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 is hydrogen, halogen, C 1-6 Alkyl or halo-C 1-6 is alkyl, R2 and R3 are each independently hydrogen or C optionally substituted with one or more halogens. 1-6 is alkyl, B is C 2-3 Alkylene, C 2-3 Alkenylene, or C2-3 is alkynylene, A is C 6-10 aryl or 5-10 membered heteroaryl; R4 is hydrogen, halogen, -CN, -S(O)2-C 1-6 Alkyl, 4-7 membered heterocyclyl optionally substituted with one or more halogen or OH; -CO-4 to 7 membered heterocyclyl optionally substituted with one or more halogen or OH; C optionally substituted with one or more halogens 1-6 Alkoxy; C optionally substituted with one or more halogens 1-6 alkyl; and C optionally substituted with one or more halogens 3-6 cycloalkyl is selected from the group consisting of n is 0, 1, 2, or 3; L is a linear or branched C 3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene; R5 is hydrogen or halogen; Y 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, C 1-6 Alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Unless otherwise defined, alkyl refers to any of the C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably C 1-3 refers to alkyl.

[0019] As used herein, "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 "cycloalkyl" refers to a substituted or unsubstituted cyclic alkyl, such as C 3-20Cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, unless otherwise defined, cycloalkyl refers to a C 3-8 Cycloalkyl or C 3-6 It may be cycloalkyl.

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

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

[0027] 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.

[0028] 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.

[0029] The present invention also provides pharmaceutical compositions comprising at least one compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.

[0030] 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.

[0031] In one embodiment, provided herein is a compound of Formula (I) as shown below, a pharmaceutically acceptable salt, diastereomer, enantiomer, racemate, tautomer, prodrug, hydrate, or solvate thereof: [ka] During the ceremony, R1 is hydrogen, halogen, C 1-6 Alkyl or halo-C 1-6 is alkyl, R2 and R3 are each independently hydrogen or C optionally substituted with one or more halogens. 1-6 is alkyl, B is C 2-3 Alkylene, C 2-3 Alkenylene, or C 2-3 is alkynylene, A is C 6-10 aryl or 5-10 membered heteroaryl; R4 is hydrogen, halogen, -CN, -S(O)2-C 1-6 Alkyl, 4-7 membered heterocyclyl optionally substituted with one or more halogen or OH; -CO-4 to 7 membered heterocyclyl optionally substituted with one or more halogen or OH; C optionally substituted with one or more halogens 1-6 Alkoxy; C optionally substituted with one or more halogens 1-6alkyl; and C optionally substituted with one or more halogens 3-6 cycloalkyl is selected from the group consisting of n is 0, 1, 2, or 3; L is a linear or branched C 3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene; R5 is hydrogen or halogen; Y is CH or N.

[0032] In certain embodiments, R1 may be hydrogen, halogen, or methyl.

[0033] In certain embodiments, R2 may be hydrogen or methyl. Preferably, R2 may be methyl.

[0034] In certain embodiments, B can be -CH2CH2-, -CH=CH-, or -C≡C-.

[0035] In certain embodiments, A can be phenyl, pyrazolyl, triazolyl, pyrazinyl, or pyridinyl.

[0036] In certain embodiments, L can be n-propylene, 1-methylpropylene, 3-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene.

[0037] Representative compounds of formula (I) are listed below. (1) (S)-2 5 -Fluoro-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (3) (S)-1 1 ,8-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (4) (S)-1 1 ,6-dimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (5) (S)-1 1 ,8-dimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (6) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (7) 1 1 ,7,7-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (8) 1 1 ,6,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (9) (R)-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (10) (S)-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (11) (S)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (12) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (13) (S)-11 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (14) (S)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (15) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (16) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (17) (S)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (18) (S)-4 5 -((1-isopropyl-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (19) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-3-yl)ethynyl)-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 -((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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)-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (23) (S)-7-Fluoro-1 1 -methyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (24) (R)-7-Fluoro-1 1 -methyl-4 5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (25) (S)-1 1 ,8-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (26) (S)-1 1 ,8-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (27) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (28) (S)-1 1 ,8-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (29) 1′-methyl-5′-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (30) 1 1 ,7,7-trimethyl-4 5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (31) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (32) (R)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (33) (R)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-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-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (35) (6S)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (36) 1 1 -methyl-4 5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (37) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (38) (R)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (39) (R)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (40) (R)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (41) (6R)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (42) (R)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (43) (S)-6-Methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (44) (S)-1 1 -ethyl-6-methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (45) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (46) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -ethyl-6-methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (47) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -isopropyl-6-methyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (48) (S)-1 1 ,2 5 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (49) (S)-1 1 ,2 6 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (50) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (51) 1′-methyl-5′-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (52) 1′-methyl-5′-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (53) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (54) (S)-1 1 ,6-dimethyl-4 5 -((5-methylpyrazin-2-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (55) (S,E)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (56) (S)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (57) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (58) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane; (59) (S)-(4-hydroxypiperidin-1-yl)(4-((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)ethynyl)phenyl)methanone; (60) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (61) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (62) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (63) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (64) (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (65) (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (66) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (67) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (68) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (69) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((4-morpholinophenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (70) (S)-1 1,1 3 ,8-trimethyl-4 5 -((4-morpholinophenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (71) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (72) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (73) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (74) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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; (75) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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; (76) (R)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; and (77) (R)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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.

[0038] Further representative compounds of formula (I) are listed below. (6) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (16) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (17) (S)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (50) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (59) (S)-(4-hydroxypiperidin-1-yl)(4-((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)ethynyl)phenyl)methanone. (60) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (61) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (62) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (63) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (66) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (67) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (68) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (70) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-morpholinophenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (71) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (72) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (73) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (74) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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; (75) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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; (76) (R)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; and (77) (R)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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. More preferred representative compounds of formula (I) are listed below. (50) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (61) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (63) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (66) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (67) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (72) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (73) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; and (75) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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 or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0043] The compounds of the present invention can be synthesized by methods known in the art or by methods illustrated in Examples 1-77 below.

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

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

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

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

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

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

[0050] [Table 1]

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 Reaction Scheme 1: [ka]

[0063] In Reaction Scheme 1, R1, R2, R3, R4, R5, A, and L are the same as above; B is C 2-3 is alkynylene; and X is halogen.

[0064] Specifically, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof can be prepared using a process comprising the steps of: reacting a compound of formula (II) with NH2-L(R5)-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (III) to obtain a compound of formula (VI), reacting the compound of formula (VI) with a compound of formula (VII) to obtain a compound of formula (VIII), and cyclizing the compound of formula (VIII) to obtain a compound of formula (Ia).

[0065] In the process of Reaction Scheme 1, compounds of formula (II), (III), and NH2-L(R5)-OH are commercially available. The reaction of compound of formula (II) with NH2-L(R5)-OH may be carried out in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, or DIPEA. The reaction may be carried out in an organic solvent such as anhydrous THF, DMF, or DMA at room temperature or under heating, for example, at a temperature of 40 to 120°C.

[0066] The Sonogashira reaction couples a compound of formula (IV) with a compound of formula (III) to give a compound of formula (VI). The reaction of compounds of formulas (IV) and (III) may be carried out in the presence of a base such as TEA or diethylamine, and a catalyst such as a palladium complex such as PdCl2(PPh3)2, Pd(PPh3)4, or copper(I) iodide, or a copper(I) halide. The reaction may be carried out in an organic solvent such as TEA or DMF at room temperature or under heating, for example, at temperatures between 40 and 100°C.

[0067] Alternatively, the compound of formula (VI) may be prepared by reacting a compound of formula (II) with a compound of formula (III) to give a compound of formula (V), and reacting the compound of formula (V) with NH2-L(R5)-OH.

[0068] The Sonogashira reaction couples a compound of formula (II) with a compound of formula (III) to give a compound of formula (V). The reaction of compounds of formulas (II) and (III) may be carried out in the presence of a base such as triethyl ether (TEA) or diethylamine, and a catalyst such as a palladium complex such as PdCl2(PPh3)2, Pd(PPh3)4, or copper(I) iodide, or a copper(I) halide. The reaction may also be carried out in an organic solvent such as TEA or DMF at room temperature or under heating, for example, at temperatures between 40 and 100°C.

