparation Example 28: (S)-3-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol To a solution of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine (189 mg, 0.558 mmol) prepared in Preparation 27 in DMA (3 mL) was added (S)-3-aminobutan-1-ol (59.68 mg, 0.669 mmol) and DIPEA (0.16 mL, 1.116 mmol). The reaction mixture was heated at 80°C for 19 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / EA=0-70%) to produce (S)-3-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol as a light brown solid (129 mg, 0.316 mmol, yield: 56.69%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (d, 1H), 8.35 (s, 1H), 7.93 (d, 1H), 7.58 (dd, 1H), 6.69 (s, 1H), 3.80-3.57 (m, 3H), 3.57 (s, 2H), 2.52 (brs, 8H), 2.29 (s, 3H), 1.90-1.74 (m, 2H), 1.31 (d, 3H)

[0143] Preparation 29: 3-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)-2,2-dimethylpropan-1-ol The title compound was prepared as a beige solid (315 mg) in the same manner as in Preparation 28, except that 3-amino-2,2-dimethylpropan-1-ol (138.85 mg, 1.346 mmol) was used instead of (S)-3-aminobutan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.58 (d, 1H), 6.66 (s, 1H), 3.58 (s, 2H), 3.46 (s, 2H), 3.09 (d, 2H), 2.51 (brs, 8H), 2.31 (s, 3H), 1.03 (s, 6H)

[0144] Preparation 30: (R)-4-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-2-ol The title compound was prepared as a brown solid (160 mg) in the same manner as in Preparation 28, except that (R)-4-aminobutan-2-ol (119.98 mg, 1.346 mmol) was used instead of (S)-3-aminobutan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.42 (d, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.62 (d, 1H), 6.66 (s, 1H), 4.03-3.98 (m, 1H), 3.59 (s, 2H), 3.51-3.33 (m, 2H), 2.54 (brs, 8H), 2.33 (s, 3H), 1.88-1.76 (m, 2H), 1.29 (d, 3H)

[0145] Preparation 31: (S)-3-((5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol Step 1: 6-((6-bromo-5-fluoropyridin-3-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane The title compound was prepared as a colorless liquid (366.6 mg) in the same manner as in Step 1 of Preparation 27, except that 2-oxa-6-azaspiro[3.3]heptane (189.02 mg, 1.907 mmol) was used instead of 1-methylpiperazine. 1 H-NMR (CDCl3, 400 MHz) δ 8.10 (d, 1H), 7.40 (dd, 1H), 4.77 (s, 4H), 3.55 (s, 2H), 3.40 (s, 4H)

[0146] Step 2: 6-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole prepared in step 1 instead of 6-((6-bromo-5-fluoropyridin-3-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (304.43 mg, 1.06 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.31 mg, 1.166 mmol) were used, except that the title compound was prepared as a brown liquid in the same manner as in preparation example 1 (330 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.46 (s, 1H), 7.52 (d, 1H), 7.24 (d, 1H), 4.79 (s, 4H), 3.66 (s, 2H), 3.46 (s, 4H)

[0147] Step 3: (S)-3-((5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a pale yellow solid (228 mg) in the same manner as in Preparation 28, except that 6-((6'-chloro-3,4'-difluoro-[2,3'-bipyridine]-5-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (292.69 mg, 0.867 mmol) prepared in Step 2 was used instead of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.32 (s, 1H), 7.92 (d, 1H), 7.51 (d, 1H), 6.71 (s, 1H), 4.79 (s, 4H), 3.83-3.80 (m, 3H), 3.61 (s, 2H), 3.45 (s, 4H), 1.86-1.84 (m, 2H), 1.29 (d, 3H)

[0148] Preparation 32: (S)-3-((6'-chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol Step 1: 2-Bromo-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridine The title compound was prepared as in Step 1 of Preparation 27, except that 3,3-difluoroazetidine hydrochloride (247 mg, 1.907 mmol) was used instead of 1-methylpiperazine, to give the title compound as a white solid (298.1 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 7.48 (dd, 1H), 3.77 (s, 2H), 3.65 (t, 4H)

[0149] Step 2: 6'-chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine The title compound was prepared as a yellow liquid in the same manner as in Preparation 1, except that 2-bromo-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridine (298 mg, 1.06 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.31 mg, 1.166 mmol) prepared in Step 1 were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.51 (s, 1H), 7.59 (d, 1H), 7.25 (d, 1H), 3.87 (s, 2H), 3.70 (t, 4H)

[0150] Step 3: (S)-3-((6'-chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a pale yellow solid (314 mg) in the same manner as in Preparation 28, except that 6'-chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine (287.44 mg, 0.867 mmol) prepared in Step 2 was used instead of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.41-8.38 (m, 2H), 7.95 (d, 1H), 7.57 (dd, 1H), 6.71 (s, 1H), 3.86-3.81 (m, 4H), 3.69 (t, 4H), 1.95-1.80 (m, 3H), 1.30 (d, 3H)

[0151] Preparation 33: (S)-3-((6'-chloro-5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol Step 1: 5-((6-bromo-5-fluoropyridin-3-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane The title compound was prepared as a colorless liquid (536.8 mg) in the same manner as in Step 1 of Preparation 27, except that 1,1-difluoro-5-azaspiro[2.3]hexane (227.11 mg, 1.907 mmol) was used instead of 1-methylpiperazine. 1 H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.47 (dd, 1H), 3.75 (s, 2H), 3.54 (d, 2H), 3.37-3.35 (m, 2H), 1.40 (t, 2H)

[0152] Step 2: 5-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole prepared in step 1 instead of 5-((6-bromo-5-fluoropyridin-3-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane (325.61 mg, 1.06 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.31 mg, 1.166 mmol) were used, except that the title compound was prepared as a yellow liquid in the same manner as in preparation example 1 (310 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.51 (s, 1H), 7.58 (d, 1H), 7.24 (d, 1H), 3.85 (s, 2H), 3.59 (d, 2H), 3.42-3.40 (m, 2H), 1.42 (t, 2H)

[0153] Step 3: (S)-3-((6'-chloro-5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a pale yellow solid (228 mg) in the same manner as in Preparation 28, except that 5-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane (310 mg, 0.867 mmol) prepared in Step 2 was used instead of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.40-8.38 (m, 2H), 7.94 (d, 1H), 7.57 (d, 1H), 6.71 (s, 1H), 3.85-3.80 (m, 5H), 3.58 (d, 2H), 3.41-3.39 (m, 2H), 1.88-1.78 (m, 3H), 1.41 (m, 2H), 1.30 (d, 3H)

[0154] Preparation 34: 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol Step 1: 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol To a solution of (2,2,2-trifluoroethyl)hydrazine hydrochloride (20.0 g, 133 mmol) in ethanol (200 mL) was added methyl 3-methoxyacrylate (15.5 g, 132.86 mmol) dropwise over 1 h at 60-65 °C. After the addition was complete, the mixture was heated to reflux for 2 h. After cooling to room temperature, a 30% solution of sodium methoxide in methanol was added to adjust the pH to 5.0. The mixture was filtered, and the filtrate was concentrated to produce the crude product, i.e., 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (33 g). This crude product was used in the next step without further purification.

[0155] Step 2: 5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazole To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (30.0 g, 180.6 mmol) prepared in Step 1 in DMF (300 mL) was added K2CO3 (37.5 g, 270.9 mmol) and benzyl bromide (25.8 mL, 216.7 mmol). 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 anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EA / n-Hex = 0-10%) to give 5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g) as a colorless oil. 1 H NMR (CDCl3, 400 MHz) δ 7.40-7.36 (m, 6H), 5.57 (d, 1H), 5.10 (s, 2H), 4.55 (q, 2H); MS (ESI) m / z=257.1 (M + H) +

[0156] Step 3: 5-(benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole To a solution of 5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g, 31.2 mmol) prepared in step 2 in MeCN (80 mL) was added N-iodosuccinimide (7.02 g, 31.2 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-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g) as a pale yellow liquid. 1 H NMR (CDCl3, 400 MHz) δ 7.46-7.40 (m, 6H), 5.33 (s, 2H), 4.36 (q, 2H); MS (ESI) m / z=383.0 (M + H) +

[0157] Step 4: 5-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole To a stirred solution of 5-(benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g, 20.9 mmol) prepared in Step 3 in THF (90 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 17.7 mL, 23.1 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 (4.27 mL, 20.9 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)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole as a white solid (4.5 g). 1 H NMR (CD3OD3, 400 MHz) δ 7.70 (s, 1H), 7.41-7.37 (m, 5H), 5.45 (s, 2H), 4.47(q, 2H), 1.32 (s, 12H); MS (ESI) m / z=383.2 (M + H) +

[0158] Step 5: 2-(5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-bromopyrimidin-4-amine (2.3 g, 13.2 mmol) and 5-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.6 g, 12.0 mmol) prepared in Step 4 in 1,4-dioxane (60 mL) was added 3 M K2CO3 solution (12.0 mL, 36.1 mmol) and Pd(dppf)Cl2 dichloromethane complex (983 mg, 1.2 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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (450 mg). 1 H NMR (CD3OD, 400 MHz) δ 8.10 (d, 1H), 7.98 (s, 1H), 7.38-7.35 (m, 5H), 6.36 (d, 1H), 5.49 (s, 2H), 4.53 (q, 2H); MS (ESI) m / z=350.2 (M + H) +

[0159] Step 6: 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (450 mg, 1.29 mmol) prepared in step 5 in methanol (5 mL) was added Pd(OH) on carbon (20% Pd, 45 mg) and stirred under an atmosphere of H 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)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (300 mg) as a gray solid.1 H NMR (CD3OD, 400 MHz) δ 7.85 (d, 1H), 7.77 (s, 1H), 6.22 (d, 1H), 5.49 (s, 2H), 4.47 (q, 2H); MS (ESI) m / z=260.1 (M + H) +

[0160] Preparation 35: 4-(4-aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol Step 1: 5-(benzyloxy)-1-isopropyl-1H-pyrazole To a solution of 1-isopropyl-1H-pyrazol-5-ol (2.0 g, 15.8 mmol) in DMF (20 mL) was added K2CO3 (3.29 g, 23.8 mmol) and benzyl bromide (2.26 mL, 19.0 mmol). 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-isopropyl-1H-pyrazole (2.07 g) as a colorless oil. 1 H NMR (CDCl3, 400 MHz) δ 7.40-7.36 (m, 5H), 7.32 (d, 1H), 5.54 (d, 1H), 5.07 (s, 2H), 4.57-4.51 (m, 1H), 1.43 (s, 3H), 1.41 (s, 3H); MS (ESI) m / z=217.1 (M + H) +

[0161] Step 2: 5-(benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole To a solution of 5-(benzyloxy)-1-isopropyl-1H-pyrazole (2.07 g, 9.57 mmol) prepared in step 1 in MeCN (20 mL) was added N-iodosuccinimide (2.15 g, 9.57 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 brine, dried over MgSO, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (EA / n-Hex = 0-20%) afforded 5-(benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole (2.30 g) as a colorless liquid. 1 H NMR (CDCl3, 400 MHz) δ 7.40-7.37 (m, 6H), 5.23 (s, 2H), 4.37-4.30 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); MS (ESI) m / z=343.1 (M + H) +

[0162] Step 3: 5-(benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a stirred solution of 5-(benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole (2.30 g, 6.72 mmol) prepared in Step 2 in THF (23 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 5.69 mL, 7.39 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 (1.65 mL, 8.07 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-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (1.91 g). 1 H NMR (CDCl3, 400 MHz) δ 7.65 (s, 1H), 7.41-7.36 (m, 5H), 5.38 (s, 2H), 4.47-4.44 (m, 1H), 1.33 (s, 12H), 1.30 (s, 3H), 1.26 (s, 3H); MS (ESI) m / z=343.3 (M + H) +

[0163] Step 4: 2-(5-(benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-bromopyrimidin-4-amine (1.0 g, 5.75 mmol) and 5-(benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.97 g, 5.75 mmol) prepared in Step 3 in 1,4-dioxane (30 mL) was added 3M K2CO3 solution (5.75 mL, 17.2 mmol) and Pd(dppf)Cl2 dichloromethane complex (470 mg, 0.57 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-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a brown solid (570 mg). 1 H NMR (CD3OD, 400 MHz) δ 8.09 (d, 1H), 7.92 (s, 1H), 7.33 (s, 5H), 6.34 (d, 1H), 5.40 (s, 2H), 4.47-4.44 (m, 1H), 1.15 (s, 3H), 1.13 (s, 3H); MS (ESI) m / z=310.2 (M + H) +

[0164] Step 5: 4-(4-aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (570 mg, 1.84 mmol) prepared in step 4 in methanol (10 mL) was added Pd(OH) on carbon (20% Pd, 57 mg) and stirred under an atmosphere of H 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)-1-isopropyl-1H-pyrazol-5-ol (340 mg) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.86 (d, 1H), 7.71 (s, 1H), 6.20 (d, 1H), 4.60-4.53 (m, 1H), 1.35 (s, 3H), 1.33 (s, 3H); MS (ESI) m / z=220.1 (M + H) +

[0165] Example 1: (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 Step 1: (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (250 mg, 1.010 mmol) prepared in Preparation 1 in DMA (6 mL) was added (R)-3-amino-1-butanol (108 mg, 1.212 mmol) and DIPEA (0.28 mL, 2.020 mmol). The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by column chromatography (EA / n-Hex=30-100%) to produce (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (250 mg) as a white solid. A mixture of (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (90 mg, 0.284 mmol), 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.2 mg, 0.381 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (1.0 mL, 0.995 mmol, 3.5 eq) in toluene (2 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-30%) to produce (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (105.5 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 8.10-8.09 (d, 1H), 7.95-7.94 (d, 2H), 7.83-7.82 (d, 1H), 7.26-6.95 (t, 1H), 6.78-6.77 (d, 1H), 6.65 (s, 1H), 6.15-6.14 (d, 1H), 5.06 (s, 2H), 4.53-4.49 (m, 1H), 4.44-4.40 (m, 1H), 3.97-3.93 (t, 1H), 3.65 (s, 3H), 3.44 (s, 2H), 2.15-2.09 (m, 2H), 1.38-1.36 (d, 3H); MS (ESI) m / z=490.2 (M + H) +

[0166] Step 2: (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 A suspension of (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.5 mg, 0.215 mmol), CsCO (210.5 mg, 0.646 mmol), XPhos (41.1 mg, 0.086 mmol), and Pd(dba) (39.4 mg, 0.043 mmol) prepared in Step 1 in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by C column chromatography (MeCN / water = 0-100%) to give (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 was prepared as a white solid (63 mg). 1H-NMR (CDCl3, 400MHz) δ 8.40 (s, 1H), 8.32-8.30 (d, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.36-7.06 (t, 1H), 6.81 (s, 1H), 6.44-6.43 (d, 1H), 4.81-4.76 (t, 1H), 4.34-4.34 (d, 1H), 4.12-4.09 (t, 1H), 3.81 (s, 3H), 2.23-2.14 (m, 2H), 2.03 (s, 1H), 1.50-1.49 (d, 3H); MS (ESI) m / z=454.2 (M + H) +

[0167] Example 2: (S)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (2630 mg, 9.406 mmol) prepared in Preparation 3 and (S)-3-aminobutan-1-ol (838.4 mg, 9.406 mmol) was purged with nitrogen gas for 10 minutes. DMF (20 mL) and DIPEA (3.28 mL, 18.811 mmol) were added, and the reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to produce (S)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (1840 mg). 1H-NMR (CDCl3, 400MHz) δ 8.19 (s, 1H), 8.00-7.98 (d, 1H), 7.49 (s, 1H), 6.60-6.57 (d, 1H), 4.74-4.67 (q, 2H), 3.87-3.76 (m, 3H), 1.93-1.90 (m, 1H), 1.88-1.85 (m, 1H), 1.28-1.26 (d, 3H)

[0168] Step 2: (S)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (S)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (500 mg, 1.434 mmol) prepared in Step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (274.1 mg, 1.434 mmol) prepared in Preparation 23, and 2.0 M (0.98 mL, 2.867 mmol, 2 eq) in toluene (10 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-30%) to produce (S)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (445 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 8.14-8.09 (m, 2H), 7.96 (s, 1H), 7.53 (s, 1H), 6.69 (s, 1H), 6.64 (s, 1H), 6.17-6.16 (d, 1H), 4.68-4.62 (q, 2H), 4.51-4.50 (t, 1H), 4.43-4.41 (d, 1H), 3.94 (s, 1H), 3.66 (s, 3H), 2.12-2.07 (m, 3H), 1.25-1.24 (d, 3H); MS (ESI) m / z=522.2 (M + H) +

[0169] Step 3: (S)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A suspension of (S)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (189 mg, 0.362 mmol) prepared in Step 2, CsCO (353.9 mg, 1.086 mmol), XPhos (69 mg, 0.145 mmol), and Pd(dba) (66.3 mg, 0.072 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by C column chromatography (MeCN / water = 0-100%) to give (S)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (27 mg). 1H-NMR (CDCl3, 400MHz) δ 8.37 (s, 1H), 8.32-8.30 (d, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 8.05-8.03 (d, 1H), 7.54 (brs, 2H), 6.7 (s, 1H), 6.37-6.35 MS (ESI) m / z=486.2 (M + H) +

[0170] Example 3: (R)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (R)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (450 mg, 1.609 mmol) prepared in Preparation 3 and (R)-3-amino-1-butanol (142.4 mg, 1.609 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.56 mL, 3.219 mmol) were added, and the reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to produce (R)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (267 mg). 1H-NMR (CDCl3, 400MHz) δ 8.22 (s, 1H), 8.00-7.98 (d, 1H), 7.50 (s, 1H), 6.61 (s, 1H), 4.74-4.68 (q, 2H), 3.85-3.81 (m, 3H), 2.31 (s, 1H), 1.91-1.81 (m, 2H), 1.30-1.28 (d, 3H) ); MS (ESI) m / z=349.1 (M + H) +

[0171] Step 2: (R)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (R)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (99 mg, 0.284 mmol) prepared in Step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (54.2 mg, 0.284 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.34 mL, 0.994 mmol, 3.5 eq) in toluene (1 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-30%) to produce (R)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (86 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.10-8.07 (m, 2H), 7.93 (s, 1H), 7.50-7.50 (d, 1H), 6.64-6.63 (d, 1H), 6.61 (s, 1H), 6.14-6.13 MS (ESI) m / z=522.1 (M + H)

[0172] Step 3: (R)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A suspension of (R)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (86 mg, 0.165 mmol) prepared in Step 2, CsCO (161 mg, 0.494 mmol), XPhos (31.4 mg, 0.066 mmol), and Pd(dba) (30.2 mg, 0.033 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by C column chromatography (MeCN / water = 0-100%) to give (R)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (14.1 mg). 1H-NMR (CDCl3, 400MHz) δ 8.91-8.89 (d, 1H), 8.49 (s, 1H), 8.36-8.35 (d, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.59 (s, 1H), 6.84-6.83 (d, 1H), 6.66 MS (ESI) m / z=486.2 (M + H) +

[0173] Example 4:1 1 -methyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol A mixture of 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (450 mg, 1.609 mmol) prepared in Preparation 3 and 3-amino-1-propanol (120.9 mg, 1.609 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.56 mL, 3.219 mmol) were added, and the reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to give 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol as a yellow solid (295 mg). 1H-NMR (CDCl3, 400MHz) δ 8.30 (s, 1H), 8.06 (s, 1H), 7.54 (s, 1H), 6.69 (s, 1H), 6.58 (s, 1H), 4.75-4.69 (q, 2H), 3.84-3.83 (d, 2H), 3.40-3.36 (q, 2H), 2.00-1.94 (m, 2H), 1.83 (s, 1H); MS (ESI) m / z=335.1 (M + H) +

[0174] Step 2: 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (90 mg, 0.269 mmol) prepared in Step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (51.4 mg, 0.269 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.32 mL, 0.941 mmol, 3.5 eq) in toluene (1 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-30%) to produce 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (96 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 8.13-8.09 (m, 2H), 7.96 (s, 1H), 7.49 (s, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 6.15-6.14 (d, 1H), 5.11 (brs, 2H), 4.60-4.54 (q, 2H), 4.46-4.43 (t, 2H), 3.69 (s, 3H), 3.52-3.48 (q, 2H), 2.49 (s, 1H), 2.21-2.15 (q, 2H); MS (ESI) m / z=508.1 (M + H) +

[0175] Step 3:1 1 -methyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A suspension of 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (96 mg, 0.189 mmol) prepared in Step 2, CsCO (184.7 mg, 0.567 mmol), XPhos (36.0 mg, 0.076 mmol), and Pd(dba) (34.6 mg, 0.038 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by C column chromatography (MeCN / water = 0-100%) to give 1 1 -methyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (5.4 mg). 1H-NMR (CDCl3, 400MHz) δ 9.10 (s, 1H), 8.55-8.53 (d, 2H), 8.40-8.39 (d, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 6.88-6.86 (d, 1H), 6.70 (s, 1H), 4.81-4.75 (q, 2H), 4.42 (s, 2H), 3.84 (s, 2H), 3.80 (s, 3H), 2.29 (s, 2H); MS (ESI) m / z=472.2 (M + H) +

[0176] Example 5: (R)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (R)-2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (270 mg, 0.827 mmol) prepared in Preparation 25, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (158.1 mg, 0.827 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.79 mL, 2.894 mmol, 3.5 eq) in toluene (2 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM=0-30%) to produce (R)-2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (209 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.21 (s, 1H), 8.15-8.14 (d, 1H), 8.00 (s, 1H), 6.48 (s, 1H), 6.26-6.25 (d, 1H), 5.08-5.06 (d, 1H), 4.44 (s, 2H), 3.93-3.90 (t, 1H), 3.71 (s, 3H), 2.13-2.10 (t, 2H), 1.39-1.37 (d, 3H); MS (ESI) m / z=500.0 (M + H) +

[0177] Step 2: (R)-2-(5-(3-((2-chloro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (R)-2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (209 mg, 0.418 mmol) prepared in Step 1 and 1-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (115.4 mg, 0.418 mmol) was added to a 3 M K2CO3 solution (0.42 mL, 1.255 mmol, 3 eq) and Pd(dppf)Cl2 dichloromethane complex (17.1 mg, 0.021 mmol, 0.05 eq). The mixture was degassed with argon and then heated to 80 °C under an argon atmosphere for 3 h. After completion, the mixture was diluted with water and extracted several times with CHCl2. The combined organic layers were dried over MgSO and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to give (R)-2-(5-(3-((2-chloro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (47.3 mg). 1H-NMR (CDCl3, 400MHz) δ 8.29 (s, 1H), 8.23 ​​(s, 1H), 8.12-8.11 (d, 1H), 8.03-8.01 (d, 1H), 7.98 (s, 1H), 6.95 (s, 1H), 6.64 (s, 1H), 6.22-6.21 MS (ESI) m / z=522.2 (M + H) +

[0178] Step 3: (R)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A suspension of (R)-2-(5-(3-((2-chloro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47.3 mg, 0.091 mmol), CsCO (88.6 mg, 0.272 mmol), XPhos (17.3 mg, 0.036 mmol), and Pd(dba) (16.6 mg, 0.018 mmol) prepared in Step 2 in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by C column chromatography (MeCN / water = 0-100%) to give (R)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (2.8 mg). 1H-NMR (CDCl3, 400MHz) δ 8.77-8.75 (d, 1H), 8.54 (s, 1H), 8.44-8.40 (m, 1H), 8.14 (s, 1H), 6.98 (s, 1H), 6.87-6.85 (d, 1H), 4.73-4.68 (t, 1H), 4.41 (s, 1H), 4.18-4.14 (q, 1H), 4.07 (s, 3H), 3.82 (s, 3H), 2.31-2.27 (t, 1H), 2.21-2.18 (t, 1H), 1.56-1.54 (d, 3H); MS (ESI) m / z=486.2 (M+H) +

[0179] Example 6: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 Step 1: 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.0 g, 3.88 mmol), 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.23 g, 5.05 mmol), 3M K2CO3 solution (3.88 mL, 11.65 mmol), and Pd(dppf)Cl2 (158.61 mg, 0.19 mmol) in 1,4-dioxane (20.0 mL) was stirred at 70 °C for 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-20%) to produce 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine as a white solid (943.40 mg, 3.81 mmol, yield: 98.1%). 1H-NMR (CDCl3, 400 MHz) δ 9.04 (d, 1H), 7.95 (d, 1H), 7.30 (t, 1H), 7.22 (d, 1H), 6.90 (t, 1H); MS (ESI) m / z=248.0 (M + H) +

[0180] Step 2: (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol To a solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (550.0 mg, 2.22 mmol) prepared in Step 1 in DMF (6.0 mL) was added (S)-3-aminobutan-1-ol (198.01 mg, 2.22 mmol) and DIPEA (0.77 mL, 4.44 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was added to water and extracted with EA. The combined organic layer was washed with saturated brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-100% → MeOH / DCM=0-35%) to produce (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (583.0 mg, 1.84 mmol, yield: 82.9%). 1 H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.85 (d, 1H), 7.77 (d, 1H), 7.19 (t, 1H), 6.59 (d, 1H), 6.57 (s, 1H), 4.12-3.78 (m, 3H), 3.74 (s, 1H), 1.96-1.78 (m, 2H), 1.27 (d, 3H); MS (ESI) m / z=317.1 (M + H) +

[0181] Step 3: (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino) butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (75.0 mg, 0.24 mmol) prepared in Step 2 in toluene (1.0 mL) was added (tributylphosphoranylidene)acetonitrile (0.19 mL, 0.71 mmol) and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (48.60 mg, 0.24 mmol) prepared in Preparation 24. 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 (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (95.0 mg, 0.19 mmol, yield: 79.6%). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.85 (s, 1H), 7.23 (t, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.24 (d, 1H), 5.53 (s, 2H), 4.27 (q, 2H), 3.89 (quin, 1H), 3.62 (s, 3H), 2.38 (s, 3H), 2.07 (q, 2H), 1.33 (d, 3H); MS (ESI) m / z=504.2 (M + H) +

[0182] Step 4: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 To a solution of (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (90.0 mg, 0.18 mmol) prepared in Step 3 in 1,4-dioxane (5.95 mL) was added cesium carbonate (174.57 mg, 0.54 mmol), Pd(dba) (32.71 mg, 0.04 mmol), and XPhos (34.06 mg, 0.07 mmol). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was added to water and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-100% → MeOH / DCM=0-10%) to give (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 was prepared (37.90 mg, 0.081 mmol, yield: 45.4%). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.97 (d, 1H), 7.87 (s, 1H), 7.21 (t, 1H), 6.82 (s, 1H), 6.43-6.39 (m, 1H), 4.84-4.79 (m, 1H), 4.20 (dd, 2H), 3.75 (s, 3H), 2.58 (s, 3H), 2.25-2.06 (m, 2H), 1.48 (d, 3H); MS (ESI) m / z=468.0 (M + H) +

[0183] Example 7:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,5-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol The title compound was prepared in a similar manner to Step 2 of Example 6, except that 3-amino-1-propanol (75.11 mg, 2.22 mmol) was used instead of (S)-3-aminobutan-1-ol (629.0 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.01 (s, 1H), 7.84 (d, 1H), 7.21 (t, 1H), 6.74 (d, 1H), 6.56 (s, 1H), 3.86 (t, 2H), 3.39 (q, 2H), 2.67 (s, 1H), 1.98 (quin, 2H); MS (ESI) m / z=303.1 (M + H) +

[0184] Step 2: N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-amine To a solution of 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (629.0 mg, 2.08 mmol) prepared in step 1 in DCM (6.0 mL) was added tert-butyldimethylchlorosilane (375.82 mg, 2.49 mmol), 4-dimethylaminopyridine (25.39 mg, 0.21 mmol), and triethylamine (0.58 mL, 4.16 mmol) in an ice bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 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 crude residue was purified by silica gel column chromatography (EA / n-Hex=0-70%) to produce N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-amine (866.0 mg, 2.01 mmol, yield: 99.9%). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.28 (t, 1H), 6.84 (d, 1H), 6.64 (s, 1H), 3.75 (t, 2H), 3.40 (q, 2H), 1.90 (quin, 2H), 0.92 (s, 9H), 0.06 (s, 6H); MS (ESI) m / z=417.1 (M + H) +

[0185] Step 3: N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-methylpyridin-4-amine To a solution of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-amine (500.0 mg, 1.20 mmol) prepared in Step 2 in THF (5.99 mL) was added sodium hydride (95.93 mg, 2.40 mmol) at 0° C. and stirred at 0° C. for 20 minutes. To this mixture was added iodomethane (0.22 mL, 3.60 mmol), followed by stirring at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl and diluted with EA. The aqueous phase was extracted with EA. The combined organic layer was washed with saturated brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-30%) to produce N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-methylpyridin-4-amine (269.78 mg, 0.63 mmol, yield: 2.2%). 1 H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.86 (s, 1H), 7.23 (t, 1H), 6.80 (s, 1H), 6.61 (s, 1H), 3.52 (t, 2H), 3.16 (t, 2H), 2.71 (s, 3H), 1.71-1.65 (m, 2H), 0.86 (s, 9H), 0.00 (s, 6H); MS (ESI) m / z=431.2 (M + H) +

[0186] Step 4: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propan-1-ol To a solution of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-methylpyridin-4-amine (267.54 mg, 0.62 mmol) prepared in Step 3 in THF (3.10 mL) was added tetrabutylammonium fluoride (1 M in THF, 1.24 mL, 1.24 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 prepare 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propan-1-ol (206.0 mg, 0.65 mmol, yield: 104.7%). 1 H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.87 (s, 1H), 7.30 (t, 1H), 6.82 (s, 1H), 6.60 (s, 1H), 3.57 (t, 2H), 3.20 (t, 2H), 2.68 (s, 3H), 2.94 (s, 1H), 1.76 (quin, 2H)

[0187] Step 5: 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared in the same manner as in Step 3 of Example 6, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol were replaced with 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propan-1-ol (100.0 mg, 0.32 mmol) prepared in Step 4 and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (60.36 mg, 0.32 mmol) prepared in Preparation Example 23, respectively (105.0 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.21 (t, 1H), 6.81 (s, 1H), 6.57 (s, 1H), 6.19 (d, 1H), 4.97 (s, 2H), 4.23 (t, 2H), 3.63 (s, 3H), 3.30 (t, 2H), 2.75 (s, 3H), 2.03-1.98 (m, 2H)

[0188] Step 6:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,5-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared in a similar manner to Step 4 of Example 6, except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.0 mg, 0.12 mmol) prepared in Step 5 was used instead of (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.0 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.26 (t, 1H), 6.57 (s, 1H), 6.36 (d, 1H), 4.45 (t, 2H), 3.81 (s, 3H), 3.76-3.74 (m, 2H), 2.60 (s, 3H), 2.26-2.24 (m, 2H); MS (ESI) m / z=454.2 (M + H) +

[0189] Example 8: (S)-2-(6-(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)-5-fluoropyridin-3-yl)propan-2-ol Step 1: 2-(6-bromo-5-fluoropyridin-3-yl)propan-2-ol To a solution of methyl 6-bromo-5-fluoropyridine-3-carboxylate (500 mg, 2.137 mmol) in THF (5 mL) was added dropwise methylmagnesium bromide solution (3 mL, 10.2 mmol, 3.4 M in 2-MeTHF) at -30 °C. The reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl. The reaction mixture was diluted with water, extracted with DCM, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (EA / n-Hex = 10-70%) to produce 2-(6-bromo-5-fluoropyridin-3-yl)propan-2-ol as a colorless oil (362.7 mg, 1.5495 mmol, yield: 72.525%). 1 H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.62 (d, 1H), 1.89 (s, 1H), 1.63 (s, 6H); MS (ESI) m / z=234.0, 236.0 (M + H) +

[0190] Step 2: 2-(6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)propan-2-ol To a solution of 2-chloro-4-fluoropyridine-5-boronic acid pinacol ester (398.2 mg, 1.547 mmol) in 1,4-dioxane (5 mL) was added 2-(6-bromo-5-fluoropyridin-3-yl)propan-2-ol (362 mg, 1.547 mmol) prepared in Step 1, Pd(dppf)Cl (189.5 mg, 0.232 mmol), and 3M KCO solution (1.55 mL, 4.640 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water and DCM, and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=10-60%) to produce 2-(6′-chloro-3,4′-difluoro-[2,3′-bipyridin]-5-yl)propan-2-ol as a light brown oil (296.9 mg, 1.0429 mmol, yield: 67.433%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.54 (d, 1H), 7.68 (d, 1H), 7.19 (d, 1H), 3.48 (s, 1H), 1.61 (s, 6H); MS (ESI) m / z=285.1 (M + H) +

[0191] Step 3: (S)-3-((6'-chloro-3-fluoro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol To a reaction mixture of (3S)-3-aminobutan-1-ol (82 mg, 0.92 mmol) and 2-(6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)propan-2-ol (174.6 mg, 0.613 mmol) prepared in Step 2 in DMA (2.5 mL) was added DIPEA (0.32 mL, 1.84 mmol), and the reaction mixture was stirred at 90° C. for 4 h. The reaction mixture was cooled, diluted with EA, washed with water, dried over MgSO4, and then concentrated. The crude product was purified by silica gel column chromatography (EA / n-Hex=30-100%) to produce (S)-3-((6'-chloro-3-fluoro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol as an off-white solid (209.7 mg, 0.5927 mmol, yield: 96.637%). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.56 (d, 1H), 6.50 (s, 1H), 4.98-4.80 (m, 2H), 3.84-3.73 (m, 3H), 1.90-1.80 (m, 1H), 1.70-1.60 (m, 1H), 1.62 (s, 3H), 1.54 (s, 3H), 1.16 (d, 3H); MS (ESI) m / z=354.1 (M + H) +

[0192] Step 4: (S)-2-(4'-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol A reaction mixture of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (112.94 mg, 0.591 mmol) prepared in Preparation 23, (S)-3-((6'-chloro-3-fluoro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (209 mg, 0.591 mmol) prepared in Step 3, and (tributylphosphoranylidene)acetonitrile (464.38 μL, 1.772 mmol) in toluene (2 mL) was stirred at 110 °C for 3 hours. The reaction mixture was cooled, diluted with EA, and extracted with 0.1 N hydrochloric acid solution. The aqueous layer was basified with saturated NaHCO3, extracted with EA, dried over MgSO4, and concentrated. The crude product was purified by silica gel column chromatography (EA / n-Hex=30-100%, MeOH / DCM=0-10%) to produce (S)-2-(4'-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol as a brown foam (207.7 mg, 0.3941 mmol, yield: 66.722%). 1 H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 2H), 8.04-8.03 (m, 1H), 7.95-7.93 (m, 2H), 7.45 (d, 1H), 6.68 (s, 1H), 6.13 (d, 1H), 4.71 (s, 2H), 4.53-4.50 (m, 1H), 4.39-4.35 (m, 1H), 3.98-3.95 (m, 1H), 3.69 (s, 3H), 2.31-2.27 (m, 1H), 2.03-2.00 (m, 1H), 1.51 (d, 6H), 1.33 (d, 3H); MS (ESI) m / z=527.2 (M+H) +