[0069] The reaction of the compound of formula (V) with NH-L(R)-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.

[0070] The compound of formula (VI) is coupled with the compound of formula (VII) via the Mitsunobu reaction to obtain the compound of formula (VIII). The reaction of the compounds of formula (VI) and (VII) 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 (VIII) is cyclized to give the compound of formula (Ia) by the Buchwald-Hartwig reaction. The cyclization reaction of the compound of formula (VIII) 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, compounds of formula (Ib) may be prepared according to the following Reaction Scheme 2: [ka]

[0073] In Reaction Scheme 2, R1, R2, R3, R4, R5, A, and L are the same as defined above.

[0074] The hydrogenolysis of compounds of formula (Ia) may be carried out in the presence of a palladium on carbon catalyst such as Pd / C, Pd(OH)2 / C, etc., under a hydrogen atmosphere, and the reaction may be carried out in an anhydrous organic solvent such as THF, DCM, MeOH, etc., at room temperature or under heating. In one embodiment, the compound of formula (VII) may be prepared according to the following reaction scheme 3: [ka]

[0075] In Reaction Scheme 3, R1, R2, or R3 is the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0076] Specifically, the compound of formula (VII) can be prepared using a process comprising the steps of reacting a compound of formula (IX) with a compound of formula (X) to obtain a compound of formula (XI), and hydrogenolysis of the compound of formula (XI) to obtain a compound of formula (VII).

[0077] In the process of Scheme 3, the compound of formula (IX) is commercially available. The reaction of the compound of formula (IX) with the compound of formula (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 THF or 1,4-dioxane under heating, for example, at a temperature of 40 to 100°C.

[0078] The hydrogenolysis of compounds of formula (XI) 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. In another embodiment, compounds of formula (X) may be prepared according to the following Reaction Scheme 4: [ka]

[0079] In Reaction Scheme 4, R2 and R3 are the same as above; X is a halogen; and M is B(OH)2 or BPin.

[0080] Specifically, the compound of formula (X) can be prepared using a process comprising the steps of: reacting a compound of formula (XII) with Bn-X to obtain a compound of formula (XIII), halogenating the compound of formula (XIII) to obtain a compound of formula (XIV), and boronating the compound of formula (XIV) to obtain a compound of formula (X).

[0081] In the process of Reaction Scheme 4, the compounds of formula (XII) and Bn-X are commercially available. The reaction of the compound of formula (XII) 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.

[0082] The halogenation of the compound of formula (XIII) 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.

[0083] The boronation of the compound of formula (XIV) may be carried out in the presence of a boron reagent such as B2Pin2, B2Cat2, or i-proOBPin, or an organometallic reagent 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 a temperature between −10 and 30° C. [Example]

[0084] 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.

[0085] 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:

[0086] [Table 2] JPEG2026507654000009.jpg138168

[0087] Production Example 1: (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol A suspension of 2-chloro-4-fluoro-5-iodopyridine (350 mg, 1.36 mmol), (2S)-3-amino-2-fluoro-propan-1-ol (126.58 mg, 1.36 mmol), and DIPEA (0.59 mL, 3.399 mmol) in DMA (6.06 mL) was stirred at 90 °C for 3 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 = 0-50%) to produce (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol as an off-white solid (375 mg, 1.135 mmol, yield: 83.45%). 1 H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 6.51 (s, 1H), 5.21 (brs, 1H), 4.90-4.73 (m, 1H), 4.02-3.83 (m, 2H), 3.62 (t, 1H), 3.58 (t, 1H), 2.37 (t, 1H)

[0088] Production Example 2: (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as an off-white solid (402 mg) in the same manner as in Preparation 1, except that (2R)-3-amino-2-fluoro-propan-1-ol (93.1 mg, 1.36 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 6.50 (s, 1H), 5.22 (brs, 1H), 4.89-4.73 (m, 1H), 4.01-3.84 (m, 2H), 3.64-3.56 (m, 2H), 2.62 (brs, 1H)

[0089] Production Example 3: (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 1, except that (R)-4-aminobutan-2-ol (89.14 mg, 1.36 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-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)

[0090] Preparation Example 4: (1-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)cyclopropyl)methanol The title compound was prepared as an off-white solid (402 mg) in the same manner as in Preparation 1, except that (1-(aminomethyl)cyclopropyl)methanol (101.15 mg, 1.632 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 6.36 (s, 1H), 5.68 (brs, 1H), 3.64 (s, 2H), 3.20 (d, 2H), 2.46 (brs, 1H), 0.67-0.60 (m, 4H)

[0091] Preparation Example 5: 3-((2-chloro-5-iodopyridin-4-yl)amino)-2,2-dimethylpropan-1-ol The title compound was prepared as an off-white solid (402 mg) in the same manner as in Preparation 1, except that 3-amino-2,2-dimethylpropan-1-ol (103.16 mg, 1.632 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 6.45 (s, 1H), 5.72 (brs, 1H), 3.56 (d, 2H), 3.12 (d, 2H), 2.04 (t, 1H), 1.05 (s, 6H)

[0092] Production Example 6: (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 / n-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); MS (ESI) m / z=327.1 (M + H) +

[0093] Preparation Example 7: 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 give 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) +

[0094] Step 2: 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole To a solution of 5-(benzyloxy)-1-methyl-1H-pyrazole (44.4 g, 236 mmol) prepared in step 1 in MeCN (675 mL) was added N-iodosuccinimide (53.1 g, 236 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Upon completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layer was washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (EA / n-Hex = 0-20%) to produce 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) +

[0095] 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) prepared in Step 2 in THF (420 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 112 mL, 145 mmol) at -10 to 0 °C under an argon atmosphere. After stirring the mixture at 0 °C for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.3 mL, 159 mmol) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for an additional 1.5 h, after which the reaction was quenched by the slow addition of saturated NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA / n-Hex=0-20%) to produce 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (32.5 g). 1 H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 7.40-7.35 (m, 5H), 5.39 (s, 2H), 3.55 (s, 3H), 1.32 (s, 12H); MS (ESI) m / z=315.2 (M + H) +

[0096] 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) prepared in Step 3 in 1,4-dioxane (460 mL) was added 3 M K2CO3 solution (91.9 mL, 276 mmol) and Pd(dppf)Cl2 dichloromethane complex (7.51 g, 9.19 mmol). The mixture was degassed with argon and then heated to 90 °C under an argon atmosphere for 5–6 h. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (MeOH / DCM=0-5%) to produce 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (11.2 g). 1 H NMR (CD3OD, 400 MHz) δ 8.08 (d, 1H), 7.87 (s, 1H), 7.34 (s, 5H), 6.34 (d, 1H), 5.41 (s, 2H), 3.39 (s, 3H); MS (ESI) m / z=282.2 (M + H) +

[0097] 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) prepared in step 4 in methanol (120 mL) was added Pd(OH) on carbon (20% Pd, 120 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)-2-methyl-pyrazol-3-ol (7.34 g) as a gray solid. 1H NMR (CD3OD, 400 MHz) δ 7.85 (d, 1H), 7.69 (s, 1H), 6.21 (d, 1H), 3.45 (s, 3H); MS (ESI) m / z=192.1 (M + H) +

[0098] Preparation Example 8: 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) +

[0099] Step 2: 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole To a solution of 5-(benzyloxy)-1,3-dimethyl-1H-pyrazole (9.20 g, 45.5 mmol) prepared in step 1 in MeCN (100 mL) was added N-iodosuccinimide (10.2 g, 45.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layer was washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (EA / n-Hex = 0-20%) to give 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole (7.40 g) as a pale yellow liquid. 1 H NMR (CDCl3, 400 MHz) δ 7.37-7.36 (s, 5H), 5.19 (s, 2H), 3.39 (s, 3H), 2.18 (s, 3H); MS (ESI) m / z=328.9 (M + H) +