[0193] Step 5: (S)-2-(6-(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)-5-fluoropyridin-3-yl)propan-2-ol A suspension of (S)-2-(4'-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol (50 mg, 0.095 mmol), CsCO (92.74 mg, 0.285 mmol), Pd(dba) (17.38 mg, 0.019 mmol), and XPhos (18.09 mg, 0.038 mmol) prepared in Step 4 in 1,4-dioxane (1 mL) was stirred at room temperature for 30 min and then at 130 °C for 3 h. The reaction mixture was cooled, diluted with DCM, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (MeOH / EA = 0-10%) and triturated with EA / iPro2O to give (S)-2-(6-(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)-5-fluoropyridin-3-yl)propan-2-ol was prepared as an off-white solid (12.1 mg, 0.0247 mmol, yield: 25.999%). 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.42 (s, 2H), 8.34 (d, 1H), 8.27 (m, 1H), 8.16 (s, 1H), 7.72 (d, 1H), 7.57 (brs, 1H), 6.40 (d, 1H), 4.85 (t, 1H), 4.40-4.20 (m, 1H), 4.13-4.11 (m, 1H), 3.83 (s, 3H), 2.23-2.15 (m, 2H), 1.70 (s, 6H), 1.45 (d, 3H); MS (ESI) m / z=491.2 (M + H) +

[0194] Example 9: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 Step 1: (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (90.00 mg, 0.284 mmol) prepared in Preparation 21, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (54.33 mg, 0.284 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.27 mL, 0.882 mmol) in toluene (1 mL) was stirred at 100° C. for 3 hours. After completion of the reaction, the volatile substances were removed and the crude product was purified by column chromatography (MeOH / DCM=0-10%) to prepare (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (120.00 mg, 0.245 mmol, yield: 86.02%). 1 H-NMR (CD3OD, 400MHz) δ 8.36 (s, 1H), 8.31 (d, 1H), 8.11 (s, 1H), 7.93 (d, 1H), 7.82 (s, 1H), 7.52 (t, 1H), 7.00 (s, 1H), 6.81 (s, 1H), 6.23 (d, 1H), 4.51-4.48 (m, 2H), 4.05-4.02 (m, 1H), 3.65 (s, 3H), 2.20-2.12 (m, 2H), 1.37 (d, 3H); MS (ESI) m / z=490.1 (M + H) +

[0195] Step 2: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 A mixture of (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (136.10 mg, 0.278 mmol) prepared in Step 1, cesium carbonate (271.56 mg, 0.833 mmol), XPhos (52.98 mg, 0.111 mmol), and Pd2(dba)3 (50.88 mg, 0.056 mmol) in 1,4-dioxane (3 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 was prepared (33.00 mg, 0.073 mmol, yield: 26.20%). 1 H-NMR (CD3OD, 400MHz) δ 8.33 (d, 2H), 8.25 (d, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.58 (t, 1H), 6.96 (s, 1H), 6.69 (d, 1H), 4.75-4.70 (m, 1H), 4.27-4.22 (m, 2H), 3.81 (s, 3H), 2.30-2.20 (m, 2H), 1.49 (d, 3H); MS (ESI) m / z=454.0 (M + H) +

[0196] Example 10:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane Step 1: 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol A mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (500.00 mg, 2.019 mmol) prepared in Preparation Example 1, 4-aminopentan-1-ol (208.32 mg, 2.019 mmol), and DIPEA (0.56 mL, 4.039 mmol) in DMA (5 mL) was stirred at 80 °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 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol (400.00 mg, 1.209 mmol, yield: 59.89%). 1 H-NMR (CD3OD, 400MHz) δ 8.37 (s, 1H), 8.31 (d, 1H), 7.60 (t, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 3.79-3.73 (m, 1H), 3.61-3.58 (m, 2H), 1.74-1.63 (m, 4H), 1.29 (d, 3H); MS (ESI) m / z=331.1 (M + H) +

[0197] Step 2: 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol (93.00 mg, 0.281 mmol) prepared in Step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (64.51 mg, 0.337 mmol) prepared in Preparation 23, DEAD (244.83 mg, 0.562 mmol), and PPh (110.62 mg, 0.422 mmol) in THF (4 mL) was stirred at 80° C. for 4 hours. The reaction mixture was cooled, 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 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (7.00 mg, 0.014 mmol, yield: 4.94%). MS (ESI) m / z=504.1 (M + H). +

[0198] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane A mixture of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (19.00 mg, 0.038 mmol) prepared in step 2, cesium carbonate (36.85 mg, 0.113 mmol), XPhos (7.19 mg, 0.015 mmol), and Pd2(dba)3 (6.91 mg, 0.008 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 5 h. The reaction mixture was cooled, filtered through a Celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give 4. 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane was prepared (3.30 mg, 0.007 mmol, yield: 18.72%). 1 H-NMR (CD3OD, 400MHz) δ 8.36-8.34 (m, 2H), 8.29 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.60 (t, 1H), 6.98 (s, 1H), 6.76 (d, 1H), 4.54-4.44 (m, 2H), 4.13-4.11 (m, 1H), 3.80 (s, 3H), 2.13-2.00 (m, 3H), 1.48 (d, 3H); MS (ESI) m / z=468.1 (M + H) +

[0199] Example 11: (6 1 S,6 3 R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane Step 1: ((1R,3S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methanol The title compound was prepared as a white solid (130.00 mg, 0.379 mmol, yield: 93.91%) in the same manner as in Step 1 of Example 10, except that ((1R,3S)-3-aminocyclopentyl)methanol (46.51 mg, 0.404 mmol) was used instead of 4-aminopentan-1-ol. 1 H-NMR (CD3OD, 400MHz) δ 8.41 (d, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 7.59 (t, 1H), 7.02 (s, 1H), 6.75 (s, 1H), 4.05-4.00 (m, 1H), 3.54 (d, 2H), 2.41-2.2 3(m, 2H), 2.14-2.07 (m, 1H), 1.93-1.86 (m, 1H), 1.73-1.68 (m, 1H), 1.62-1.54 (m, 1H), 1.42-1.35 (m, 1H); MS (ESI) m / z=343.1 (M+H) +

[0200] Step 2: 2-(5-(((1R,3S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (41.00 mg, 0.079 mmol, yield: 54.48%) in the same manner as in Step 1 of Example 9, except that ((1R,3S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methanol (50.00 mg, 0.146 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 8.39 (d, 1H), 8.34 (s, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.84 (s, 1H), 7.48 (t, 1H), 6.97 (s, 1H), 6.75 (s, 1H), 6.26 (d, 1H), 4.32-4.25 (m, 2H), 4.08-4.05 (m, 1H), 3.65 (s, 3H), 2.63-2.59 (m, 1H), 2.46-2.39 (m, 1H), 2.17-2.13 (m, 1H), 2.05-1.98 (m, 1H), 1.82-1.74 (m, 1H), 1.63-1.56 (m, 1H); MS (ESI) m / z=516.1 (M + H) +

[0201] Step 3: (6 1 S,6 3 R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane The title compound was prepared as a white solid (2.50 mg, 0.005 mmol, yield: 4.48%) in the same manner as in Step 3 of Example 10, except that 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (60.00 mg, 0.116 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.37 (s, 1H), 8.30 (d, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.60 (t, 1H), 7.29 (s, 1H), 6.98 (s, 1H), 6.74 (d, 1H), 4.60-4.55 (m, 1H), 4.26-4.21 (m, 1H), 4.13-4.09 (m, 1H), 3.73 (s, 3H), 2.72-2.67 (m, 2H), 2.44-2.39 (m, 1H), 2.15-2.04 (m, 2H), 1.87-1.80 (m, 1H), 1.75-1.70 (m, 2H); MS (ESI) m / z=480.1 (M + H) +

[0202] Example 12: (R)-4 5 -(3-fluoropyridin-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 Step 1: 6'-chloro-3,4'-difluoro-2,3'-bipyridine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-fluoropyridine (170.86 mg, 0.971 mmol), 1 M K2CO3 solution (2.91 mL, 2.913 mmol), and Pd(dppf)Cl2 (118.93 mg, 0.046 mmol) in 1,4-dioxane (3 mL) was stirred at 90 °C for 2 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (hexane / EA = 0-30%) to give 6'-chloro-3,4'-difluoro-2,3'-bipyridine (99.00 mg, 0.437 mmol, yield: 45.00%). 1 H-NMR (CD3OD, 400MHz) δ 8.64-8.58 (m, 2H), 7.83-7.78 (m, 1H), 7.63-7.54 (m, 2H); MS (ESI) m / z=227.1 (M + H)+

[0203] Step 2: (R)-3-((6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol A mixture of 6'-chloro-3,4'-difluoro-2,3'-bipyridine (104.45 mg, 0.461 mmol), (R)-3-aminobutan-1-ol (49.30 mg, 0.553 mmol), and DIPEA (0.13 mL, 0.922 mmol) in DMA (3 mL) was stirred at 80 °C overnight. The reaction mixture was cooled, 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 (R)-3-((6'-chloro-3-fluoro-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (90 mg, 0.034 mmol, yield: 66.02%). 1 H-NMR (CD3OD, 400MHz) δ 8.49 (s, 1H), 8.14 (s, 1H), 7.80-7.73 (m, 1H), 7.49-7.45 (m, 1H), 6.83 (s, 1H), 3.89-3.84 (m, 1H), 3.71-3.62 (m, 2H), 1.80-1.75 (m, 2H), 1.25 (d, 3H); MS (ESI) m / z=296.1 (M + H) +

[0204] Step 3: (R)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-[2,3′-bipyridine]-4′-amine The title compound was prepared as a white solid (136.00 mg, 0.290 mmol, yield: 89.27%) in the same manner as in Step 1 of Example 9, except that (R)-3-((6'-chloro-3-fluoro-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (96.09 mg, 0.325 mmol) prepared in Step 2 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CD3OD, 400MHz) δ 8.29 (d, 1H), 8.08 (s, 1H), 7.91 (d, 1H), 7.84 (s, 1H), 7.63-7.58 (m, 1H), 7.34-7.30 (m, 1H), 6.87 (s, 1H), 6.24 (d, 1H), 4.49-4.38 (m, 2H), 4.06-4.03 (m, 1H), 3.66 (s, 3H), 2.23-2.01 (m, 2H), 1.33 (d, 3H); MS (ESI) m / z=469.1 (M + H) +

[0205] Step 4: (R)-4 5 -(3-fluoropyridin-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 The title compound was prepared as a white solid (18.70 mg, 0.043 mmol, yield: 14.86%) in the same manner as in Step 3 of Example 10, except that (R)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-[2,3′-bipyridine]-4′-amine (136.50 mg, 0.291 mmol) prepared in Step 3 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.52 (d, 1H), 8.30-8.28 (m, 3H), 8.20 (d, 1H), 7.92 (s, 1H), 7.89-7.84 (m, 1H), 7.75 (d, 1H), 7.46-7.43 (m, 1H), 6.78 (d, 1H), 4.55-4.51 (m, 1H), 4.32-4.30 (m, 1H), 4.06-4.03 (m, 1H), 2.16-1.97 (m, 2H), 1.34 (d, 3H); MS (ESI) m / z=433.1 (M + H) +

[0206] Example 13:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,7-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropan-1-ol A mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (150.00 mg, 0.606 mmol) prepared in Preparation Example 1, 3-amino-2-methylpropan-1-ol (64.80 mg, 0.727 mmol), and DIPEA (0.17 mL, 1.212 mmol) in DMA (3 mL) was stirred at 80 ° C. overnight. The reaction mixture was cooled, 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 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropan-1-ol (130.00 mg, 0.410 mmol, yield: 67.75%). 1MS (ESI) m / z=317.1 (M + H) +

[0207] Step 2: 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (104.00 mg, 0.212 mmol, yield: 65.34%) in the same manner as in Step 1 of Example 9, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropan-1-ol (102.91 mg, 0.325 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CD3OD, 400MHz) δ 8.35 (s, 1H), 8.09 (s, 1H), 7.92 (d, 1H), 7.84 (s, 1H), 7.42 (t, 1H), 6.98 (s, 1H), 6.78 (s, 1H), 6.23 (d, 3H), 4.37-4.29 (m, 2H), 3.67 (s, 3H), 3.56-3.35 (m, 2H), 2.50-2.42 (m, 1H), 1.20 (d, 3H); MS (ESI) m / z=490.1 (M + H) +

[0208] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,7-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid in the same manner as in Step 3 of Example 10, except that 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (142.61 mg, 0.291 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400MHz) δ 8.45 (s, 1H), 8.34-8.24 (m, 3H), 7.94 (s, 1H), 7.88 (t, 1H), 7.14 (s, 1H), 6.78 (d, 1H), 4.37-4.32 (m, 1H), 4.13-4.11 (m, 1H), 3.78 (s, 3H), 3.70-3.32 (m, 2H), 1.99 (d, 3H); MS (ESI) m / z=454.1 (M + H) +

[0209] Example 14:4 5 -(3-methoxypyridin-2-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)propan-1-ol A mixture of 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (100.00 mg, 0.419 mmol) prepared in Preparation 22, 3-aminopropan-1-ol (31.47 mg, 0.419 mmol), and DIPEA (0.12 mL, 0.838 mmol) in DMA (3 mL) was stirred at 80 °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 3-((6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)propan-1-ol (90.00 mg, 0.306 mmol, yield: 73.12%). MS (ESI) m / z = 294.0 (M + H). +

[0210] Step 2: N-(3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)-6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-amine The title compound was prepared as a white solid (100.00 mg, 0.214 mmol, yield: 59.91%) in the same manner as in Step 1 of Example 9, except that 3-((6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)propan-1-ol (105.02 mg, 0.358 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z=467.0 (M + H) +

[0211] Step 3:4 5 -(3-methoxypyridin-2-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (10.00 mg, 0.023 mmol, yield: 32.81%) in the same manner as in Step 3 of Example 10, except that N-(3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)-6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-amine (33.06 mg, 0.071 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400MHz) δ 8.26 (s, 1H), 8.23-8.21 (m, 2H), 8.00 (s, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.43-7.39 (m, 1H), 6.66 (d, 1H), 4.43-4.41 (m, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.58-3.57 (m, 2H), 2.14-2.13 (m, 2H); MS (ESI) m / z=431.0 (M + H) +

[0212] Example 15: (S)-4 5 -(3-methoxypyridin-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 Step 1: (S)-3-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol A mixture of 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (100.00 mg, 0.419 mmol) prepared in Preparation 22, (S)-3-aminobutan-1-ol (37.35 mg, 0.419 mmol), and DIPEA (0.12 mL, 0.838 mmol) in DMA (3 mL) was stirred at 80 °C overnight. The reaction mixture was cooled, 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)-3-((6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (113.00 mg, 0.367 mmol, yield: 87.62%). MS (ESI) m / z=308.0 (M + H) +

[0213] Step 2: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-methoxy-[2,3′-bipyridine]-4′-amine The title compound was prepared as a white solid (137.00 mg, 0.285 mmol, yield: 79.68%) in the same manner as in Step 1 of Example 9, except that (S)-3-((6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (110.03 mg, 0.358 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z=481.0 (M + H) +

[0214] Step 3: (S)-4 5 -(3-methoxypyridin-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 The title compound was prepared as a white solid (10.08 mg, 0.024 mmol, yield: 34.31%) in the same manner as in Step 3 of Example 10, except that (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-methoxy-[2,3′-bipyridine]-4′-amine (34.06 mg, 0.071 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CD3OD, 400MHz) δ 8.28 (s, 1H), 8.22-8.20 (m, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.59 (d, 1H), 7.41-7.38 (m, 1H), 6.65 (d, 1H), 4.71-4.66 (m, 1H), 4.18-4.08 (m, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 2.17-2.01 (m, 2H), 1.31 (d, 3H); MS (ESI) m / z=445.1 (M + H) +

[0215] Example 16:4 5 -(3-methoxypyridin-2-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane Step 1: 4-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)pentan-1-ol A mixture of 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (100.00 mg, 0.419 mmol) prepared in Preparation 22, 4-aminopentan-1-ol (43.23 mg, 0.419 mmol), and DIPEA (0.12 mL, 0.838 mmol) in DMA (3 mL) was stirred at 80 °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 give 4-((6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)pentan-1-ol (89.00 mg, 0.277 mmol, yield: 66.00%). MS (ESI) m / z = 322.0 (M + H). +

[0216] Step 2: N-(5-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentan-2-yl)-6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-amine The title compound was prepared as a white solid (32.00 mg, 0.065 mmol, yield: 18.08%) in the same manner as in Step 1 of Example 9, except that 4-((6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)pentan-1-ol (115.04 mg, 0.358 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z=495.0 (M + H) +

[0217] Step 3:4 5 -(3-methoxypyridin-2-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane The title compound was prepared as a white solid (4.01 mg, 0.009 mmol, yield: 12.63%) in the same manner as in Step 3 of Example 10, except that N-(5-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentan-2-yl)-6'-chloro-3-methoxy-[2,3'-bipyridine]-4'-amine (35.05 mg, 0.071 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CD3OD, 400MHz) δ 8.28 (d, 1H), 8.23 ​​(s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.60 (d, 1H), 7.43-7.40 (m, 1H), 6.75 (d, 1H), 4.59-4.55 (m, 1H), 4.35-4.09 (m, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 2.07-2.00 (m, 2H), 1.94-1.92 (m, 1H), 1.62-1.55 (m, 1H), 1.31 (d, 3H); MS (ESI) m / z=459.1 (M+H) +