[0100] 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) prepared in Step 2 in THF (75 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 26 mL, 33.8 mmol) at -10 to 0 °C under an argon atmosphere. After stirring the mixture at 0 °C for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.90 mL, 33.8 mmol) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for an additional 1.5 h, after which the reaction was quenched by the slow addition of saturated NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA / n-Hex=0-20%) to produce 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (6.48 g). 1 H NMR (CDCl3, 400 MHz) δ 7.41-7.33 (m, 5H), 5.29 (s, 2H), 3.43 (s, 3H), 2.31 (s, 3H), 1.31 (s, 12H); MS (ESI) m / z=329.1 (M + H) +

[0101] 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) prepared in Step 3 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) +

[0102] 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) prepared in step 4 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) +

[0103] Preparation 9: 4-(4-amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol Step 1: 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine To a solution of 2-chloro-5-fluoropyrimidin-4-amine (2.11 g, 14.3 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.50 g, 14.3 mmol) prepared in Step 3 of Preparation 7 in dioxane (70.0 mL) was added 3 M K2CO3 solution (14.3 mL, 42.9 mmol) and Pd(dppf)Cl2 dichloromethane complex (1.16 g, 1.43 mmol). The mixture was degassed with argon and then stirred at 90 °C 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 silica gel column chromatography (EA / DCM=0-80%) to prepare 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine as a brown solid (960.0 mg, yield: 22%). 1 H NMR (CD3OD, 400 MHz) δ 8.06 (d, 1H), 7.85 (s, 1H), 7.35 (s, 5H), 5.41 (s, 2H), 3.38 (s, 3H); MS (ESI) m / z=300.1 (M + H) +

[0104] Step 2: 4-(4-amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (270.0 mg, 0.90 mmol) in methanol (1.0 mL) and THF (3.5 mL), acetic acid (1 drop) and Pd(OH) on carbon (108.0 mg, 40% wt) were added under a H atmosphere. The reaction mixture was stirred at 55 °C for 3 hours, filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / DCM = 10-30%) to prepare 4-(4-amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (186.0 mg, 0.89 mmol, yield: 98.6%). 1 H-NMR (DMSO-d6, 400 MHz) δ 8.15-8.14 (m, 3H), 7.49 (s, 1H), 3.16 (s, 3H); MS (ESI) m / z=210.0 (M + H) +

[0105] Preparation 10: 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (3.50 g, 13.600 mmol), 4-ethynyl-1-methylpyrazole (1.59 g, 14.956 mmol), PdCl(PPh) (477 mg, 0.680 mmol), and CuI (518 mg, 2.719 mmol) was purged with nitrogen gas for 10 min. DMF (40 mL) and TEA (3.79 mL, 27.192 mmol) were added, and the reaction mixture was stirred at 50 °C for 1 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 / n-Hex=0-40%) to produce 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine as an off-white solid (2.00 g). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (d, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.13 (d, 1H), 3.93 (s, 3H); MS (ESI) m / z=236.0 (M + H) +

[0106] Preparation 11: 2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.0 g, 3.88 mmol), 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (606 mg, 3.88 mmol), PdCl(PPh) (136 mg, 0.19 mmol), and CuI (148 mg, 0.78 mmol) was purged with nitrogen gas for 10 min. DMF (20 mL) and TEA (1.08 mL, 7.77 mmol) were added, and the reaction mixture was stirred at 50 °C for 1 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 / n-Hex=0-40%) to produce 2-chloro-5-((1-(2,2-difluoroethyl-1H-pyrazol-4-yl)ethynyl)4-fluoropyridine as an off-white solid (0.9 g). MS (ESI) m / z=285.9 (M + H). +

[0107] Preparation 12: 2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine Step 1: 3-((2-chloro-5-iodopyridin-4-yl)amino)propan-1-ol A mixture of 2-chloro-4-fluoro-5-iodopyridine (0.50 g, 1.942 mmol) and 3-amino-1-propanol (145 mg, 1.942 mmol) was purged with nitrogen gas for 10 minutes. After adding DMF (6 mL) and DIPEA (0.68 mL, 3.885 mmol), 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 3-((2-chloro-5-iodopyridin-4-yl)amino)propan-1-ol as an off-white solid (595 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 2H), 6.43 (s, 1H), 5.39 (s, 1H), 3.89-3.85 (q, 2H), 3.39-3.34 (q, 2H), 1.98-1.92 (m, 2H); MS (ESI) m / z=312.9 (M + H) +

[0108] Step 2: 2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 3-((2-chloro-5-iodopyridin-4-yl)amino)propan-1-ol (570 mg, 1.824 mmol) prepared in Step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (348.69 mg, 1.824 mmol) prepared in Preparation 7, and (tributylphosphoranylidene)acetonitrile (1.75 mL, 6.383 mmol) in toluene (2 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-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (427 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.26-8.25 (d, 2H), 8.17-8.15 (d, 1H), 8.01 (s, 1H), 6.45 (s, 1H), 6.25-6.24 (d, 1H), 5.69 (s, 1H), 5.42 (s, 1H), 4.42-4.39 (t, 2H), 3.73 (s, 3H), 3.56-3.54 (d, 2H), 1.75-1.68 (m, 1H), 1.53-1.39 (m, 1H); MS (ESI) m / z=486.0 (M + H) +

[0109] Preparation Example 13: 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.902 g, 7.389 mmol), 1-(difluoromethyl)-4-ethynyl-1H-pyrazole (1.00 g, 7.037 mmol), PdCl(PPh) (246 mg, 0.352 mmol), and CuI (268 mg, 1.407 mmol) was purged with nitrogen gas for 10 min. DMF (50 mL) and TEA (1.96 mL, 14.074 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine as an off-white solid (1.39 g). 1 H-NMR (CDCl3, 400 MHz) δ 8.51-8.49 (d, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.35-7.05 (m, 2H); MS (ESI) m / z=272.0 (M + H) +

[0110] Production Example 14: (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) 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 produce (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (2.56 g) as an off-white solid. 1 H-NMR (CDCl3, 400 MHz) 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) +

[0111] Preparation 15: 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 solution of 30% sodium methoxide in methanol was added and the pH was adjusted to 5.0. The mixture was filtered, and the filtrate was concentrated to produce the crude product, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (33 g). This crude product was used in the next step without further purification.

[0112] 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) +

[0113] 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. After completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layer was washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (EA / n-Hex = 0-20%) to produce 5-(benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g) as a pale yellow liquid. 1H 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) +

[0114] 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) +

[0115] 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, J=6.0 Hz, 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) +

[0116] 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) +

[0117] Preparation 16: 4-(4-aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol Step 1: 5-(benzyloxy)-1-ethyl-1H-pyrazole To a solution of 1-ethyl-1H-pyrazol-5-ol (2.0 g, 17.8 mmol) in DMF (20 mL) was added K2CO3 (3.7 g, 26.8 mmol) and benzyl bromide (2.54 mL, 21.4 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 give 5-(benzyloxy)-1-ethyl-1H-pyrazole as a colorless oil (2.28 g). 1 H NMR (CDCl3, 400 MHz) δ 7.40-7.34 (m, 5H), 7.31 (d, 1H), 5.54 (d, 1H), 5.07 (s, 2H), 4.02 (q, 2H), 1.36 (t, 3H); MS (ESI) m / z=203.1 (M + H) +

[0118] Step 2: 5-(benzyloxy)-1-ethyl-4-iodo-1H-pyrazole To a solution of 5-(benzyloxy)-1-ethyl-1H-pyrazole (2.28 g, 11.3 mmol) prepared in step 1 in MeCN (23 mL) was added N-iodosuccinimide (2.54 g, 11.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layer was washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (EA / n-Hex = 0-20%) to give 5-(benzyloxy)-1-ethyl-4-iodo-1H-pyrazole (2.51 g) as a pale yellow liquid. 1 H NMR (CDCl3, 400 MHz) δ 7.39-7.37 (m, 6H), 5.24 (s, 2H), 3.82 (q, 2H), 1.19 (t, 3H); MS (ESI) m / z=329.0 (M + H) +

[0119] Step 3: 5-(benzyloxy)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a stirred solution of 5-(benzyloxy)-1-ethyl-4-iodo-1H-pyrazole (2.51 g, 7.65 mmol) prepared in Step 2 in THF (25 mL) was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 6.47 mL, 8.41 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 (1.87 mL, 9.18 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-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (2.16 g). 1 H NMR (CDCl3, 400 MHz) δ 7.63 (s, 1H), 7.40-7.35 (m, 5H), 5.39 (s, 2H), 3.92 (q, 2H), 1.32 (s, 12 H), 1.25 (t, 3H); MS (ESI) m / z=328.8 (M + H) +

[0120] Step 4: 2-(5-(benzyloxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 2-bromopyrimidin-4-amine (1.14 g, 6.55 mmol) and 5-(benzyloxy)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.15 g, 6.55 mmol) prepared in Step 3 in 1,4-dioxane (33 mL) was added 3M K2CO3 solution (6.55 mL, 19.6 mmol) and Pd(dppf)Cl2 dichloromethane complex (535 mg, 0.66 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-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a brown solid (550 mg). 1 H NMR (CD3OD, 400 MHz) δ 8.08 (d, 1H), 7.90 (s, 1H), 7.35-7.34 (m, 5H), 6.34 (d, 1H), 5.41 (s, 2H), 3.80 (q, 2H), 1.13 (t, 3H); MS (ESI) m / z=296.2 (M + H) +

[0121] Step 5: 4-(4-aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (550 mg, 1.86 mmol) prepared in step 4 in methanol (10 mL) was added Pd(OH) on carbon (20% Pd, 55 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-ethyl-1H-pyrazol-5-ol (350 mg) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.86 (d, 1H), 7.70 (s, 1H), 6.20 (d, 1H), 3.86 (q, 2H), 1.29 (t, 3H); MS (ESI) m / z=206.1 (M + H) +

[0122] Preparation 17: 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 give 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) +

[0123] 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. After completion, the reaction was quenched by adding saturated NaSO solution, followed by extraction with EA. The combined organic layer was washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (EA / n-Hex = 0-20%) to produce 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) +

[0124] 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) in THF (23 mL), a solution of iPrMgCl LiCl complex in THF (1.3 M, 5.69 mL, 7.39 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 (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) +

[0125] 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) 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) +

[0126] 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) in methanol (10 mL) was added Pd(OH)2 on carbon (20% Pd, 57 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)-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) +

[0127] Preparation 18: 4-(4-amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol Step 1: 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine To a solution of 2-chloro-5-methylpyrimidin-4-amine (4.0 g, 27.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.75 g, 27.9 mmol), prepared in Step 3 of Preparation 7, in 1,4-dioxane (140 mL) was added 3M K2CO3 solution (27.9 mL, 83.6 mmol) and Pd(dppf)Cl2 dichloromethane complex (2.28 g, 2.79 mmol). The mixture was degassed with argon and then heated to 90 °C under an argon atmosphere for 8 h. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (MeOH / DCM=0-5%) to produce 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine as a brown solid (1.34 g). 1 H NMR (CD3OD, 400 MHz) δ 7.96 (s, 1H), 7.85 (s, 1H), 7.33 (s, 5H), 5.39 (s, 2H), 3.39 (s, 3H), 2.09 (s, 3H); MS (ESI) m / z=296.1 (M + H) +

[0128] Step 2: 4-(4-amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine (2.12 g, 7.18 mmol) in methanol (50 mL) was added Pd(OH)2 on carbon (20% Pd, 212 mg) and stirred under H2 atmosphere at 25 °C for 6-7 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-amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (1.42 g) as a gray solid. 1 H NMR (CD3OD, 400 MHz) δ 7.75 (s, 1H), 7.68 (s, 1H), 3.45 (s, 3H), 2.06 (s, 3H); MS (ESI) m / z=206.1 (M + H) +

[0129] Preparation 19: 4-(4-amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol Step 1: 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine To a solution of 2-chloro-6-methylpyrimidin-4-amine (3.0 g, 20.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.56 g, 20.9 mmol), prepared in Step 3 of Preparation 7, in 1,4-dioxane (105 mL) was added 3M K2CO3 solution (20.9 mL) and Pd(dppf)Cl2 dichloromethane complex (1.71 g, 2.09 mmol). The mixture was degassed with argon and then heated to 90 °C under an argon atmosphere for 8 hours. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (MeOH / DCM=0-5%) to produce 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine as a brown solid (1.11 g).1 H NMR (CD3OD, 400 MHz) δ 7.88 (s, 1H), 7.34-7.33 (m, 5H), 6.21 (s, 1H), 5.40 (s, 2H), 3.43 (s, 3H), 2.31 (s, 3H); MS (ESI) m / z=296.5 (M + H) +

[0130] Step 2: 4-(4-amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine (1.34 g, 4.54 mmol) in methanol (30 mL) was added Pd(OH)2 on carbon (20% Pd, 134 mg) and stirred under H2 atmosphere at 25 °C for 6-7 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-amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol as a gray solid (870 mg). 1 H NMR (CD3OD, 400 MHz) δ 7.68 (s, 1H), 6.06 (s, 1H), 3.46 (s, 3H), 2.36 (s, 3H); MS (ESI) m / z=206.0 (M + H) +

[0131] Preparation 20: (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.50 g, 5.827 mmol) and 3-aminomethyloxetan-3-ylmethanol (682 mg, 5.827 mmol) was purged with nitrogen gas for 10 minutes. After adding DMF (30 mL) and DIPEA (2.03 mL, 11.654 mmol), 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 produce (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol as an off-white solid (1.774 g). 1 H-NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 6.50 (s, 1H), 5.85-5.83 (t, 1H), 4.58-4.56 (d, 2H), 4.51-4.50 (d, 1H), 4.16-4.09 (m, 2H), 3.61-3.60 (d, 2H)

[0132] Preparation 21: 4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol Step 1: 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-amine To a solution of 2-bromopyridin-4-amine (16.0 g, 92.5 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.1 g, 92.5 mmol), prepared in Step 3 of Preparation 7, in 1,4-dioxane (460 mL) was added 3M K2CO3 solution (92.5 mL, 277 mmol) and Pd(dppf)Cl2 dichloromethane complex (7.55 g, 9.25 mmol). The mixture was degassed with argon and then heated to 90 °C under an argon atmosphere for 8 hours. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (MeOH / DCM=0-5%) to produce 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-amine as a brown solid (6.90 g). 1 H NMR (CD3OD, 400 MHz) δ 7.98 (d, 1H), 7.69 (s, 1H), 7.35-7.34 (m, 5H), 6.87 (d, 1H), 6.47 (dd, 1H), 5.07 (s, 2H), 3.43 (s, 3H); MS (ESI) m / z=281.2 (M + H) +

[0133] Step 2: 4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-amine (6.90 g, 24.6 mmol) in methanol (70 mL) was added Pd(OH)2 on carbon (20% Pd, 690 mg) and stirred under H2 atmosphere at 25 °C for 6-7 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-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol as a brown solid (4.31 g). 1H NMR (CD3OD, 400 MHz) δ 7.74 (d, 1H), 7.59 (s, 1H), 6.63 (s, 1H), 6.37 (d, 1H), 3.46 (s, 3H); MS (ESI) m / z=190.9 (M + H) +

[0134] Preparation 22: (4-((6-chloro-4-fluoropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone The title compound was prepared as a solid (1121 mg) in the same manner as in Preparation 10, except that (4-ethynylphenyl)-(4-hydroxy-1-piperidinyl)methanone (1000 mg, 4.36 mmol) was used instead of 4-ethynyl-1-methylpyrazole. MS (ESI) m / z=359.1 (M + H). +