[0218] Example 17: (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,8-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane Step 1: (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutan-1-ol A mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (150.00 mg, 0.606 mmol) prepared in Preparation 1, (R)-4-amino-2-methylbutan-1-ol (75.00 mg, 0.727 mmol), and DIPEA (0.17 mL, 1.212 mmol) in DMA (3 mL) was stirred overnight at 80° C. 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 produce (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutan-1-ol (190.00 mg, 0.574 mmol, yield: 94.82%). 1 MS (ESI) m / z=331.1 (M + H) +

[0219] Step 2: (R)-2-(5-(4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (15.00 mg, 0.030 mmol, yield: 4.48%) in the same manner as in Step 1 of Example 9, except that (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutan-1-ol (220.00 mg, 0.665 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z=504.1 (M + H) +

[0220] Step 3: (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,8-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane The title compound was prepared as a white solid (7.90 mg, 0.017 mmol, yield: 13.52%) in the same manner as in Step 3 of Example 10, except that (R)-2-(5-(4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (63.00 mg, 0.125 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CD3OD, 400MHz) δ 8.28 (s, 1H), 8.24-8.22 (m, 2H), 8.09 (s, 1H), 7.94 (s, 1H), 7.58 (t, 1H), 6.92 (s, 1H), 6.70 (d, 1H), 4.12-4.08 MS (ESI) m / z=468.1 (M + H) +

[0221] Example 18: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 Step 1: (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-ol A mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (130.00 mg, 0.525 mmol) prepared in Preparation Example 1, (R)-4-aminobutan-2-ol (56.16 mg, 0.630 mmol), and DIPEA (0.15 mL, 1.050 mmol) in DMA (3 mL) was stirred at 80 °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 produce (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-ol (95.00 mg, 0.300 mmol, yield: 57.13%). MS (ESI) m / z=317.1 (M + H) +

[0222] Step 2: (S)-2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (75.00 mg, 0.153 mmol, yield: 37.30%) in the same manner as in Step 1 of Example 9, except that (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-ol (130.00 mg, 0.410 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z=490.1 (M + H) +

[0223] Step 3: (S)-4 5-(1-(difluoromethyl)-1H-pyrazol-3-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 The title compound was prepared as a white solid (12.10 mg, 0.027 mmol, yield: 17.43%) in the same manner as in Step 3 of Example 10, except that (S)-2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75.00 mg, 0.153 mmol) prepared in Step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400MHz) δ 8.42 (s, 1H), 8.32-8.30 (m, 2H), 8.23 ​​(s, 1H), 8.17-8.13 (m, 1H), 7.86 (d, 1H), 7.27 (t, 1H), 6.81 (d, 1H), 6.37 MS (ESI) m / z=454.1 (M + H) +

[0224] Example 19: (S)-4 5 -(3-(difluoromethoxy)pyridin-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 Step 1: 6'-chloro-3-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-(difluoromethoxy)pyridine (231.1 mg, 0.971 mmol), 1 M KCO solution (2.91 mL, 2.913 mmol), and Pd(dppf)Cl (118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90° C. for 2 hours. The reaction mixture was cooled, filtered through a pad of Celite, and then concentrated. The crude product was purified by column chromatography (hexane / EA=0-30%) to prepare 6′-chloro-3-(difluoromethoxy)-4′-fluoro-2,3′-bipyridine (121.00 mg, 0.441 mmol, yield: 45.38%). 1 H-NMR (CDCl3, 400MHz) δ 8.63-8.56 (m, 2H), 7.68 (d, 1H), 7.46-7.43 (m, 1H), 7.22 (d, 1H), 6.50 (t, 1H); MS (ESI) m / z=275.1 (M + H) +

[0225] Step 2: (S)-3-((6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol A mixture of 6'-chloro-3-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine (121.00 mg, 0.441 mmol), (S)-3-aminobutan-1-ol (39.27 mg, 0.441 mmol), and DIPEA (0.12 mL, 0.881 mmol) prepared in Step 1 in DMA (3 mL) was stirred at 80 °C overnight. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (S)-3-((6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (150.00 mg, 0.436 mmol, yield: 99.04%). MS (ESI) m / z=344.0 (M + H)+

[0226] Step 3: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-(difluoromethoxy)-[2,3′-bipyridine]-4′-amine A mixture of (S)-3-((6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (141.09 mg, 0.410 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.47 mg, 0.410 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.437 mmol) in toluene (1 mL) was stirred at 130°C for 3 hours. After the reaction was completed, the volatiles were removed and the crude product was purified by column chromatography (MeOH / DCM = 0-10%) to produce (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridine]-4'-amine (75.00 mg, 0.153 mmol, yield: 37.30%). MS (ESI) m / z = 490.1 (M + H). +

[0227] Step 4: (S)-4 5 -(3-(difluoromethoxy)pyridin-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 A mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridine]-4'-amine (75.00 mg, 0.153 mmol), cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3 (28.04 mg, 0.031 mmol) prepared in Step 3 in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give (S)-4 5 -(3-(difluoromethoxy)pyridin-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 was prepared (9.7 mg, 0.020 mmol, yield: 13.19%). 1 H-NMR (CDCl3, 400MHz) δ 8.55-8.53 (m, 1H), 8.41 (s, 1H), 8.30 (d, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.70-7.68 (m, 1H), 7.32-7.29 (m, 1H), 7.05 MS (ESI) m / z=481.1 (M + H) +

[0228] Example 20: (S)-1 1 ,6-dimethyl-4 5 -(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 6'-chloro-4'-fluoro-3-(2,2,2-trifluoroethoxy)-2,3'-bipyridine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-(2,2,2-trifluoroethoxy)pyridine (234.94 mg, 0.971 mmol), 1 M KCO solution (2.91 mL, 2.913 mmol), and Pd(dppf)Cl (118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90° C. for 2 hours. The reaction mixture was cooled, filtered through a pad of Celite, and then concentrated. The crude product was purified by column chromatography (hexane / EA=0-30%) to produce 6′-chloro-4′-fluoro-3-(2,2,2-trifluoroethoxy)-2,3′-bipyridine (152.00 mg, 0.496 mmol, yield: 51.06%). 1 H-NMR (CDCl3, 400MHz) δ 8.57 (d, 1H), 8.46 (d, 1H), 7.43-7.34 (m, 2H), 7.19 (d, 1H), 4.44-4.38 (m, 2H); MS (ESI) m / z=242.1 (M + H) +

[0229] Step 2: (S)-3-((6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol A mixture of 6'-chloro-4'-fluoro-3-(2,2,2-trifluoroethoxy)-2,3'-bipyridine (135.10 mg, 0.441 mmol) prepared in Step 1, (S)-3-aminobutan-1-ol (39.27 mg, 0.441 mmol), and DIPEA (0.12 mL, 0.881 mmol) in DMA (3 mL) was stirred overnight at 80° C. After cooling, the reaction mixture was diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (S)-3-((6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (164.00 mg, 0.436 mmol, yield: 99.06%). MS (ESI) m / z = 376.0 (M + H). +

[0230] Step 3: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-(2,2,2-trifluoroethoxy)-[2,3′-bipyridine]-4′-amine A mixture of (S)-3-((6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (154.23 mg, 0.410 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.47 mg, 0.410 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.437 mmol) in toluene (1 mL) was stirred at 130°C for 3 hours. After the reaction was completed, the volatiles were removed and the crude product was purified by column chromatography (MeOH / DCM = 0-10%) to produce (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4'-amine (113.00 mg, 0.206 mmol, yield: 50.15%). MS (ESI) m / z = 549.1 (M + H). +

[0231] Step 4: (S)-1 1 ,6-dimethyl-4 5 -(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4'-amine (84.04 mg, 0.153 mmol) prepared in Step 3, cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3 (28.04 mg, 0.031 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give (S)-1 1 ,6-dimethyl-4 5 -(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared (29.30 mg, 0.057 mmol, yield: 37.35%). 1 H-NMR (CDCl3, 400MHz) δ 8.40-8.37 (m, 3H), 8.27 (d, 1H), 8.12 (s, 1H), 7.40-7.38 (m, 1H), 7.33 (d, 1H), 7.26-7.24 (m, 1H), 6.39 (d, 1H), 4.85-4.79 (m, 1H), 4.36-4.24 (m, 3H), 4.10-4.05 (m, 1H), 3.79 (s, 3H), 2.21-2.07 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z=513.1 (M + H) +

[0232] Example 21: (S)-4 5 -(5-fluoro-3-methoxypyridin-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 Step 1: 6'-chloro-4',5-difluoro-3-methoxy-2,3'-bipyridine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-5-fluoro-3-methoxypyridine (200.01 mg, 0.971 mmol), 1 M KCO solution (2.91 mL, 2.913 mmol), and Pd(dppf)Cl (118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90° C. for 2 hours. The reaction mixture was cooled, filtered through a pad of Celite, and then concentrated. The crude product was purified by column chromatography (hexane / EA=0-30%) to prepare 6′-chloro-4′,5-difluoro-3-methoxy-2,3′-bipyridine (105.00 mg, 0.409 mmol, yield: 42.14%). 1 H-NMR (CDCl3, 400MHz) δ 8.51 (d, 1H), 8.23 ​​(s, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 3.87 (s, 3H); MS (ESI) m / z=257.1 (M + H) +

[0233] Step 2: (S)-3-((6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol A mixture of 6'-chloro-4',5-difluoro-3-methoxy-2,3'-bipyridine (113.07 mg, 0.441 mmol), (S)-3-aminobutan-1-ol (39.27 mg, 0.441 mmol), and DIPEA (0.12 mL, 0.881 mmol) in DMA (3 mL) was stirred at 80 °C overnight. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (S)-3-((6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (133.00 mg, 0.408 mmol, yield: 92.66%). MS (ESI) m / z=326.0 (M + H) +

[0234] Step 3: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-5-fluoro-3-methoxy-[2,3′-bipyridine]-4′-amine A mixture of (S)-3-((6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (133.71 mg, 0.410 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.47 mg, 0.410 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.437 mmol) in toluene (1 mL) was stirred at 130°C for 3 hours. After the reaction was completed, the volatiles were removed and the crude product was purified by column chromatography (MeOH / DCM = 0-10%) to produce (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridine]-4'-amine (129.00 mg, 0.259 mmol, yield: 62.99%). MS (ESI) m / z = 499.1 (M + H). +

[0235] Step 4: (S)-4 5 -(5-fluoro-3-methoxypyridin-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 A mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridine]-4'-amine (76.38 mg, 0.153 mmol), cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3 (28.04 mg, 0.031 mmol) prepared in Step 3 in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give (S)-4 5 -(5-fluoro-3-methoxypyridin-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 was prepared (5.40 mg, 0.012 mmol, yield: 7.63%). 1 H-NMR (CDCl3, 400MHz) δ 8.40 (s, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.16 (d, 1H), 8.13 (s, 1H), 7.14-7.11 (m, 1H), 7.05 (d, 1H), 6.40 (d, 1H), 4.87-4.82 (m, 1H), 4.30-4.24 (m, 1H), 4.11-4.05 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.15-2.11 (m, 2H), 1.37 (d, 3H); MS (ESI) m / z=463.1 (M+H) +

[0236] Example 22: (S)-4 5 -(3-(2,2-difluoroethoxy)pyridin-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 Step 1: 6'-chloro-3-(2,2-difluoroethoxy)-4'-fluoro-2,3'-bipyridine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-(2,2-difluoroethoxy)pyridine (231.10 mg, 0.971 mmol), 1 M KCO solution (2.91 mL, 2.913 mmol), and Pd(dppf)Cl (118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90° C. for 2 hours. The reaction mixture was cooled, filtered through a pad of Celite, and then concentrated. The crude product was purified by column chromatography (hexane / EA = 0-30%) to produce 6'-chloro-3-(2,2-difluoroethoxy)-4'-fluoro-2,3'-bipyridine (138.00 mg, 0.478 mmol, yield: 49.24%). MS (ESI) m / z = 289.1 (M + H). +

[0237] Step 2: (S)-3-((6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol A mixture of 6'-chloro-3-(2,2-difluoroethoxy)-4'-fluoro-2,3'-bipyridine (150.00 mg, 0.520 mmol), (S)-3-aminobutan-1-ol (50.95 mg, 0.572 mmol), and DIPEA (0.15 mL, 1.039 mmol) prepared in Step 1 in DMA (3 mL) was stirred at 80 °C overnight. The reaction mixture was cooled, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (S)-3-((6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (130.00 mg, 0.363 mmol, yield: 69.92%). MS (ESI) m / z=358.0 (M + H) +

[0238] Step 3: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-(2,2-difluoroethoxy)-[2,3′-bipyridine]-4′-amine A mixture of (S)-3-((6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (133.00 mg, 0.372 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (71.07 mg, 0.372 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.36 mL, 1.301 mmol) in toluene (1 mL) was stirred at 130°C for 3 hours. After the reaction was completed, the volatiles were removed and the crude product was purified by column chromatography (MeOH / DCM = 0-10%) to produce (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridine]-4'-amine (49.00 mg, 0.092 mmol, yield: 24.83%). MS (ESI) m / z = 531.1 (M + H). +

[0239] Step 4: (S)-4 5 -(3-(2,2-difluoroethoxy)pyridin-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 A mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridine]-4'-amine (81.28 mg, 0.153 mmol), cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3 (28.04 mg, 0.031 mmol) prepared in Step 3 in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give (S)-4 5 -(3-(2,2-difluoroethoxy)pyridin-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 was prepared (9.10 mg, 0.018 mmol, yield: 12.02%). 1 H-NMR (CDCl3, 400MHz) δ 8.39 (s, 1H), 8.36-8.34 (m, 2H), 8.29 (d, 1H), 8.14 (s, 1H), 7.40-7.23 (m, 2H), 6.38 (d, 1H), 6.22-5.94 (m, 1H), 4.86-4.80 (m, 1H), 4.28-4.16 (m, 3H), 4.11-4.07 (m, 1H), 3.80 (s, 3H), 2.19-2.11 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z=495.1 (M + H) +

[0240] Example 23: (S)-1 1 ,6-dimethyl-4 5 -(pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 2-(6-chloro-4-fluoropyridin-3-yl)pyrazine A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromopyrazine (154.35 mg, 0.971 mmol), 1 M K2CO3 solution (2.91 mL, 2.913 mmol), and Pd(dppf)Cl2 (118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90 °C for 2 hours. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (hexane / EA = 0-30%) to produce 2-(6-chloro-4-fluoropyridin-3-yl)pyrazine (54.00 mg, 0.258 mmol, yield: 26.53%). MS (ESI) m / z=210.1 (M + H) +

[0241] Step 2: (S)-3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-(6-chloro-4-fluoropyridin-3-yl)pyrazine (54.00 mg, 0.258 mmol) prepared in Step 1, (S)-3-aminobutan-1-ol (27.56 mg, 0.309 mmol), and DIPEA (0.07 mL, 0.515 mmol) in DMA (3 mL) was stirred at 80 °C overnight. After cooling, the reaction mixture was diluted with DCM, washed with water, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to produce (S)-3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (50.00 mg, 0.179 mmol, yield: 69.63%). MS (ESI) m / z = 279.0 (M + H). +

[0242] Step 3: (S)-2-(5-(3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (S)-3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (100.00 mg, 0.359 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (68.59 mg, 0.359 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.34 mL, 1.256 mmol) in toluene (1 mL) was stirred at 130° C. for 3 hours. After completion of the reaction, the volatile substances were removed and the crude product was purified by column chromatography (MeOH / DCM=0-10%) to prepare (S)-2-(5-(3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.00 mg, 0.111 mmol, yield: 30.84%). 1 H-NMR (CDCl3, 400MHz) δ 9.02 (s, 1H), 8.85 (d, 1H), 8.48-8.46 (m, 2H), 8.38-8.37 (m, 1H), 8.09 (d, 1H), 7.98 (s, 1H), 6.72 (s, 1H), 6.15 (d, 1H), 4.94 (s, 2H), 4.56-4.42 (m, 2H), 3.99-3.96 (m, 1H), 2.17-2.12 (m, 2H), 1.39 (d, 3H); MS (ESI) m / z=452.1 (M + H) +

[0243] Step 4: (S)-1 1 ,6-dimethyl-4 5 -(pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A mixture of (S)-2-(5-(3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.00 mg, 0.111 mmol) prepared in Step 3, cesium carbonate (108.15 mg, 0.332 mmol), XPhos (21.10 mg, 0.044 mmol), and Pd2(dba)3 (20.26 mg, 0.022 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give (S)-1 1 ,6-dimethyl-4 5 -(pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared (2.00 mg, 0.005 mmol, yield: 4.35%). 1 H-NMR (DMSO-d6, 400MHz) δ 9.29 (s, 1H), 8.97 (d, 1H), 8.67 (s, 1H), 8.63-8.62 (m, 1H), 8.51 (d, 1H), 8.31-8.29 (m, 1H), 7.93 (s, 1H), 6.81 MS (ESI) m / z=416.1 (M + H) +