[0135] Example 1: (S)-2 5 -Fluoro-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (3.0 g, 11.65 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)pyrazole (2.03 g, 11.65 mmol), PdCl(PPh) (408.98 mg, 0.58 mmol), and CuI (444.10 mg, 2.33 mmol) was purged with nitrogen gas for 10 minutes, and then DMF (60.0 mL) and TEA (3.25 mL, 23.31 mmol) were added. The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was cooled to room temperature and worked up using EA and water. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / n-Hex=0-50%) to produce 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (649.80 mg, 2.14 mmol, yield: 18.4%). 1 H-NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H), 7.78 (s, 2H), 7.16 (d, 1H), 4.74 (q, 2H); MS (ESI) m / z=303.9 (M + H) +

[0136] Step 2: (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol To a solution of 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (99.60 mg, 0.33 mmol) prepared in step 1 in DMA (2.0 mL) was added (S)-3-aminobutan-1-ol (29.24 mg, 0.33 mmol) and DIPEA (0.09 mL, 0.66 mmol). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with DCM. The combined organic layers were washed with saturated brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM=0-10%) to produce (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100.0 mg, 0.27 mmol, yield: 81.8%). 1 H-NMR (CD3OD, 400 MHz) δ 8.06 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 6.70 (s, 1H), 4.98 (q, 1H), 3.86 (sex, 1H), 3.78-3.68 (m, 2H), 1.92-1.82 (m, 2H), 1.29 (d, 3H); MS (ESI) m / z=372.9 (M + H) +

[0137] Step 3: (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine To a solution of (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (60.0 mg, 0.16 mmol) prepared in Step 2 in toluene (1.16 mL) was added (tributylphosphoranylidene)acetonitrile (121.58 mg, 0.40 mmol) and 4-(4-amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (33.76 mg, 0.16 mmol) prepared in Preparation 9. 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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (80.0 mg, 0.14 mmol, yield: 87.9%). 1 H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 6.51 (s, 1H), 5.84 (d, 1H), 5.42 (s, 2H), 4.61 (q, 2H), 4.50-4.48 (m, 1H), 4.39-4.35 (m, 1H), 3.91 (quin, 1H), 3.60 (s, 3H), 2.20-2.02 (m, 2H), 1.36 (d, 3H)

[0138] Step 4: (S)-2 5 -Fluoro-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (80.0 mg, 0.14 mmol) prepared in step 3 in 1,4-dioxane (2.84 mL) was added CsCO (138.66 mg, 0.43 mmol), Pd(dba) (25.98 mg, 0.03 mmol), and XPhos (27.05 mg, 0.06 mmol). The reaction mixture was stirred at 130 °C for 2 hours. 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 residue was purified by silica gel column chromatography (EA / n-Hex=0-100%) and (MeOH / DCM=0-30%) to give (S)-2 5 -Fluoro-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared (29.0 mg, 0.06 mmol, yield: 38.8%). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.25 (s, 1H), 8.07(s, 1H), 8.05 (s, 1H), 7.75 (s, 2H), 5.11 (d, 1H), 4.78-4.67 (m, 3H), 4.28 (t, 1H), 4.10-4.07 (m, 1H), 3.80 (s, 3H), 2.19 (d, 2H), 1.50 (d, 3H); MS (ESI) m / z=528.0 (M + H) +

[0139] Example 2: (S)-1 1 ,6-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol To a solution of 2-chloro-4-fluoro-5-iodopyridine (3.0 g, 11.65 mmol) in DMA (23.31 mL) was added (S)-3-aminobutan-1-ol (1.35 g, 15.15 mmol) and DIPEA (4.95 mL, 29.13 mmol). The reaction mixture was stirred at 90 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-50%) to produce (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol as a white solid (3.32 g, 10.17 mmol, yield: 87.3%). 1 H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 6.49 (s, 1H), 5.12 (d, 1H), 3.92-3.80 (m, 3H), 1.97-1.81 (m, 3H), 1.34 (d, 3H); MS (ESI) m / z=326.8 (M + H) +

[0140] Step 2: (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol To a solution of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (300.0 mg, 0.92 mmol) prepared in Step 1 in DMF (3.67 mL) was added 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole (161.89 mg, 0.92 mmol), PdCl(PPh) (64.48 mg, 0.09 mmol), CuI (34.99 mg, 0.18 mmol), and TEA (0.32 mL, 2.3 mmol). The reaction mixture was stirred at 70 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-70%) to produce (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (257.0 mg, 0.69 mmol, yield: 74.6%). 1 H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.69 (s, 1H), 7.68 (s, 1H), 6.56 (s, 1H), 5.53 (d, 1H), 4.37 (sep, 1H), 4.15 (dd, 2H), 3.90-3.82 (m, 3H), 3.57 (td, 2H), 2.14-2.07 (m, 4H), 1.92-1.84 (m, 2H), 1.54 (t, 1H), 1.33 (d, 3H); MS (ESI) m / z=374.9 (M + H) +

[0141] Step 3: (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100.0 mg, 0.27 mmol) prepared in Step 2 in toluene (1.07 mL) was added 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (51.0 mg, 0.27 mmol) prepared in Preparation 7 and (tributylphosphoranylidene)acetonitrile (181.68 μL, 0.67 mmol). The reaction mixture was stirred at 110° C. for 6 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (MeOH / DCM=0-10%) to produce (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a brown solid (44.30 mg, 0.08 mmol, yield: 30.3%). 1 H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 6.58 (s, 1H), 6.20 (d, 1H), 5.90 (d, 1H), 4.76 MS (ESI) m / z=547.9 (M + H) +

[0142] Step 4: (S)-1 1 ,6-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-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-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (44.30 mg, 0.08 mmol) in 1,4-dioxane (1.0 mL) was added Pd(dba) (11.10 mg, 0.01 mmol), XPhos (11.56 mg, 0.02 mmol), and CsCO (79.01 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then heated to 95 °C for 2 hours. The reaction mixture was filtered through a pad of Celite and washed with DCM, after which the organic solution was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (MeOH / DCM=0-10%) to give (S)-1 1 ,6-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a yellow solid (2.0 mg, 0.004 mmol, yield: 4.8%). 1 H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.35 (d, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 6.43 (d, 1H), 5.00 MS (ESI) m / z=511.9 (M + H) +

[0143] Example 3: (S)-1 1 ,8-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol The title compound was prepared as a white solid (3.67 g) in the same manner as in Step 1 of Example 2, except that (R)-4-aminobutan-2-ol (1.35 g, 15.15 mmol) was used instead of (S)-3-aminobutan-1-ol. 1 MS (ESI) m / z=326.8 (M + H) +

[0144] Step 2: (R)-4-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a brownish-yellow solid (292.10 mg) in the same manner as in Step 2 of Example 2, except that (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (300.0 mg, 0.92 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 6.50 (s, 1H), 5.90 (t, 1H), 4.36 (sep, 1H), 4.16 (dd, 2H), 4.12-4.05 (m, 1H), 3.56 (td, 2H), 3.43-3.33 (m, 2H), 2.13-2.07 (m, 4H), 1.88-1.79 (m, 2H), 1.67 (d, 1H), 1.32 (d, 3H); MS (ESI) m / z=374.9 (M + H)+

[0145] Step 3: (S)-2-(5-((4-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)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 (44.30 mg) in the same manner as in Step 3 of Example 2, except that (R)-4-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (100.0 mg, 0.27 mmol) prepared in Step 2 was used instead of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.37 (s, 1H), 7.09 (s, 1H), 6.75 (t, 1H), 6.55 (s, 1H), 6.16 (d, 1H), 5.03 (t, 1H), 4.79 (s, 2H), 4.24 (sep, 1H), 4.12 (dd, 2H), 3.69-3.52 (m, 7H), 2.17-2.03 (m, 6H), 1.16 (d, 3H); MS (ESI) m / z=547.9 (M + H) +