[0244] Example 24:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-7-(trifluoromethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 2-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol A mixture of 2-chloro-4-fluoro-5-iodopyridine (500.00 mg, 1.942 mmol), 2-(aminomethyl)-3,3,3-trifluoropropan-1-ol (277.96 mg, 1.942 mmol), and DIPEA (0.68 mL, 3.885 mmol) in DMA (7 mL) was stirred at 80 °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 2-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (640.00 mg, 1.682 mmol, yield: 86.59%). MS (ESI) m / z = 381.1 (M + H). +

[0245] Step 2: 2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol A mixture of 2-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (639.80 mg, 1.681 mmol) prepared in Step 1, 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (533.43 mg, 2.186 mmol), 1 M KCO solution (5.04 mL, 5.04 mmol), and Pd(dppf)Cl (68.65 mg, 0.084 mmol) in 1,4-dioxane (5 mL) was stirred at 70 °C for 4 hours. The reaction mixture was cooled, filtered through a pad of Celite, and concentrated. The crude product was purified by column chromatography (hexane / EA=0-30%) to produce 2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (284.00 mg, 0.766 mmol, yield: 45.56%). 1 H-NMR (CD3OD, 400MHz) δ 8.42 (s, 1H), 8.17 (s, 1H), 7.56 (t, 1H), 7.04 (d, 1H), 6.89 (s, 1H), 3.95-3.80 (m, 2H), 3.77-3.68 (m, 2H), 2.79-2.69 (m, 1H); MS (ESI) m / z=371.1 (M + H) +

[0246] Step 3: 2-(5-(2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of 2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (243.93 mg, 0.658 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (125.80 mg, 0.658 mmol) prepared in Preparation 23, and (tributylphosphoranylidene)acetonitrile (0.63 mL, 2.303 mmol) in toluene (2 mL) was stirred at 130° C. for 3 hours. After completion of the reaction, the volatile substances were removed and the crude product was purified by column chromatography (MeOH / DCM=0-10%) to prepare 2-(5-(2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (22.00 mg, 0.040 mmol, yield: 6.15%). 1 H-NMR (CD3OD, 400MHz) δ 8.41 (s, 1H), 8.12 (s, 1H), 7.91-7.87 (m, 2H), 7.39 (t, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 6.22 (d, 1H), 8.09 (d, 1H), 4.81-4.67 (m, 2H), 3.97-3.86 (m, 2H); MS (ESI) m / z=544.1 (M + H) +

[0247] Step 4:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-7-(trifluoromethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A mixture of 2-(5-(2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (22.00 mg, 0.040 mmol) prepared in step 3, cesium carbonate (39.54 mg, 0.121 mmol), XPhos (7.71 mg, 0.016 mmol), and Pd(dba) (7.41 mg, 0.008 mmol) in 1,4-dioxane (2 mL) was stirred at 130 °C for 3 h. The reaction mixture was cooled, filtered through a Celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to give 4. 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-7-(trifluoromethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared (8.50 mg, 0.017 mmol, yield: 41.41%). 1 H-NMR (CD3OD, 400MHz) δ 8.33 (s, 1H), 8.24-8.20 (m, 2H), 8.09-8.05 (m, 2H), 7.57 (t, 1H), 6.92 (d, 1H), 6.65 (d, 1H), 4.55-4.51 (m, 1H), 4.14-4.10 (m, 1H), 3.84-3.81 (m, 1H), 3.77 (s, 3H), 3.08-3.06 (m, 1H), 1.30-1.24 (m, 1H); MS (ESI) m / z=508.1 (M + H) +

[0248] Example 25:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane Step 1: 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol To a solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (150 mg, 0.606 mmol) prepared in Preparation 1 in DMA (3 mL) was added 2-aminoethan-1-ol (47.53 μL, 0.788 mmol) and DIPEA (169.34 μL, 1.212 mmol). The reaction mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by flash column chromatography (EA / n-Hex=30-100%) to produce 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol as a white solid (156 mg, 0.54 mmol, yield: 89.2%). 1 H-NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 8.37 (s, 1H), 8.23 ​​(s, 1H), 7.84 (t, 1H), 7.18 (s, 1H), 6.77 (s, 1H), 4.91 (t, 1H), 3.62 (q, 1H), 3.35 (t, 2H)

[0249] Step 2: 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol (58.29 mg, 0.202 mmol) prepared in Step 1 in toluene (1 mL) was added 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (38.6 mg, 0.202 mmol) prepared in Preparation 23 and (tributylphosphoranylidene)acetonitrile (138.13 μL, 0.505 mmol). The reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was concentrated and purified by column chromatography (MeOH / EA=0-15%) to produce 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a white solid (20 mg, 0.043 mmol, yield: 21.49%). 1 H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 2H), 8.17 (d, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.05 (t, 1H), 6.84 (s, 1H), 6.66 (s, 1H), 6.19 (d, 1H), 4.76 (s, 2H), 4.71 (t, 2H), 3.69 (t, 2H), 3.67 (s, 3H)

[0250] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane To a solution of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (18 mg, 0.039 mmol) prepared in step 2 in 1,4-dioxane (1 mL) was added Pd(dba) (7.14 mg, 0.008 mmol), XPhos (7.43 mg, 0.016 mmol), and CsCO (38.09 mg, 0.117 mmol). The reaction mixture was heated at 100 °C for 2 h. The reaction mixture was added to water and extracted with DCM. The combined organic layers were washed with water, dried over MgSO, and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / EA = 0-10%) to give 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane was prepared as a white solid (5 mg, 0.012 mmol, yield: 30.16%). 1 H-NMR (DMSO-d6, 400 MHz) δ 10.01 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.29 (d, 1H), 7.84 (t, 1H), 7.84 (s, 1H), 7.13 (s, 1H), 6.74 (d, 1H), 4.49 (t, 1H), 3.90 (t, 1H), 3.75 (s, 3H); MS (ESI) m / z=426.1 (M + H) +

[0251] Example 26:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol The title compound was prepared as in Step 1 of Example 25, except that 3-aminopropan-1-ol (92.67 μL, 1.212 mmol) was used instead of 2-aminoethan-1-ol, to give the title compound as a white solid (158 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.21 (t, 1H), 6.83 (s, 1H), 6.63 (s, 1H), 3.86 (t, 2H), 3.42 (q, 2H), 1.99 (quin, 2H)

[0252] Step 2: 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (32.5 mg) in a similar manner to Step 2 of Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (64.06 mg, 1.212 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (DMSO-d6, 400 MHz) δ 8.51 (s, 1H), 8.37 (s, 1H), 8.37 (t, 1H), 7.97 (d, 1H), 7.78 (t, 1H), 7.76 (s, 1H), 7.19 (s, 1H), 6.80 (s, 1H), 6.66 (s, 2H), 6.16 (d, 1H), 4.46 (t, 2H), 3.61 (s, 3H), 3.53 (q, 2H), 2.12 (t, 2H)

[0253] Step 3:4 5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (5.4 mg) in a similar manner to Step 3 of Example 25, except that 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (29 mg, 0.061 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.89 (s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 8.27 (s, 2H), 8.22 (t, 1H), 7.93 (s, 1H), 7.88 (t, 1H), 7.13 (s, 1H), 6.78 (d, 1H), 4.40 (s, 1H), 3.74 (s, 3H), 3.65 (s, 2H), 2.17 (s, 2H); MS (ESI) m / z=440.1 (M + H) +

[0254] Example 27:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane Step 1: 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as in Step 1 of Example 25, except 4-aminobutan-1-ol (0.07 mL, 0.808 mmol) was used instead of 2-aminoethan-1-ol, to give the title compound as a white solid (111 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.23 (t, 1H), 6.83 (s, 1H), 6.59 (s, 1H), 3.75 (s, 2H), 3.30 (q, 2H), 1.88-1.81 (m, 2H), 1.76-1.71 (m, 2H), 1.26 (s, 1H)

[0255] Step 2: 2-(5-(4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (73 mg) in a similar manner to Step 2 of Example 25, except that 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (110 mg, 0.347 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (DMSO-d6, 400 MHz) δ 8.52 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.86 (t, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 6.78 (s, 1H), 6.66 (s, 2H), 6.17 (d, 1H), 4.40 (t, 2H), 3.61 (s, 3H), 3.43-3.37 (m, 3H), 0.89 (t, 3H)

[0256] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane The title compound was prepared as an off-white solid (3.8 mg) in a similar manner to Step 3 of Example 25, except that 2-(5-(4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70 mg, 0.143 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.34 (d, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 8.05 (t, 1H), 7.86 (s, 1H), 7.49 (brs, 1H), 7.27 (t, 1H), 6.82 (s, 1H), 6.40 (d, 1H), 4.29 (s, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 1.99-1.95 (m, 4H); MS (ESI) m / z=454.2 (M + H) +

[0257] Example 28: (S)-1 1 ,6-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a white solid (41.5 mg) in the same manner as in Step 1 of Example 25, except that 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine (52 mg, 0.185 mmol) prepared in Preparation 26 and (S)-3-aminobutan-1-ol (21.39 mg, 0.24 mmol) were used instead of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine and 2-aminoethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.26 (d, 1H), 8.05 (d, 1H) 6.68 (s, 1H), 5.66 (t, 1H), 5.03 (t, 2H), 4.78 (t, 2H), 3.86-3.81 (m, 3H), 1.85 (q, 2H), 1.30 (s, 3H)

[0258] Step 2: (S)-2-(5-(3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (33 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (40 mg, 0.114 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.25 (s, 1H), 8.12-8.09 (m, 3H), 7.99 (s, 1H), 6.69 (s, 1H), 6.17 (d, 1H), 5.57 (q, 1H), 5.01 (t, 2H), 4.78-4.73 (m, 4H), 4.52-4.43 (m, 2H), 4.41-3.93 (m, 1H), 3.70 (s, 3H), 2.15-2.11 (m, 2H), 1.39 (d, 3H)

[0259] Step 3: (S)-1 1 ,6-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (7.4 mg) in a similar manner to Step 3 of Example 25, except that (S)-2-(5-(3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (32 mg, 0.061 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.86 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.27-8.26 (m, 2H), 8.11 (d, 1H) 7.91 (s, 1H), 6.77 (d, 1H), 5.66-5.62 (m, 1H), 4.93 (t, 2H), 4.63 (s, 2H), 4.53 (t, 1H), 4.32 (brs, 1H), 4.04 (brs, 1H), 3.90 (s, 3H), 2.13 (brs, 1H), 2.01 (brs, 1H), 1.37 (s, 3H); MS (ESI) m / z=488.2 (M + H) +

[0260] Example 29: (6S)-1 1 ,6-dimethyl-4 5 -(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 2-Bromo-5-((tetrahydrofuran-3-yl)oxy)pyrazine The title compound was prepared as a white solid (100 mg) in the same manner as in Step 1 of Preparation 26, except that tetrahydrofuran-3-ol (64.08 μL, 0.42 mmol) was used instead of 3-hydroxyoxetane. 1 H-NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 8.03 (s, 1H), 5.49 (s, 1H), 4.05-3.98 (m, 2H), 3.94-3.89 (m, 2H), 2.32-2.26 (m, 1H), 2.18-2.13 (m, 1H)

[0261] Step 2: 2-(6-chloro-4-fluoropyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazine The title compound was prepared as a white solid (82 mg) in the same manner as in Step 2 of Preparation 26, except that 2-bromo-5-((tetrahydrofuran-3-yl)oxy)pyrazine (91.22 mg, 0.372 mmol) prepared in Step 1 was used instead of 2-bromo-5-(oxetan-3-yloxy)pyrazine. 1 H-NMR (CDCl3, 400 MHz) δ 9.00 (d, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 7.23 (d, 1H), 5.61 (s, 1H), 4.10-3.92 (m, 4H), 2.38-2.29 (m, 1H), 2.22-2.18 (m, 1H)

[0262] Step 3: (3S)-3-((2-chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a white solid (60 mg) in the same manner as in Step 1 of Example 25, except that 2-(6-chloro-4-fluoropyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazine (54.92 mg, 0.185 mmol) and (S)-3-aminobutan-1-ol (21.39 mg, 0.24 mmol) prepared in Step 2 were used instead of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine and 2-aminoethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.03 (d, 1H), 6.68 (s, 1H), 5.59 (s, 1H), 4.08-3.91 (m, 4H), 3.85-3.80 (m, 3H), 2.35-2.30 (m, 1H), 2.20-2.17 (m, 1H), 1.85 (q, 2H), 1.30 (d, 3H)

[0263] Step 4: 2-(5-((3S)-3-((2-chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (36 mg) in the same manner as in Step 2 of Example 25, except that (3S)-3-((2-chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (41.6 mg, 0.114 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.26 (s, 1H), 8.12-8.06 (m, 2H), 8.02 (s, 1H), 7.98 (s, 1H), 6.69 (s, 1H), 6.16 (d, 1H), 5.53 (s, 1H), 4.75-4.73 (m, 2H), 4.50-4.43 (m, 2H), 4.06-3.94 (m, 5H), 3.70 (s, 3H), 2.32-2.28 (m, 1H), 2.18-2.11 (m, 3H), 1.38 (d, 3H)

[0264] Step 5: (6S)-1 1 ,6-dimethyl-4 5 -(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid in a similar manner to Step 3 of Example 25, except that 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (32.86 mg, 0.061 mmol) prepared in Step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (7.7 mg). 1H-NMR (DMSO-d6, 400 MHz) δ 9.86 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.26 (s, 2H), 8.08 (d, 1H), 7.91 (s, 1H), 6.77 (d, 1H), 5.55 (s, 1H), 4.53 (t, 1H), 4.32-4.30 (m, 1H), 4.04-3.94 (m, 1H), 3.93-3.77 (m, 3H), 3.66 (s, 3H), 2.67-2.28 (m, 1H), 2.26-2.15 (m, 4H), 1.40 (s, 3H); MS (ESI) m / z=502.2 (M + H) +

[0265] Example 30: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid in the same manner as in Step 2 of Example 25, except that 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol were used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (61.1 mg, 0.193 mmol) prepared in Preparation Example 21 and 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (50 mg, 0.193 mmol) prepared in Preparation Example 34 were used (34 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.14 (d, 1H), 8.09 (s, 1H), 7.93 (d, 1H), 7.87 (s, 1H), 7.13 (s, 1H), 6.83 (t, 1H), 6.66 (s, 1H), 6.20 (d, 1H), 4.76 (s, 2H), 4.65-4.54 (m, 4H), 3.96-3.93 (m, 2H), 2.19 -2.16 (m, 2H), 1.41 (d, 3H)

[0266] Step 2: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as an off-white solid (9.6 mg) in a similar manner to Step 3 of Example 25, except that (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (26 mg, 0.047 mmol) prepared in Step 1 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.95 (s, 1H), 8.47 (s, 1H) 8.32-8.30 (m, 2H), 8.23 ​​(s, 1H), 8.11 (s, 1H), 8.07 (d, 1H), 7.88 (t, 1H), 7.14 (s, 1H), 6.83 (d, 1H), 5.09-4.98 (m, 2H), 4.80 (t, 1H), 4.26-4.24 (m, 1H), 4.11 (brs, 1H), 2.14 (brs, 2H), 1.43 (d, 3H); MS (ESI) m / z=522.1 (M + H)+

[0267] Example 31: (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as a white solid (78.6 mg) in the same manner as in Step 1 of Example 25, except that (R)-3-amino-2-fluoropropan-1-ol (79.03 μL, 0.565 mmol) was used instead of 2-aminoethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.23 ​​(s, 1H), 7.89 (d, 1H), 7.23 (t, 1H), 6.84 (d, 1H), 6.65 (s, 1H), 4.94-4.77 (m, 1H), 3.97-3.86 (m, 2H), 3.67-3.64 (m, 1H), 3.62-3.59 (m, 1H)

[0268] Step 2: (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (53.4 mg) in a similar manner to Step 2 of Example 25, except that (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (71 mg, 0.221 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1 H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.27 (t, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.89 (d, 1H), 7.15 (t, 1H), 6.85 (d, 1H), 6.67 (s, 1H), 6.20 (d, 1H), 5.31-5.06 (m, 1H), 4.78 (s, 2H), 4.75-4.65 (m, 2H), 3.81-3.73 (m, 5H)

[0269] Step 3: (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid in a similar manner to Step 3 of Example 25, except that (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50 mg, 0.101 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (11 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36-8.34 (m, 2H), 8.28-8.26 (m, 2H), 8.17 (s, 1H), 7.89 (d, 1H), 7.51 (s, 1H), 7.28 (t, 1H), 6.82 (d, 1H), 6.40 (d, 1H), 5.04-4.91 (m, 1H), 4.84-4.71 (m, 1H), 4.58-4.50 (m, 1H), 4.30-4.24 (m, 1H), 3.85 (s, 3H), 3.73-3.63 (m, 1H); MS (ESI) m / z=458.0 (M + H) +

[0270] Example 32:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 Step 1: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol The title compound was prepared as in Step 1 of Example 25, except that 3-amino-2,2-dimethylpropan-1-ol (83.33 mg, 0.808 mmol) was used instead of 2-aminoethan-1-ol, to give the title compound as a white solid (127 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.18 (t, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 3.52 (s, 2H), 3.17 (d, 1H), 1.67 (s, 1H), 1.05 (s, 6H)

[0271] Step 2: 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (44 mg) in a similar manner to Step 2 of Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (55 mg, 0.166 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31 (s, 1H), 8.13 (d, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 6.94 (t, 1H), 6.82 (s, 1H), 6.67 (s, 1H), 6.17 (d, 1H), 4.86 (s, 2H), 4.16 (s, 2H), 3.66 (s, 3H), 3.38 (d, 2H), 1.23 (s, 6H)

[0272] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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 The title compound was prepared as a white solid (4 mg) in a similar manner to Step 3 of Example 25, except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (38 mg, 0.075 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.34-8.30 (m, 3H), 8.17 (s, 1H), 8.11 (t, 1H), 7.86 (d, 1H), 7.50 (s, 1H), 7.24 (t, 1H), 6.83 (d, 1H), 6.38 (d, 1H), 4.86 (brs, 1H), 4.30 (brs, 1H), 3.86 (s, 3H), 3.55 (brs, 1H), 2.98 (brs, 1H), 1.42 (brs, 3H), 0.99 (brs, 3H); MS (ESI) m / z=467.9 (M + H) +

[0273] Example 33: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as a white solid (78.6 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-amino-2-fluoropropan-1-ol (31.58 mg, 0.339 mmol) was used instead of 2-aminoethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.22 (s, 1H), 7.89 (d, 1H), 7.22 (t, 1H), 6.85 (d, 1H), 6.66 (s, 1H), 4.92-4.78 (m, 1H), 3.98-3.86 (m, 2H), 3.67-3.59 (m, 2H), 1.97 (brs, 1H)

[0274] Step 2: (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (50 mg) in a similar manner to Step 2 of Example 25, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (48.48 mg, 0.151 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.26 (t, 1H), 8.16 (d, 1H), 8.02 (s, 1H), 7.88 (d, 1H), 7.14 (t, 1H), 6.84 (d, 1H), 6.66 (s, 1H), 6.19 (d, 1H), 5.19-5.03 (m, 1H), 4.77 (s, 2H), 4.74-4.64 (m, 2H), 3.78-3.72 (m, 5H)

[0275] Step 3: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (12 mg) in a similar manner to Step 3 of Example 25, except that (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47 mg, 0.095 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.99 (s, 1H), 8.48 (s, 1H), 8.36-8.29 (m, 3H), 8.15 (s, 1H), 7.98 (s, 1H), 7.89 (t, 1H), 7.15 (d, 1H), 6.81 (d, 1H), 4.97-4.84 (m, 1H), 4.79-4.67 (m, 1H), 4.41 (t, 1H), 4.27-4.20 (m, 1H), 3.76 (s, 3H), 3.66-3.64 (m, 1H); MS (ESI) m / z=458.2 (M + H) +

[0276] Example 34: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -isopropyl-6-methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid in the same manner as in Step 2 of Example 25, except that 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol were used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (61.1 mg, 0.193 mmol) prepared in Preparation Example 21 and 4-(4-aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol (42.73 mg, 0.195 mmol) prepared in Preparation Example 35 were used (48 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.19 (d, 1H), 8.03 (s, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.13 (t, 1H), 6.84 (d, 1H), 6.72 (s, 1H), 6.19 (d, 1H), 4.74 (s, 2H), 4.60-4.49 (m, 2H), 4.38-4.37 (m, 1H), 4.15-4.05 (m, 1H), 2.20-2.16 (m, 2H), 1.42 (d, 6H), 1.32 (d, 3H)

[0277] Step 2: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -isopropyl-6-methyl-11 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (15 mg) in a similar manner to Step 3 of Example 25, except that (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.087 mmol) prepared in Step 1 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.35-8.33 (m, 2H), 8.21 (s, 1H), 7.92 (d, 1H), 7.88 (d, 1H), 7.44 (s, 1H), 7.23 (t, 1H), 6.84 (d, 1H), 6.38 (d, 1H), 4.96 (t, 1H), 4.52 (quin, 1H), 4.40-4.38 (m, 1H), 4.02-3.98 (m, 1H), 2.27-2.20 (m, 2H), 1.60 (d, 3H), 1.51 (d, 6H); MS (ESI) m / z=481.9 (M + H) +

[0278] Example 35:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutan-1-ol The title compound was prepared as in Step 1 of Example 25, except that 3-amino-3-methyl-butan-1-ol (50 mg, 0.485 mmol) was used instead of 2-aminoethan-1-ol, to give the title compound as a white solid (65.3 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.89 (d, 1H), 7.21 (t, 1H), 6.83 (d, 1H), 6.81 (s, 1H), 3.83 (q, 2H), 2.11 (t, 2H), 1.52 (s, 6H)

[0279] Step 2: 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (53.2 mg) in a similar manner to Step 2 of Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutan-1-ol (60 mg, 0.181 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.20 (s, 1H), 8.13 (d, 1H), 7.98 (s, 1H), 7.86 (d, 1H), 7.14 (t, 1H), 6.81-6.80 (m, 2H), 6.16 (d, 1H), 4.71 (s, 2H), 4.49 (t, 2H), 3.68 (s, 3H), 2.40 (t, 2H), 1.56 (s, 6H)

[0280] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6,6-trimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (12.5 mg) in a similar manner to Step 3 of Example 25, except that 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50 mg, 0.099 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.35-8.33 (m, 2H), 8.24 (s, 1H), 8.14 (s, 1H), 7.87 (d, 1H), 7.42 (s, 1H), 7.20 (t, 1H), 6.83 (d, 1H), 6.39 (d, 1H), 4.66 (t, 2H), 3.82 (s, 3H), 2.43 (t, 2H), 1.64 (s, 6H); MS (ESI) m / z=467.9 (M + H) +

[0281] Example 36:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropan-1-ol The title compound was prepared as a white solid (106.8 mg) in the same manner as in Step 1 of Example 25, except that 3-amino-2,2-difluoropropan-1-ol (53.84 mg, 0.485 mmol) was used instead of 2-aminoethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.33 (s, 1H), 7.91 (d, 1H), 7.23 (t, 1H), 6.86 (d, 1H), 6.77 (s, 1H), 3.95-3.81 (m, 4H), 2.36 (s, 1H)

[0282] Step 2: 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (53 mg) in a similar manner to Step 2 of Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropan-1-ol (100 mg, 0.295 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.39 (t, 1H), 8.10 (d, 1H), 8.04 (s, 1H), 7.90 (d, 1H), 7.10 (t, 1H), 6.87 (d, 1H), 6.80 (s, 1H), 6.18 (d、1H)、4.81-4.74 (m、4H)、4.01 (t、2H)、3.78 (s、3H)

[0283] Step 3:4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-1 1 -methyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (13 mg) in a similar manner to Step 3 of Example 25, except that 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.5 mg, 0.101 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 10.07 (s, 1H), 8.54 (s, 1H), 8.38-8.35 (m, 2H), 8.31 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.90 (t、1H)、7.18 (d、1H)、6.83 (d、1H)、4.61 (brs、2H)、4.16 (brs、2H)、3.78 (s、3H); MS (ESI) m / z=475.9 (M + H) +

[0284] Example 37:1 1 ,7,7-trimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine The title compound was prepared as an off-white solid (586 mg) in the same manner as in Preparation 1, except that (1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)boronic acid (587.57 mg, 3.03 mmol) was used instead of 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H-NMR (CDCl3, 400 MHz) δ 9.00 (d, 1H), 7.61 (d, 1H), 7.18 (d, 1H), 6.79 (dd, 1H), 4.80 (q, 2H)

[0285] Step 2: 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol The title compound was prepared as a white solid (165 mg) in the same manner as in Step 1 of Example 25, except that 3-amino-2,2-dimethyl-1-propanol (126.36 mg, 1.225 mmol) and 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (137 mg, 0.49 mmol) prepared in Step 1 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.20 (s, 1H), 7.58 (d, 1H), 6.75 (d, 1H), 6.66 (s, 1H), 3.52 (s, 2H), 3.17 (d, 2H), 1.07 (s, 6H)

[0286] Step 3: 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (137 mg) in the same manner as in Step 2 of Example 25, except that 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (160 mg, 0.441 mmol) prepared in Step 2 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.32 (t, 1H), 8.14 (d, 1H), 7.99 (s, 1H), 7.52 (d, 1H), 6.73 (d, 1H), 6.66 (s, 1H), 6.17 (d, 1H), 4.72 (s, 2H), 4.52 (q, 2H), 4.20 (s, 2H), 3.65 (s, 3H), 3.38 (d, 2H), 1.24 (s, 6H)

[0287] Step 4:1 1 ,7,7-trimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (12 mg) in the same manner as in Step 3 of Example 25, except that 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (130 mg, 0.243 mmol) prepared in Step 3 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.34-8.28 (m, 4H), 8.18 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.73 (d, 1H), 6.37 (d, 1H), 4.86 (brs, 1H), 4.73 (s, 2H), 4.27 (brs, 1H), 3.87 (s, 3H), 3.56 (brs, 1H), 2.96 (brs, 1H), 1.44 (brs, 3H), 0.98 (brs, 3H); MS (ESI) m / z=499.9 (M + H) +

[0288] Example 38:1 1 ,7,7-trimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol The title compound was prepared as a white solid (95.8 mg) in the same manner as in Step 1 of Example 25, except that 3-amino-2,2-dimethyl-1-propanol (41.2 mg, 0.399 mmol) and 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine (75 mg, 0.266 mmol) prepared in Preparation 26 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 8.47 (d, 1H), 8.31 (s, 1H), 8.27 (d, 1H), 6.66 (s, 1H), 5.71-5.65 (m, 1H), 5.05 (t, 2H), 4.81-4.77 (m, 2H), 3.50 (s, 2H), 3.13 (d, 2H), 1.04 (s, 6H)

[0289] Step 2: 2-(5-(3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (45 mg) in the same manner as in Step 2 of Example 25, except that 3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (79.04 mg, 0.217 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.40 (t, 1H), 8.33 (d, 1H), 8.24 (s, 1H), 8.07 (d, 1H), 8.00 (s, 1H), 7.91 (d, 1H), 6.69 (s, 1H), 6.14 (d, 1H), 5.60-5.53 (m, 1H), 5.00 (t, 1H), 4.76-4.73 (m, 2H), 4.71 (s, 2H), 4.12 (s, 2H), 3.70 (s, 3H), 3.36 (d, 2H)

[0290] Step 3:1 1 ,7,7-trimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (5.5 mg) in a similar manner to Step 3 of Example 25, except that 2-(5-(3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (43 mg, 0.08 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.55 (t, 1H), 8.48 (d, 1H), 8.35 (d, 2H), 8.29 (s, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.45 (s, 1H), 6.39 (d, 1H), 5.71-5.65 MS (ESI) m / z=502.2 (M + H) +

[0291] Example 39: (S)-1 1 ,8-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-4-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a white solid (77.6 mg) in the same manner as in Step 1 of Example 25, except that (2R)-4-aminobutan-2-ol (35.6 mg, 0.399 mmol) and 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine (75 mg, 0.266 mmol) prepared in Preparation 26 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.44 (d, 1H), 8.30 (s, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 6.64 (s, 1H), 5.69-5.65 (m, 1H), 5.06-5.03 (m, 2H), 4.80-4.77 (m, 2H), 4.01 (s, 1H), 3.40-3.35 (m, 2H), 1.89-1.77 (m, 2H), 1.31 (d, 3H)

[0292] Step 2: (S)-2-(5-((4-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid (75 mg) in the same manner as in Step 2 of Example 25, except that (S)-4-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-ol (79.04 mg, 0.217 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H), 8.20 (s, 1H), 8.14 (t, 1H), 8.08 (d, 1H), 8.03 (s, 1H), 7.89 (d, 1H), 6.67 (s, 1H), 6.16 (d, 1H), 5.78-5.55 (m, 1H), 5.09-5.06 (m, 1H), 5.01 (t, 2H), 4.78-4.73 (m, 4H), 3.71 (s, 3H), 3.63-3.52 (m, 2H), 2.24-2.20 (m, 1H), 2.00-1.96 (m, 1H), 1.26 (d, 3H)

[0293] Step 3: (S)-1 1 ,8-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as an off-white solid (3 mg) in a similar manner to Step 3 of Example 25, except that (S)-2-(5-((4-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg, 0.139 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.53 (t, 1H), 8.47 (d, 1H), 8.42 (s, 1H), 8.36 (d, 1H), 8.26 (s, 2H), 8.25 (s, 1H), 7.33 (brs, 1H), 6.38 (d, 1H), 5.71-5.65 (m, 1H), 5.54-5.52 (m, 1H), 5.06 (t, 2H), 4.81 (t, 2H), 4.10-4.02 (m, 1H), 3.78 (s, 3H), 3.60-3.49 (m, 1H), 2.31-2.27 (m, 1H), 1.96-1.91 (m, 1H), 1.13 (d, 3H); MS (ESI) m / z=487.9 (M + H) +

[0294] Example 40: (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-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 Step 1: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3′-bipyridine]-4′-amine The title compound was prepared as a light brown solid (96 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (61.4 mg, 0.321 mmol) prepared in Preparation 28 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.17 (s, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.99 (s, 1H), 7.48 (dd, 1H), 6.72 (s, 1H), 6.17 (d, 1H), 4.74 (s, 2H), 4.48-4.43 (m, 2H), 3.99-3.94 (m, 1H), 3.70 (s, 3H), 3.48 (s, 2H), 2.49 (brs, 8H), 2.31 (s, 3H), 2.24-2.16 (m, 1H), 2.11-2.03 (m, 1H), 1.39 (d, 3H)

[0295] Step 2: (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-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 The title compound was prepared as a white solid in a similar manner to Step 3 of Example 25, except that 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine was replaced with (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3′-bipyridine]-4′-amine (83 mg, 0.143 mmol) prepared in Step 1 was used (21 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.43-8.42 (m, 2H), 8.38 (s, 1H), 8.35-8.33 (m, 2H), 8.31 (s, 1H), 8.16 (s, 1H), 7.60 (d, 1H), 6.42 (d, 1H), 4.84 (t, 1H), 4.33-4.31 (m, 1H), 4.13-4.11 (m, 1H), 3.83 (s, 3H), 3.60 (s, 2H), 2.56-2.51 (m, 8H), 2.34 (s, 3H), 2.26-2.15 (m, 1H), 2.04-2.03 (m, 1H), 1.44 (d, 3H); MS (ESI) m / z=545.2 (M + H) +

[0296] Example 41: (S)-1 1 ,6-dimethyl-4 5 -(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 2-Bromo-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridine To a solution of 2-bromo-4-fluoro-pyridine (150 mg, 0.852 mmol) in DMA (2 mL) was added 3-(2,2,2-trifluoroethyl)azetidine hydrochloride (179.58 mg, 1.023 mmol) and DIPEA (0.36 mL, 2.557 mmol). The reaction mixture was heated at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by column chromatography (EA / n-Hex=0-40%) to produce 2-bromo-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridine as a colorless oil (225 mg, 0.761 mmol, yield: 89.46%). 1H-NMR (CDCl3, 400 MHz) δ 7.97 (d, 1H), 6.42 (d, 1H), 6.20 (dd, 1H), 4.19 (t, 2H), 3.74 (t, 2H), 3.19-3.12 (m, 1H), 2.57-2.47 (m, 2H)

[0297] Step 2: 6'-chloro-4'-fluoro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-2,3'-bipyridine The title compound was prepared as a pale yellow solid in the same manner as in Preparation 1, except that 2-bromo-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridine (220 mg, 0.746 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (230.36 mg, 0.895 mmol) prepared in Step 1 were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (149.8 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.97 (d, 1H), 8.37 (d, 1H), 7.18 (d, 1H), 6.66 (t, 1H), 6.31 (dd, 1H), 4.24 (t, 2H), 3.79 (t, 2H), 3.21-3.15 (m, 1H), 2.59-2.51 (m, 2H)

[0298] Step 3: (S)-3-((6'-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a white solid (80.3 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminobutan-1-ol (79.84 mg, 0.862 mmol) and 6'-chloro-4'-fluoro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-2,3'-bipyridine (149 mg, 0.431 mmol) prepared in Step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.92 (d, 1H), 8.25 (s, 1H), 8.20 (d, 1H), 6.63 (s, 1H), 6.53 (d, 1H), 6.24 (dd, 1H), 4.24 (t, 2H), 3.84-3.75 (m, 5H), 3.19-3.16 (m, 2H), 2.59-2.49 (m, 2H), 1.90-1.84 (m, 2H), 1.29 (d, 3H)

[0299] Step 4: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3′-bipyridine]-4′-amine The title compound was prepared as a white foam (61 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (78 mg, 0.188 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 9.21 (d, 1H), 8.26 (s, 1H), 8.15 (d, 1H), 8.11 (d, 1H), 7.98 (s, 1H), 6.63 (s, 1H), 6.49 (d, 1H), 6.18 (dd, 2H), 4.86 (s, 2H), 4.56-4.51 (m, 1H), 4.43-4.38 (m, 1H), 4.20 (t, 2H), 3.94-3.88 (m, 1H), 3.76-3.72 (m, 2H), 3.20-3.10 (m, 1H), 2.66 (s, 3H), 2.55-2.50 (m, 2H), 2.13-2.12 (m, 2H), 1.37 (d, 3H)

[0300] Step 5: (S)-1 1 ,6-dimethyl-4 5 -(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (5.1 mg) in a similar manner to Step 3 of Example 25, except that (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3′-bipyridine]-4′-amine (33 mg, 0.056 mmol) prepared in Step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 9.29 (d, 1H), 8.34-8.33 (m, 2H), 8.25-8.24 (m, 2H), 8.15 (s, 1H), 7.63 (brs, 1H), 6.58 (d, 1H), 6.40 (d, 1H), 6.23 (dd,1H), 4.83 (t,1H), 4.29-4.23 (m,2H), 4.12-4.09 (m,1H), 3.83 (s,3H), 3.81-3.77 (m,2H), 3.21-3.14 (m,1H), 2.57-2.52 (m,2H), 2.24-2.16 (m, 3H), 1.45 (d, 3H); MS (ESI) m / z=552.3 (M + H) +