[0146] Step 4: (S)-1 1 ,8-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-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 yellow solid (20.60 mg) in the same manner as in Step 4 of Example 2, except that (S)-2-(5-((4-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.20 mg, 0.19 mmol) prepared in Step 3 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.35 (d, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 6.38 (d, 1H), 5.52-5.43 (m, 2H), 4.40 (sep, 1H), 4.17-4.05 (m, 3H), 3.77 (s, 3H), 3.58 (td, 3H), 2.29-1.94 (m, 6H), 1.11 (d, 3H); MS (ESI) m / z=512.0 (M + H) +

[0147] Example 4: (S)-1 1 ,6-dimethyl-4 5 -(pyridin-3-ylethynyl)-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-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a brown viscous oil (212.70 mg) in the same manner as in Step 2 of Example 2, except that 3-ethynylpyridine (110.52 mg, 1.07 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.83 (d, 1H), 7.34 (t, 1H), 6.58 (s, 1H), 5.81 (d, 1H), 3.96-3.93 (m, 1H), 3.89-3.84 (m, 2H), 1.99-1.82 (m, 2H), 1.74 (s, 1H), 1.35 (d, 3H); MS (ESI) m / z=302.0 (M + H) +

[0148] Step 2: (S)-2-(5-(3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a brown viscous oil (77.30 mg) in the same manner as in Step 3 of Example 2, except that (S)-3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-1-ol (205.0 mg, 0.68 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.57 (d, 1H), 8.52 (dd, 1H), 8.16 (s, 1H), 8.13 (d, 1H), 7.94 (s, 1H), 7.52 (dt, 1H), 7.18 (dd, 1H), 6.62 (s, 1H), 6.16 (d, 1H), 5.93 (d, 1H), 4.74 (s, 2H), 4.56-4.46 (m, 2H), 4.09 (sep, 1H), 3.68 (s, 3H), 2.28-2.08 (m, 2H), 1.45 (d, 3H); MS (ESI) m / z=474.9 (M + H) +

[0149] Step 3: (S)-1 1 ,6-dimethyl-4 5 -(pyridin-3-ylethynyl)-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 yellow solid (22.80 mg) in the same manner as in Step 4 of Example 2, except that (S)-2-(5-(3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (77.30 mg, 0.15 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.76 (d, 1H), 8.57 (dd, 1H), 8.41 (s, 1H), 8.34 (d, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 7.80 (dt, 1H), 7.47 (s, 1H), 7.32 MS (ESI) m / z=438.9 (M + H) +

[0150] Example 5: (S)-1 1 ,8-dimethyl-4 5 -(pyridin-3-ylethynyl)-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-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a light brown solid (249.80 mg) in the same manner as in Step 2 of Example 3, except that 3-ethynylpyridine (110.52 mg, 1.07 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1 H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.59 (d, 1H), 8.17 (s, 1H), 7.83 (d, 1H), 7.33 (dd, 1H), 6.52 (s, 1H), 6.16 (s, 1H), 4.12 (s, 1H), 3.48-3.32 (m, 2H), 1.94-1.80 (m, 2H), 1.74 (d, 1H), 1.34 (d, 3H); MS (ESI) m / z=301.9 (M + H) +

[0151] Step 2: (S)-2-(5-((4-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a brown solid (80.20 mg) in the same manner as in Step 3 of Example 2, except that (R)-4-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-ol (249.80 mg, 0.82 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.46 (dd, 1H), 8.36 (d, 1H), 8.10 (s, 1H), 8.07 (d, 1H), 7.86 (s, 1H), 7.24-7.23 (m, 1H), 7.11 (dd, 1H), 6.90-6.88 MS (ESI) m / z=474.8 (M + H) +

[0152] Step 3: (S)-1 1 ,8-dimethyl-4 5 -(pyridin-3-ylethynyl)-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 (9.30 mg) in the same manner as in Step 4 of Example 2, except that (S)-2-(5-((4-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (80.0 mg, 0.16 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.79 (d, 1H), 8.59 (dd, 1H), 8.46 (s, 1H), 8.36 (d, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.84 (dt, 1H), 7.34 (m, 2H), 6.37 MS (ESI) m / z=438.9 (M + H) +

[0153] Example 6: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(pyridin-3-ylethynyl)-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-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a pink foamy solid (72.80 mg) in the same manner as in Step 2 of Example 4, except that 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (40.34 mg, 0.20 mmol) prepared in Preparation 8 was used instead of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.57 (d, 1H), 8.52 (dd, 1H), 8.16 (s, 1H), 8.15 (d, 1H), 7.52 (dt, 1H), 7.16 (dd, 1H), 6.59 (s, 1H), 6.17 (d, 1H), 5.95 (d, 1H), 4.71 (s, 2H), 4.46-4.32 (m, 2H), 3.97 (sep, 1H), 3.63 (s, 3H), 2.45 (s, 3H), 2.20-2.04 (m, 2H), 1.41 (d, 3H); MS (ESI) m / z=488.9 (M + H) +

[0154] Step 2: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(pyridin-3-ylethynyl)-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 yellow solid (18.90 mg) in the same manner as in Step 4 of Example 2, except that (S)-2-(5-(3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70.10 mg, 0.14 mmol) prepared in Step 1 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.59 (d, 1H), 8.38 (d, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.82 (d, 1H), 7.33 (dd, 1H), 6.38 (d, 1H), 4.96 (d, 1H), 4.80 (t, 1H), 4.31 (q, 1H), 4.03-4.00 (m, 1H), 3.76 (s, 3H), 2.60 (s, 3H), 2.18 (dt, 2H), 1.50 (d, 3H); MS (ESI) m / z=453.0 (M + H) +

[0155] Example 7:1 1 ,7,7-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (3.00 g, 11.65 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)pyrazole (2.03 g, 11.65 mmol), PdCl(PPh) (408.98 mg, 0.58 mmol), and CuI (444.10 mg, 2.33 mmol) was purged with nitrogen gas for 10 min. DMF (60.0 mL) and TEA (3.25 mL, 23.31 mmol) were added. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with EA. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (Hex / n-Hex=0-50%) to produce 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (650 mg, 2.141 mmol, yield: 18.37%). 1H-NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H), 7.78 (s, 2H), 7.16 (d, 1H), 4.74 (q, 2H); MS (ESI) m / z=303.9 (M + H) +

[0156] Step 2: 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol To a solution of 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (120 mg, 0.395 mmol) prepared in step 1 in DMA (1 mL) was added 3-amino-2,2-dimethyl-1-propanol (48.92 mg, 0.474 mmol) and DIPEA (138.09 μL, 0.988 mmol). The reaction mixture was stirred at 80° C. for 4 h. 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 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol as a white solid (89 mg, 0.23 mmol, yield: 58.22%). 1 H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.75 (d, 1H), 6.70 (s, 1H), 6.24 (s, 1H), 4.73 (q, 2H), 3.92-3.91 (m, 2H), 1.99 (t, 2H), 1.50 (s, 6H)

[0157] Step 3: 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (83 mg, 0.215 mmol) prepared in Step 2 in toluene (1 mL) was added 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (41.03 mg, 0.215 mmol) prepared in Preparation 7 and (tributylphosphoranylidene)acetonitrile (140.58 μL, 0.536 mmol). The reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was concentrated and purified by column chromatography (EA / n-Hex=50-100% → MeOH / EA=0-15%) and recrystallized (DCM / Hex) to prepare 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a light brown solid (70 mg, 0.125 mmol, yield: 58.26%). 1 H-NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 6.74 (s, 1H), 6.19 (d, 1H), 5.32 (s, 2H), 4.73-4.53 (m, 4H), 3.60 (s, 3H), 2.29 (t, 2H), 1.61 (s, 6H)

[0158] Step 4:1 1 ,7,7-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane To a solution of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (65 mg, 0.116 mmol) prepared in step 3 in 1,4-dioxane (1 mL) was added Pd(dba) (15.94 mg, 0.017 mmol), XPhos (16.6 mg, 0.035 mmol), and CsCO (113.46 mg, 0.348 mmol). The reaction mixture was stirred at 95 °C for 2 h. The reaction mixture was added to water and extracted with DCM. The crude residue was purified by column chromatography (MeOH / EA = 0-15%) and recrystallized (MeOH) to give 1. 1 ,7,7-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (17 mg, 0.032 mmol, yield: 27.98%). 1 H-NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.35 (d, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 7.73 (s, 1H), 6.38 (d, 1H), 4.75 (q, 2H), 4.62 (t, 2H), 3.82 (s, 3H), 2.36 (t, 2H), 1.63 (s, 6H); MS (ESI) m / z=523.9 (M + H) +

[0159] Example 8:1 1 ,6,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutan-1-ol The title compound was prepared as a white solid (75 mg) in the same manner as in Step 2 of Example 7, except that 3-amino-3,3-dimethylpropanol (35 mg, 0.339 mmol) was used instead of 3-amino-2,2-dimethyl-1-propanol. 1 H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.74 (s, 2H), 6.69 (s, 1H), 6.21 (s, 1H), 4.72 (q, 2H), 3.90 (q, 2H), 1.98 (t, 2H), 1.49 (s, 6H)

[0160] Step 2: 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a brown solid (62 mg) in the same manner as in Step 3 of Example 7, except that 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutan-1-ol (63.97 mg, 0.165 mmol) prepared in Step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 6.74 (s, 1H), 6.20-6.18 (m, 2H), 4.73 (s, 2H), 4.62-4.53 (m, 4H), 3.60 (s, 3H), 2.29 (t, 2H), 2.03 (s, 2H), 1.60 (s, 6H)

[0161] Step 3:1 1 ,6,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (20 mg) in the same manner as in Step 4 of Example 7, except that 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (60 mg, 0.107 mmol) prepared in Step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.95 (s, 1H), 8.43 (s, 1H), 8.29 (d, 1H), 8.24 (s 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 6.78 (d, 1H), 5.34 (s, 1H), 5.19 (q, 1H), 4.55 (t, 2H), 3.76 (s, 3H), 2.32 (t, 2H), 1.53 (s, 6H); MS (ESI) m / z=523.9 (M + H) +

[0162] Example 9: (R)-7-fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as a white solid (91 mg) in the same manner as in Step 2 of Example 7, except that (2R)-3-amino-2-fluoro-propan-1-ol (27.6 mg, 0.296 mmol) was used instead of 3-amino-2,2-dimethyl-1-propanol. 1 H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.75 (s, 2H), 6.56 (s, 1H), 5.52 (t, 1H), 4.87-4.84 (m, 1H), 4.77-4.71 (m, 2H), 4.01-3.82 (m, 2H), 3.65-3.57 (m, 2H), 2.09 (s, 1H)

[0163] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a brown solid (51 mg) in the same manner as in Step 3 of Example 7, except that (R)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (80.84 mg, 0.215 mmol) prepared in Step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 2H), 8.15 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 6.07 (s, 1H), 6.18 (d, 1H), 5.92 (t, 1H), 5.11-4.96 (m, 1H), 4.89 (s, 2H), 4.73-4.62 (m, 4H), 3.86-3.73 (m, 5H)

[0164] Step 3: (R)-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 the same manner as in Step 4 of Example 7, except that (R)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (43 mg, 0.078 mmol) prepared in Step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (7.6 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.77 (d, 2H), 7.42 (s, 1H), 6.39 (d, 1H), 5.47 (t, 1H), 4.98-4.85 (m, 1H), 4.83-4.70 (m, 3H), 4.53-4.45 (m, 1H), 4.31-4.25 (m, 1H), 3.86 (s, 3H), 3.71-3.61 (m, 1H); MS (ESI) m / z=514.1 (M + H) +

[0165] Example 10: (S)-7-fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as a white solid (81 mg) in the same manner as in Step 2 of Example 7, except that (2S)-3-amino-2-fluoro-propan-1-ol (27.6 mg, 0.296 mmol) was used instead of 3-amino-2,2-dimethyl-1-propanol. 1 H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.75 (s, 2H), 6.56 (s, 1H), 5.52 (s, 1H), 4.87-4.83 (m, 1H), 4.77-4.70 (m, 2H), 4.01-3.82 (m, 2H), 3.65-3.57 (m, 2H), 2.05 (s, 1H)

[0166] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)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 mg) in the same manner as in Step 3 of Example 7, except that (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (80.84 mg, 0.215 mmol) prepared in Step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 6.61 (s, 1H), 6.18 (d, 2H), 5.92 (t, 1H), 5.10-4.97 (m, 1H), 4.90 (s, 2H), 4.73-4.60 (m, 4H), 3.87-3.71 (m, 5H)

[0167] Step 3: (S)-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (9.8 mg) in the same manner as in Step 4 of Example 7, except that (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (43 mg, 0.078 mmol) prepared in Step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1 H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.77 (d, 2H), 7.40 (s, 1H), 6.39 (d, 1H), 5.47 (t, 1H), 4.97-4.85 (m, 1H), 4.83-4.70 (m, 4H), 4.53-4.45 (m, 1H), 4.31-4.25 (m, 1H), 3.86 (s, 3H), 3.69-3.65 (m, 1H); MS (ESI) m / z=514.1 (M + H) +

[0168] Example 11: (S)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine Instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol, (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol, The title compound was prepared as a light brown solid (62 mg) in the same manner as in Step 3 of Example 7, except that 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (40 mg, 0.154 mmol) prepared in Preparation 15 was used. 1 H-NMR (CDCl3, 400 MHz) δ 8.14 (d, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 6.55 (s, 1H), 6.20 (d, 1H), 5.63 (d, 1H), 4.77 (s, 2H), 4.71-4.63 (m, 4H), 4.56-4.50 (m, 2H), 3.95-3.90 (m, 1H), 2.26-2.07 (m, 2H), 1.42 (d, 3H)

[0169] Step 2: (S)-6-Methyl-1 1 -(2,2,2-trifluoroethyl)-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (19 mg) in the same manner as in Step 4 of Example 7, except that (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (60 mg, 0.098 mmol) prepared in Step 1 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.74 (d, 2H), 7.44 (s, 1H), 6.40 (d, 1H), 5.18-5.15 (m, 1H), 5.13-5.12 (m, 1H), 4.97-4.70 (m, 3H), 4.59-4.53 (m, 1H), 4.36-4.31 (m, 1H), 4.03-3.99 (m, 1H), 2.27-2.20 (m, 1H), 2.12-2.06 (m, 1H), 1.45 (d, 3H); MS (ESI) m / z=578.2 (M + H) +

[0170] Example 12: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol To a solution of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol) prepared in Preparation 6 in DMF (3 mL) was added 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (122.57 mg, 0.766 mmol), PdCl(PPh) (53.73 mg, 0.077 mmol), CuI (29.16 mg, 0.153 mmol), and TEA (0.27 mL, 1.914 mmol). The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with EA. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was purified by column chromatography (EA / n-Hex=0-70%) to produce (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (214 mg, 0.597 mmol, yield: 77.92%). 1 H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 6.57 (s, 1H), 5.68 (d, 1H), 3.94-3.82 (m, 3H), 1.99-1.85 (m, 1H), 1.83-1.79 (m, 1H), 1.66 (brs, 1H), 1.33 (d, 3H)

[0171] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a light brown solid in the same manner as in Step 3 of Example 7, except that 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol were used instead of (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (194 mg, 0.541 mmol) prepared in Step 1 and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (110.98 mg, 0.541 mmol) prepared in Preparation Example 8 were used (181 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 6.58 (s, 1H), 6.17 (d, 1H), 6.08 (d, 1H), 4.73 (s, 2H), 4.50-4.44 (m, 1H), 4.35-4.30 (m, 1H), 3.98-3.94 (m, 1H), 3.64 (s, 3H), 2.48 (s, 3H), 2.25-2.20 (m, 1H), 2.07-2.03 (m, 1H), 1.41 (d, 3H)