[0301] Example 42: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol The title compound was prepared as a white solid (167 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminopentan-1-ol hydrochloride (169.17 μL, 1.212 mmol) was used instead of 2-aminoethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.90-7.86 (m, 2H), 7.20 (t, 1H), 6.79 (d, 1H), 6.69 (s, 1H), 3.82 (t, 2H), 3.74-3.73 (m, 1H), 2.07 (brs, 1H), 1.98-1.94 (m, 1H), 1.82-1.63 (m, 5H)

[0302] Step 2: (S)-2-(5-((3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (48 mg) in a similar manner to Step 2 of Example 25, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol (163 mg, 0.493 mmol) prepared in Step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.15 (d, 1H), 8.10 (s, 1H), 8.01-7.99 (m, 2H), 7.88 (d, 1H), 7.13 (t, 1H), 6.84 (d, 1H), 6.70 (s, 1H), 6.19 (d, 1H), 4.86 (s, 2H), 4.54-4.50 (m, 1H), 4.45-4.43 (m, 1H), 3.85-3.80 (m, 1H), 3.70 (s, 3H), 2.23-2.20 (m, 1H), 2.08-2.04 (m, 1H), 1.96-1.88 (m, 2H), 1.86-1.69 (m, 2H), 1.48-1.42 (m, 1H), 1.04 (t, 3H)

[0303] Step 3: (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a white solid (11.7 mg) in a similar manner to Step 3 of Example 25, except that (S)-2-(5-((3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.089 mmol) prepared in Step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.35-8.33 (m, 2H), 8.17 (s, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.49 (brs, 1H), 7.21 (t, 1H), 6.85 (d, 1H), 6.40 (d, 1H), 4.93-4.87 (m, 1H), 4.16-4.11 (m, 1H), 4.10-4.07 (m, 1H), 3.83 (s, 3H), 2.30-2.24 (m, 2H), 2.16-2.13 (m, 1H), 1.88-1.85 (m, 1H), 1.21 (t, 3H); MS (ESI) m / z=468.2 (M + H) +

[0304] Example 43: (S)—N-(3,3-difluorocyclobutyl)-2-(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)pyridin-4-amine Step 1: 2-Bromo-N-(3,3-difluorocyclobutyl)pyridin-4-amine The title compound was prepared as a colorless oil (170.2 mg) in the same manner as in Step 1 of Example 41, except that 3,3-difluorocyclobutanamine hydrochloride (183.54 mg, 1.278 mmol) was used instead of 3-(2,2,2-trifluoroethyl)azetidine hydrochloride.1 H-NMR (CDCl3, 400 MHz) δ 7.98 (d, 1H), 6.58 (d, 1H), 6.39 (dd, 1H), 4.71 (brs, 1H), 3.92-3.86 (m, 1H), 3.17-3.08 (m, 2H), 2.57-2.50 (m, 2H)

[0305] Step 2: 6'-chloro-N-(3,3-difluorocyclobutyl)-4'-fluoro-[2,3'-bipyridine]-4-amine The title compound was prepared as a pale yellow solid in the same manner as in Preparation 1, except that 2-bromo-N-(3,3-difluorocyclobutyl)pyridin-4-amine (220.24 mg, 0.837 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (258.69 mg, 1.005 mmol) prepared in Step 1 were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (173 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.97 (d, 1H), 8.37 (d, 1H), 7.17 (d, 1H), 6.83 (s, 1H), 6.43 (dd, 1H), 4.50 (d, 1H), 3.97-3.95 (m, 1H), 3.16-3.07 (m, 2H), 2.56-2.49 (m, 2H)

[0306] Step 3: (S)-3-((6'-chloro-4-((3,3-difluorocyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a white solid (132.6 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminobutan-1-ol (98.32 mg, 1.103 mmol) and 6'-chloro-N-(3,3-difluorocyclobutyl)-4'-fluoro-[2,3'-bipyridine]-4-amine (173 mg, 0.551 mmol) prepared in Step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.23-8.22 (m, 2H), 6.76 (s, 1H), 6.64 (s, 1H), 6.40 (dd, 1H), 4.86 (brs, 1H), 4.02-3.98 (m, 1H), 3.99-3.77 (m, 3H), 3.20-3.04 (m, 2H), 2.62-2.50 (m, 2H), 1.94-1.80 (m, 2H), 1.30 (d, 3H)

[0307] Step 4: (S)-N 4 '-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N 4 -(3,3-difluorocyclobutyl)-[2,3'-bipyridine]-4,4'-diamine The title compound was prepared as a light brown solid (69 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-4-((3,3-difluorocyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (116.34 mg, 0.304 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 9.16 (d, 1H), 8.25 (s, 1H), 8.17-8.13 (m, 2H), 8.00 (s, 1H), 6.70 (d, 1H), 6.65 (s, 1H), 6.33 (dd, 1H), 6.18 (d, 1H), 4.80 (s, 2H), 4.78-4.76 (m, 1H), 4.57-4.52 (m, 1H), 4.46-4.40 (m, 1H), 3.94-3.92 (m, 2H), 3.68 (s, 3H), 3.13-3.11 (m, 2H), 2.56-2.51 (m, 2H), 2.15-2.11 (m, 2H), 1.38 (d, 3H)

[0308] Step 5: (S)-N-(3,3-difluorocyclobutyl)-2-(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)pyridin-4-amine Instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine, (S)-N 4 '-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N 4 The title compound was prepared as in Step 3 of Example 25, except that -(3,3-difluorocyclobutyl)-[2,3'-bipyridine]-4,4'-diamine (56 mg, 0.101 mmol) was used, to give the title compound as a beige solid (18.1 mg). 1H-NMR (CDCl3, 400 MHz) δ 9.27 (d, 1H), 8.35-8.33 (m, 2H), 8.26-8.23 (m, 2H), 8.16 (s, 1H), 7.68 (s, 1H), 6.75 (d, 1H), 6.42-6.37 (m, 2H), 4.87-4.80 (m, 1H), 4.48-4.47 (m, 1H), 4.30-4.28 (m, 1H), 4.16-4.10 (m, 1H), 4.09-3.99 (m, 1H), 3.83 (s, 3H), 3.19-3.12 (m, 2H), 2.56-2.51 (m, 2H), 2.24-2.17 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=520.3 (M + H) +

[0309] Example 44: (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-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 Step 1: 4-((6-bromo-5-fluoropyridin-3-yl)methyl)morpholine The title compound was prepared as a white solid (254.7 mg) in the same manner as in Step 1 of Preparation 27, except that morpholine (102.49 mg, 1.176 mmol) was used instead of 1-methylpiperazine. 1 H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 7.51 (dd, 1H), 3.73 (t, 4H), 3.52 (s, 2H), 2.47 (t, 4H)

[0310] Step 2: 4-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)morpholine Instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 4-((6-bromo-5-fluoropyridin-3-yl)methyl)morpholine (254 mg, 0.923 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (246.63 mg, 0.958 mmol) prepared in step 1 were used, in the same manner as in preparation example 1, except that the title compound was prepared as a pale yellow solid (54 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (d, 1H), 8.50 (s, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.11 (t, 4H), 3.60 (s, 2H), 2.51 (t, 4H)

[0311] Step 3: (S)-3-((6'-chloro-3-fluoro-5-(morpholinomethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a white solid (125 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminobutan-1-ol (98.32 mg, 1.103 mmol) and 4-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)morpholine (154 mg, 0.473 mmol) prepared in Step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.41-8.39 (m, 2H), 7.98 (d, 1H), 7.64 (d, 1H), 6.71 (s, 1H), 3.86-3.76 (m, 7H) 3.60 (s, 2H), 2.53 (s, 4H), 1.89-1.79 (m, 3H), 1.30 (d, 3H)

[0312] Step 4: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-5-(morpholinomethyl)-[2,3′-bipyridine]-4′-amine The title compound was prepared as a light brown solid (130 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-5-(morpholinomethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (120 mg, 0.304 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.16 (s, 1H), 8.11 (d, 1H), 8.06 (d, 1H), 7.98 (s, 1H), 7.47 (d, 1H), 6.72 (s, 1H), 6.17 (d, 1H), 4.73 (s, 2H), 4.48-4.43 (m, 2H), 4.00-3.97 (m, 1H), 3.74-3.72 (m, 4H), 3.70 (s, 3H), 3.45 (s, 2H), 2.47-2.45 (m, 4H), 2.24-2.19 (m, 1H), 2.10-2.05 (m, 1H), 1.29 (d, 3H)

[0313] Step 5: (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-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 The title compound was prepared as a pale yellow solid (21.48 mg) in the same manner as in Step 3 of Example 25, except that (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-5-(morpholinomethyl)-[2,3′-bipyridine]-4′-amine (102 mg, 0.18 mmol) prepared in Step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.43-8.42 (m, 2H), 8.39 (s, 1H), 8.35 (d, 1H), 8.29 (d, 1H), 8.16 (s, 1H), 7.63-7.60 (m, 2H), 6.40 (d, 1H), 4.84-4.82 MS (ESI) m / z=532.3 (M + H) +

[0314] Example 45: (S)-4 5 -(3-fluoro-5-(piperidin-1-ylmethyl)pyridin-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 Step 1: 2-Bromo-3-fluoro-5-(piperidin-1-ylmethyl)pyridine The title compound was prepared as a white solid (132.1 mg) in the same manner as in Step 1 of Preparation 27, except that piperidine (100.18 mg, 1.176 mmol) was used instead of 1-methylpiperazine. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.50 (dd, 1H), 3.47 (s, 2H), 2.39 (s, 4H), 1.62-1.57 (m, 4H), 1.49-1.45 (m, 2H)

[0315] Step 2: 6'-chloro-3,4'-difluoro-5-(piperidin-1-ylmethyl)-2,3'-bipyridine Instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 2-bromo-3-fluoro-5-(piperidin-1-ylmethyl)pyridine (132 mg, 0.483 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (149.33 mg, 0.58 mmol) prepared in step 1 were used, in the same manner as in preparation example 1, except that the title compound was prepared as a pale yellow solid (87 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.65 (d, 1H), 8.47 (s, 1H), 7.60 (d, 1H), 7.22 (d, 1H), 3.56 (s, 2H), 2.43 (s, 4H), 1.64-1.58 (m, 4H), 1.50-1.27 (m, 2H)

[0316] Step 3: (S)-3-((6'-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a white solid (125 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminobutan-1-ol (28.58 mg, 0.321 mmol) and 6'-chloro-3,4'-difluoro-5-(piperidin-1-ylmethyl)-2,3'-bipyridine (86.5 mg, 0.267 mmol) prepared in Step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1 H-NMR (CDCl3, 400 MHz) δ 8.40-8.37 (m, 2H), 7.98 (d, 1H), 7.62 (d, 1H), 6.70 (s, 1H), 3.85-3.78 (m, 3H), 3.55 (d, 2H), 2.45 (s, 4H), 1.89-1.81 (m, 3H), 1.65 (s, 4H), 1.50-1.49 (m, 2H), 1.31 (d, 3H)

[0317] Step 4: (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3′-bipyridine]-4′-amine The title compound was prepared as a light brown solid (77.5 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3'-bipyridine]-4'-yl)amino)butan-1-ol (58.1 mg, 0.304 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.18 (s, 1H), 8.13-8.08 (m, 2H), 7.99 (s, 1H), 7.50 (d, 1H), 6.72 (s, 1H), 6.17 (d, 1H), 4.73 (s, 2H), 4.48-4.44 (m, 2H), 3.99-3.94 (m, 1H), 3.71 (s, 3H), 3.44 (s, 2H), 2.40 (s, 4H), 2.23-2.16 (m, 1H), 2.11-2.04 (m, 1H), 1.47 (s, 4H), 1.39 (d, 3H), 1.36-1.27 (m, 2H)

[0318] Step 5: (S)-4 5 -(3-fluoro-5-(piperidin-1-ylmethyl)pyridin-2-yl)-1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane The title compound was prepared as a pale yellow solid (16 mg) in the same manner as in Step 3 of Example 25, except that (S)—N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6′-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3′-bipyridine]-4′-amine (57 mg, 0.101 mmol) prepared in Step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.41-8.40 (d, 2H), 8.38 (s, 1H), 8.35 (d, 1H), 8.28 (d, 1H), 8.16 (s, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 6.40 (d, 1H), 4.84 (t, 1H), 4.32-4.31 (m, 1H), 4.13-4.11 (m, 1H), 3.83 (s, 3H), 3.55 (s, 2H), 2.45 (s, 4H), 2.21-2.05 (m, 2H), 1.66-1.61 (m, 4H), 1.50 (d, 3H), 1.15 (d, 3H); MS (ESI) m / z=530.3 (M + H) +

[0319] Example 46: 2-((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)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine Step 1: 2-Bromo-N-((1r,3r)-3-methoxycyclobutyl)pyridin-4-amine The title compound was prepared as a colorless oil (182.4 mg) in the same manner as in Step 1 of Example 41, except that (1r,3r)-3-methoxycyclobutan-1-amine hydrochloride (183.54 mg, 1.278 mmol) was used instead of 3-(2,2,2-trifluoroethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 7.94 (d, 1H), 6.54 (d, 1H), 6.33 (dd, 1H), 4.47 (s, 1H), 4.15-4.02 (m, 2H), 3.29 (s, 3H), 2.51-2.44 (m, 2H), 2.21-2.16 (m, 2H)

[0320] Step 2: 6'-chloro-4'-fluoro-N-((1r,3r)-3-methoxycyclobutyl)-[2,3'-bipyridine]-4-amine The title compound was prepared as a pale yellow solid in the same manner as in Preparation 1, except that 2-bromo-N-((1r,3r)-3-methoxycyclobutyl)pyridin-4-amine (215.26 mg, 0.837 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (258.69 mg, 1.005 mmol) prepared in Step 1 were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (124 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.95 (d, 1H), 8.32 (d, 1H), 7.16 (d, 1H), 6.78 (s, 1H), 6.39 (dd, 1H), 4.46-4.44 (m, 1H), 4.13-4.07 (m, 2H), 3.28 (s, 3H), 2.51-2.45 (m, 2H), 2.23-2.16 (m, 2H)

[0321] Step 3: (S)-3-((6'-chloro-4-(((1r,3S)-3-methoxycyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a white solid (109.4 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminobutan-1-ol (65.38 mg, 0.733 mmol) and 6'-chloro-4'-fluoro-N-((1r,3r)-3-methoxycyclobutyl)-[2,3'-bipyridine]-4-amine (112.86 mg, 0.367 mmol) prepared in Step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1 H-NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 8.21-8.17 (m, 2H), 6.72 (s, 1H), 6.63 (s, 1H), 6.37 (d, 1H), 4.17-4.10 (m, 2H), 3.84-3.77 (m, 3H), 3.30 (s, 3H), 2.53-2.47 (m, 2H), 2.26-2.18 (m, 2H), 1.95-1.84 (m, 2H), 1.30 (d, 3H)

[0322] Step 4:N 4 '-((S)-4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N 4 -((1r,3S)-3-Methoxycyclobutyl)-[2,3'-bipyridine]-4,4'-diamine The title compound was prepared as a light brown solid (126.3 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-4-(((1r,3S)-3-methoxycyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (94.48 mg, 0.251 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 9.23 (d, 1H), 8.27 (s, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 6.67-6.64 (m, 2H), 6.32-6.30 (m, 1H), 6.18 (d, 1H), 4.75 (s, 2H), 4.54-4.44 (m, 3H), 4.14-4.10 (m, 2H), 3.68 (s, 3H), 3.30 (s, 3H), 2.52-2.47 (m, 2H), 2.22-2.11 (m, 4H), 1.38 (d, 3H)

[0323] Step 5: 2-((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)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine Instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine, 4 '-((S)-4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N 4 The title compound was prepared as in Step 3 of Example 25, except that -((1r,3S)-3-methoxycyclobutyl)-[2,3′-bipyridine]-4,4′-diamine (108 mg, 0.196 mmol) was used, to give a pale yellow solid (24.3 mg). 1H-NMR (CDCl3, 400 MHz) δ 9.25 (d, 1H), 8.34-8.32 (d, 2H), 8.24 (s, 1H), 8.21 (d, 1H), 8.15 (s, 1H), 7.70 (brs, 1H), 6.71 (d, 1H), 6.39 (d, 1H), 6.34 (dd, 1H), 4.84 (t, 1H), 4.44-4.43 (m, 1H), 4.29-4.27 (m, 1H), 4.18-4.08 (m, 3H), 3.83 (s, 3H), 3.31 (s, 3H), 2.53-2.48 (m, 2H), 2.26-2.16 (m, 3H), 1.45 (d, 3H); MS (ESI) m / z=514.3 (M + H) +

[0324] Example 47: 2-((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)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine Step 1: 2-Bromo-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine The title compound was prepared as a colorless oil (162.7 mg) in the same manner as in Step 1 of Example 41, except that (1S,3S)-3-methoxycyclopentan-1-amine hydrochloride (175.93 mg, 1.278 mmol) was used instead of 3-(2,2,2-trifluoroethyl)azetidine hydrochloride. 1 H-NMR (CDCl3, 400 MHz) δ 7.92 (d, 1H), 6.62 (d, 1H), 6.38 (dd, 1H), 4.25 (s, 1H), 4.00-3.92 (m, 2H), 3.32 (s, 3H), 2.29-2.23 (m, 2H), 2.01-1.82 (m, 1H), 1.65-1.58 (m, 1H), 1.49-1.44 (m, 1H), 1.30-1.26 (m, 1H)

[0325] Step 2: 6'-chloro-4'-fluoro-N-((1S,3S)-3-methoxycyclopentyl)-[2,3'-bipyridine]-4-amine The title compound was prepared as a pale yellow solid in the same manner as in Preparation 1, except that 2-bromo-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine (227 mg, 0.837 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (258.69 mg, 1.005 mmol) prepared in Step 1 were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (118 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.94 (d, 1H), 8.30 (d, 1H), 7.16 (d, 1H), 6.84 (d, 1H), 6.47 (dd, 1H), 4.26-4.24 (m, 1H), 4.04-3.92 (m, 1H), 3.30 (s, 3H), 2.30-2.25 (m, 2H), 2.02-1.98 (m, 1H), 1.84-1.76 (m, 1H), 1.66-1.52 (m, 1H), 1.46 (m, 1H), 1.27-1.24 (m, 1H)

[0326] Step 3: (S)-3-((6'-chloro-4-(((1S,3S)-3-methoxycyclopentyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol The title compound was prepared as a white solid (100.8 mg) in the same manner as in Step 1 of Example 25, except that (S)-3-aminobutan-1-ol (65.38 mg, 0.733 mmol) and 6'-chloro-4'-fluoro-N-((1S,3S)-3-methoxycyclopentyl)-[2,3'-bipyridine]-4-amine (118 mg, 0.367 mmol) prepared in Step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine. 1H-NMR (CDCl3, 400 MHz) δ 8.77 (brs, 1H), 8.21 (s, 1H), 8.16 (d, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 6.44 (dd, 1H), 4.16-4.06 (m, 2H), 3.97-3.96 (m, 1H), 3.84-3.77 (m, 3H), 3.32 (s, 3H), 2.32-2.27 (m, 2H), 2.05-1.89 (m, 1H), 1.86-1.66 (m, 5H), 1.30 (d, 3H)

[0327] Step 4:N 4 '-((S)-4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N 4 -((1S,3S)-3-Methoxycyclopentyl)-[2,3'-bipyridine]-4,4'-diamine The title compound was prepared as a light brown solid (107.2 mg) in the same manner as in Step 2 of Example 25, except that (S)-3-((6'-chloro-4-(((1S,3S)-3-methoxycyclopentyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (98 mg, 0.251 mmol) prepared in Step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 9.23 (d, 1H), 8.27 (s, 1H), 8.18 (d, 1H), 8.09 (d, 1H), 8.00 (s, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 6.38 (dd, 1H), 6.18 (d, 1H), 4.74 (s, 2H), 4.56-4.52 (m, 1H), 4.45-4.41 (m, 1H), 4.27-4.25 (m, 1H), 4.07-3.97 (m, 1H), 3.98-3.90 (m, 2H), 3.68 (s, 3H), 3.33 (s, 3H), 2.30-2.26 (m, 2H), 2.15-2.09 (m, 2H), 2.07-1.98 (m, 1H), 1.86-1.82 (m, 1H), 1.38 (d, 3H)

[0328] Step 5: 2-((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)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine Instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine, 4 '-((S)-4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N 4 The title compound was prepared as in Step 3 of Example 25, except that -((1S,3S)-3-methoxycyclopentyl)-[2,3′-bipyridine]-4,4′-diamine (195 mg, 0.168 mmol) was used, to give a pale yellow solid (25.77 mg). 1H-NMR (CDCl3, 400 MHz) δ 9.24 (d, 1H), 8.34-8.32 (m, 2H), 8.24 (s, 1H), 8.19 (d, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 6.78 (d, 1H), 6.41-6.38 (m, 2H), 4.84 (t, 1H), 4.24-4.08 (m, 3H), 3.97-3.96 (m, 1H), 3.83 (s, 3H), 3.33 (s, 3H), 2.32-2.15 (m, 4H), 2.07-2.03 (m, 2H), 1.71-1.64 (m, 2H), 1.46-1.45 (m, 1H), 1.29 (d, 3H); MS (ESI) m / z=528.3 (M + H) +

[0329] Example 48: (3-fluoro-2-(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)pyridin-4-yl)methanol Step 1: tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate To a solution of 3-amino-2,2-dimethylpropan-1-ol (347.18 mg, 3.365 mmol) in DCM (6 mL) was added TEA, followed by di-tert-butyl dicarbonate. The reaction mixture was stirred at room temperature overnight. Water was added, and the reaction mixture was extracted with DCM. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to produce tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (690 mg, 3.394 mmol, quantitative) as a white solid. 1 H-NMR (CDCl3, 400 MHz) δ 4.85 (s, 1H), 3.69 (t, 1H), 3.21 (d, 2H), 2.98 (d, 2H), 1.47 (s, 9H), 0.87 (s, 6H)

[0330] Step 2: (6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-4-yl)methanol The title compound was prepared as an off-white solid in the same manner as in Preparation 1, except that (2-bromo-3-fluoropyridin-4-yl)methanol (200 mg, 0.971 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (299.99 mg, 1.165 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (176 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.67 (d, 1H), 8...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: During the ceremony, R １ and R ２ are each independently hydrogen or C optionally substituted with one or more halogens. １－６ is alkyl, A is a 5-10 membered heteroaryl; R ３ and R ４ are independent of each other, hydrogen; halogen; Halogen, hydroxy, and halogen, hydroxy, C １－６ Alkyl, Hydroxyl-C １－６ Alkyl, C substituted with one or more halogens １－６ alkyl, C optionally substituted with one or more halogens １－６ Alkoxy, -CH ２ -S(O) ２ -C １－６ C optionally substituted with alkyl, oxo, and one or more OH ３－６ C optionally substituted with one or more substituents selected from the group consisting of 4- to 8-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of cycloalkyl １－６ Alkyl; C optionally substituted with one or more halogens １－６ Alkoxy; -S(O) ２ -C １－６ Alkyl; Halogen, C optionally substituted with one or more halogens １－６ Alkyl, and mono- or di-(C １－６ 4-8 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of (alkyl)amino; Halogen, C １－６ Alkyl, and halo-C １－６ -O-4 to 8 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl; or Halogen and C optionally substituted with one or more halogens １－６ -NHC optionally substituted with one or more substituents selected from the group consisting of alkoxy ３－６ is cycloalkyl, L is a linear or branched C ２－６ alkylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene; R ５ is hydrogen or C １－６ is alkyl, R ６ and R ７ are, independently of each other, hydrogen, halogen, or halo-C １－６ is alkyl, X １ is CH or N.

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 C optionally substituted with one or more halogens １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, pyrazinyl, thiazolyl, pyridinyl, or pyrimidinyl.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered heterocyclyl is azetidinyl, oxetanyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[2.3]hexanyl, pyrrolidinyl, 2-thio-6-azaspiro[3.3]heptanyl, hexahydro-1H-thieno[3,4-c]pyrrolyl, or 2-azaspiro[3.3]heptanyl.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is ethylene, n-propylene, 1-methylpropylene, 1-ethylpropylene, 3-methylpropylene, 2-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, n-butylene, 1-methylbutylene, 3-methylbutylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene.

8. (1) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (2) (S)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (3) (R)-1 1 ,6-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (4) 1 1 -methyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (5) (R)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (6) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (7) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,5-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (8) (S)-2-(6-(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)-5-fluoropyridin-3-yl)propan-2-ol; (9) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (10) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (11) (6 1 S,6 3 R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane; (12) (R)-4 5 -(3-fluoropyridin-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; (13) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,7-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (14) 4 5 -(3-methoxypyridin-2-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (15) (S)-4 5 -(3-methoxypyridin-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; (16) 4 5 -(3-methoxypyridin-2-yl)-1 1 ,6-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (17) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,8-dimethyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (18) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (19) (S)-4 5 -(3-(difluoromethoxy)pyridin-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; (20) (S)-1 1 ,6-dimethyl-4 5 -(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (21) (S)-4 5 -(5-fluoro-3-methoxypyridin-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; (22) (S)-4 5 -(3-(2,2-difluoroethoxy)pyridin-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; (23) (S)-1 1 ,6-dimethyl-4 5 -(pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (24) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-7-(trifluoromethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (25) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-8-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane; (26) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (27) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -methyl-1 1 H-10-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane; (28) (S)-1 1 ,6-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (29) (6S)-1 1 ,6-dimethyl-4 5 -(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (30) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (31) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (32) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (33) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (34) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 -isopropyl-6-methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (35) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (36) 4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (37) 1 1 ,7,7-trimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (38) 1 1 ,7,7-trimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (39) (S)-1 1 ,8-dimethyl-4 5 -(5-(oxetan-3-yloxy)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (40) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-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; (41) (S)-1 1 ,6-dimethyl-4 5 -(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (42) (S)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (43) (S)-N-(3,3-difluorocyclobutyl)-2-(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)pyridin-4-amine; (44) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-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; (45) (S)-4 5 -(3-fluoro-5-(piperidin-1-ylmethyl)pyridin-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; (46) 2-((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)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine; (47) 2-((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)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine; (48) (3-fluoro-2-(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)pyridin-4-yl)methanol; (49) (S)-(1-((6-(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)-5-fluoropyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methanol; (50) (S)-4 5 -(3-fluoro-5-((4-fluoropiperidin-1-yl)methyl)pyridin-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; (51) 4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (52) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (53) 4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (54) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-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; (55) (S)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (56) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-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; (57) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-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; (58) (S)-4 5 -(5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridin-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; (59) (S)-4 5 -(5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridin-2-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; (60) (S)-4 5 -(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-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; (61) (S)-4 5 -(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-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; (62) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[oxetane-3,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (63) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[cyclopropane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (64) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[cyclobutane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (65) 5′-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1′-methylspiro[cyclopentane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (66) (R)-4 5 -(1-(difluoromethyl)-1H-pyrazol-3-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; (67) (S)-1 1 ,6-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (68) (S)-1 1 ,8-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (69) (S)-7-Fluoro-1 1 -methyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (70) (R)-7-Fluoro-1 1 -methyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (71) 1 1 ,7,7-trimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (72) (R)-1 1 ,8-dimethyl-4 5 -(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (73) (S)-1 1 ,8-dimethyl-4 5 -(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (74) (S)-1 1 ,6-dimethyl-4 5 -(2-(trifluoromethyl)thiazol-4-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (75) (R)-1 1 ,6-dimethyl-4 5 -(2-(trifluoromethyl)thiazol-4-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (76) (S)-4 5 -(1,4-dimethyl-1H-pyrazol-3-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; (77) (S)-4 5 -(1,4-dimethyl-1H-pyrazol-3-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; (78) (S)-4 5 -(5-(difluoromethoxy)pyrazin-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; (79) (S)-2-(6-(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)pyridin-3-yl)propan-2-ol; (80) (S)-2-(6-(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)pyridin-3-yl)propan-2-ol; (81) (S)-4 5 -(4-(difluoromethoxy)pyridin-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; (82) (S)-4 5 -(4-(difluoromethoxy)pyridin-2-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; (83) (S)-4 5 -(4-(difluoromethoxy)pyridin-2-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; (84) 4 5 -(4-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (85) (S)-4 5 -(5-(difluoromethoxy)pyridin-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; (86) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-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; (87) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (88) (R)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-7-fluoro-1 1 -methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (89) 4 5 -(5-(difluoromethoxy)pyridin-2-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; (90) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-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; (91) 4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,7,7-tetramethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (92) (S)-4 5 -(4-(difluoromethoxy)-3-fluoropyridin-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; (93) (S)-1 1 ,6-dimethyl-4 5 -(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (94) (S)-4 5 -(3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-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; (95) 2-(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)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol; (96) 2-(6-((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)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol; (97) 1,1,1-trifluoro-2-(6-(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)pyridin-3-yl)propan-2-ol; (98) 1,1,1-trifluoro-2-(6-((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 -yl)pyridin-3-yl)propan-2-ol; (99) (S)-4 5 -(4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridin-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; (100) (S)-4 5 -(4-(3-(2,2-difluoropropyl)azetidin-1-yl)pyridin-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; (101) (S)-1 1 ,6-dimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (102) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (103) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (104) 1 1 ,1 3 ,7,7-tetramethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (105) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (106) (S)-4 5 -(5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-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; (107) (S)-4 5 -(5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-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; (108) (S)-4 5 -(5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-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; (109) (S)-4 5 -(5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (110) (S)-4 5 -(5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (111) (S)-4 5 -(5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-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; (112) (S)-4 6 -(1-(difluoromethyl)-1H-pyrazol-3-yl)-1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4),4(3,5)-dipyrimidina-1(4,5)-pyrazolacyclononaphane; (113) (S)-2-(5-fluoro-6-(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)pyridin-3-yl)propan-2-ol; (114) (S)-2-(5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (115) (S)-4 5 -(3-fluoro-5-(methylsulfonyl)pyridin-2-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; (116) (S)-4 5 -(3-fluoro-5-(methylsulfonyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (117) 1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol; (118) 1-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol; (119) (S)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (120) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-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; (121) (S)-4 5 -(3-fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (122) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-2-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; (123) (S)-4 5 -(3-fluoro-5-(morpholinomethyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (124) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (125) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-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; (126) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (127) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(morpholinomethyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (128) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-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; (129) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-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; (130) (S)-4 5 -(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (131) (S)-4 5 -(5-((4,4-difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (132) (S)-4 5 -(5-(difluoromethoxy)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (133) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (134) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (135) (S)-2-(5-(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)pyrazin-2-yl)propan-2-ol; (136) (S)-4 5 -(3-fluoro-5-(((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (137) (S)-4 5 -(3-fluoro-5-(((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (138) (S)-4 5 -(3-fluoro-5-(((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (139) (S)-2-(5-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyrazin-2-yl)propan-2-ol; (140) (S)-6-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (141) (S)-6-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; (142) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (143) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyrazin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (144) 5-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide; (145) 5-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide; (146) (S)-4 5 -(3-fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (147) (S)-4 5 -(3-fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (148) (S)-4 5 -(3-fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-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; (149) (S)-4 5 -(3-fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (150) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyrimidin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (151) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(methylsulfonyl)pyrimidin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (152) (R)-2-(5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (153) (R)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(methylsulfonyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (154) (R)-4 5 -(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (155) (S)-2-(2-(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)pyrimidin-5-yl)propan-2-ol; (156) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (157) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol; (158) (S)-2-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (159) (S)-1-(1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (160) (S)-2-((5-fluoro-6-(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)pyridin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-ol; (161) (S)-2-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol; (162) (S)-1-(1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol; (163) (S)-2-(2-(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)pyridin-4-yl)propan-2-ol; (164) (S)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-4-yl)propan-2-ol; (165) (S)-2-(6-(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)pyridin-2-yl)propan-2-ol; (166) (S)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-2-yl)propan-2-ol; (167) (R)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (168) (R)-1-((5-fluoro-6-((S)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)pyrrolidin-3-ol; (169) (S)-1-((5-fluoro-6-(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)pyridin-3-yl)methyl)piperidin-4-ol; (170) (S)-1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)piperidin-4-ol; (171) (S)-1-((5-fluoro-6-(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)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol; (172) (S)-1-((5-fluoro-6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol; (173) (R)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)piperidin-3-ol; (174) (S)-1-((5-fluoro-6-((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 -yl)pyridin-3-yl)methyl)piperidin-3-ol; (175) (S)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (176) (R)-2-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)propan-2-ol; (177) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-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; (178) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (179) (R)-4 5 -(5-(2-fluoropropan-2-yl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (180) (S)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyrimidin-5-yl)propan-2-ol; (181) (R)-2-(2-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyrimidin-5-yl)propan-2-ol; (182) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyrimidin-2-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; (183) (S)-4 5 -(5-(2-fluoropropan-2-yl)pyrimidin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (184) (S)-N,N-dimethyl-1-(6-(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)pyridin-3-yl)piperidin-4-amine; (185) (S)-N,N-dimethyl-1-(6-(1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -yl)pyridin-3-yl)piperidin-4-amine; (186) (S)-4 5 -(5-(difluoromethyl)pyridin-2-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; (187) (S)-4 5 -(5-(difluoromethyl)pyridin-2-yl)-1 1 ,1 3 ,8-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (188) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(trifluoromethyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (189) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(trifluoromethyl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (190) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and (191) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane 2. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

9. 10. 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 8, or a pharmaceutically acceptable salt thereof.

10. 10. The method of claim 9, wherein the protein kinase-mediated disease is cancer or an immune disease.

11. 11. The method of claim 10, 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.

12. The method of claim 10, wherein the cancer is lung cancer.

13. 11. The method of claim 10, wherein the cancer is non-small cell lung cancer.

14. 10. 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 8, or a pharmaceutically acceptable salt thereof, or administering to a patient a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

15. 15. The method of claim 14, 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.

16. 15. The method of claim 14, 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).

17. 15. The method of claim 14, 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.

18. 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 15. The method of claim 14, wherein the mutant is at least one triple mutant selected from the group consisting of L858R / T790M / L718X (X = Q, V).

19. 15. The method of claim 14, 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.

20. A pharmaceutical composition for treating a protein kinase-mediated disease, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient.

21. 21. The pharmaceutical composition of claim 20, wherein the protein kinase-mediated disease is cancer or an immune disease.

22. 22. The pharmaceutical composition of claim 21, 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.

23. 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 8 or a pharmaceutically acceptable salt thereof as an active ingredient.

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