[0172] Step 3: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (60.5 mg) in the same manner as in Step 4 of Example 7, except that (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (157.04 mg, 0.288 mmol) prepared in Step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 6.37 (d, 1H), 4.87 (d, 1H), 4.82-4.77 (m, 1H), 4.32-4.27 (m, 1H), 4.04-3.99 (m, 1H), 3.76 (s, 3H), 2.60 (s, 3H), 2.30-2.23 (m, 1H), 2.11-2.05 (m, 1H), 1.48 (d, 3H); MS (ESI) m / z=510.2 (M+H) +

[0173] Example 13: (S)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol), 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (621.92 mg, 3.885 mmol), PdCl(PPh) (136.33 mg, 0.194 mmol), and CuI (148.03 mg, 0.777 mmol) was purged with nitrogen gas for 10 min. DMF (20 mL) and triethanolamine (TEA) (1.08 mL, 7.769 mmol) were added, and the reaction mixture was stirred at 50 °C for 4 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 / n-Hex=0-40%) to produce 2-chloro-4-fluoro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (890.00 mg, 3.073 mmol, yield: 79.11%). 1 H-NMR (CDCl3, 400MHz) δ 8.51 (d, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.17 (d,1H); MS (ESI) m / z=290.1 ​​(M + H) +

[0174] Step 2: (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (95.00 mg, 0.328 mmol) prepared in Step 1, (S)-3-aminobutan-1-ol (29.24 mg, 0.328 mmol), and DIPEA (0.09 mL, 0.656 mmol) in DMA (2 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 (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (94.00 mg, 0.262 mmol, yield: 79.88%). 1 H-NMR (CD3OD, 400MHz) δ 8.51 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 6.72 (s, 1H), 3.95-3.87 (m, 1H), 3.83-3.69 (m, 2H), 1.95-1.78 (m, 2H), 1.29 (d, 3H); MS (ESI) m / z=358.9 (M + H) +

[0175] Step 3: (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (130.00 mg, 0.362 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (69.28 mg, 0.362 mmol) prepared in Preparation 7, and (tributylphosphoranylidene)acetonitrile (0.35 mL, 1.268 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (140.00 mg, 0.263 mmol, yield: 72.63%). 1 H-NMR (CD3OD, 400MHz) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.80 (d, 2H), 6.76 (s, 1H), 6.25 (d, 1H), 4.53-4.46 (m, 2H), 4.07-4.04 (m, 1H), 3.65 (s, 3H), 2.27-2.08 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z=532.0 (M + H) +

[0176] Step 4: (S)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (20.00 mg, 0.038 mmol) prepared in Step 3, CsCO (36.75 mg, 0.113 mmol), XPhos (7.17 mg, 0.015 mmol), and Pd(dba) (6.89 mg, 0.008 mmol) in 1,4-dioxane (4 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 (S)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared (3.60 mg, 0.007 mmol, yield: 19.32%). 1 H-NMR (CD3OD, 400MHz) δ 8.51 (s, 1H), 8.30 (s, 1H), 8.23 ​​(d, 1H), 8.02-7.99 (m, 3H), 6.67 (d, 1H), 4.71-4.66 (m, 1H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 2.29-1.99 (m, 2H); MS (ESI) m / z=496.1 (M + H) +

[0177] Example 14: (S)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (3.00 g, 11.654 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.29 g, 11.654 mmol), PdCl(PPh) (408.98 mg, 0.583 mmol), and CuI (444.10 mg, 2.331 mmol) was purged with nitrogen gas for 10 minutes. DMF (60 mL) and TEA (3.25 mL, 23.307 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (650.00 mg, 2.141 mmol, yield: 18.37%). 1 H-NMR (CDCl3, 400MHz) δ 8.50 (d, 1H), 7.78 (s, 2H), 4.77-4.71 (m, 2H); MS (ESI) m / z=303.9 (M + H) +

[0178] Step 2: (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (99.60 mg, 0.328 mmol) prepared in Step 1, (S)-3-aminobutan-1-ol (29 mg, 0.328 mmol), and DIPEA (0.09 mL, 0.656 mmol) in DMA (2 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-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100.00 mg, 0.268 mmol, yield: 81.78%). 1 H-NMR (CD3OD, 400MHz) δ 8.06 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 6.70 (s, 1H), 5.01-4.95 (m, 2H), 3.92-3.91 (m, 1H), 3.89-3.68 (m, 2H), 1.92-1.80 (m, 2H), 1.29 (d, 3H); MS (ESI) m / z=372.9 (M + H) +

[0179] Step 3: (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)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-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (135.08 mg, 0.362 mmol) prepared in Step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (69.28 mg, 0.362 mmol) prepared in Preparation 7, and (tributylphosphoranylidene)acetonitrile (0.35 mL, 1.268 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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (143.00 mg, 0.262 mmol, yield: 72.28%). 1 H-NMR (CD3OD, 400MHz) δ 7.98-7.96 (m, 2H), 7.84-7.78 (m, 2H), 7.56 (s, 1H), 6.73 (s, 1H), 6.26 (d, 1H), 4.94-4.87 (m, 2H), 4.54-4.46 (m, 2H), 4.05-4.01 (m, 1H), 3.64 (s, 3H), 2.25-2.10 (m, 2H), 1.37 (d, 3H); MS (ESI) m / z=546.0 (M + H) +

[0180] Step 4: (S)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (20.53 mg, 0.038 mmol) prepared in Step 3, CsCO (36.75 mg, 0.113 mmol), XPhos (7.17 mg, 0.015 mmol), and Pd(dba) (6.89 mg, 0.008 mmol) in 1,4-dioxane (4 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 (S)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared (3.40 mg, 0.007 mmol, yield: 17.75%). 1 H-NMR (CD3OD, 400MHz) δ 8.29 (s, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 6.67 (d, 1H), 5.03-4.96 (m, 2H), 4.66-4.61 (m, 1H), 4.20-4.17 (m, 2H), 3.80 (s, 3H), 2.28-2.00 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z=510.0 (M + H) +

[0181] Example 15: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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: (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (200.00 mg, 0.612 mmol) prepared in Preparation 6, 1-(difluoromethyl)-4-ethynyl-1H-pyrazole (87.03 mg, 0.612 mmol), PdCl(PPh) (21.49 mg, 0.031 mmol), CuI (23.34 mg, 0.122 mmol), and TEA (0.17 mL, 1.225 mmol) in DMF (3 mL) was stirred at 50° 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 (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (134.00 mg, 0.393 mmol, yield: 64.21%). 1 H-NMR (CD3OD, 400MHz) δ 8.37 (s, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.52 (t, 1H), 6.72 (s, 1H), 3.94-3.89 (m, 1H), 3.84-3.70 (m, 2H), 1.94-1.81 (m, 2H), 1.30 (d, 3H); MS (ESI) m / z=341.1 (M + H) +

[0182] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (134.00 mg, 0.393 mmol), 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (75.18 mg, 0.393 mmol) prepared in Preparation 8, and (tributylphosphoranylidene)acetonitrile (0.38 mL, 1.376 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 (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (114.00 mg, 0.216 mmol, yield: 54.91%). 1 H-NMR (CD3OD, 400MHz) δ 8.19 (s, 1H), 8.02-7.99 (m, 2H), 7.76 (s, 1H), 7.46 (t, 1H), 6.73 (s, 1H), 6.29-6.26 (m, 1H), 4.38-4.29 (m, 2H), 4.04-3.99 (m, 1H), 3.37 (s, 3H), 2.35 (s, 3H), 2.35-2.03 (m, 2H), 1.33 (d, 3H); MS (ESI) m / z=528.1 (M + H) +

[0183] Step 3: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 A mixture of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (114.00 mg, 0.216 mmol) prepared in Step 2, CsCO (211.06 mg, 0.648 mmol), XPhos (41.18 mg, 0.086 mmol), and Pd(dba) (39.55 mg, 0.043 mmol) in 1,4-dioxane (4 mL) was stirred at 100 °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 (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (30 mg, 0.061 mmol, yield: 28.27%). 1 H-NMR (CD3OD, 400MHz) δ 8.35 (s, 1H), 8.29 (d, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.52 (t, 1H), 6.60 (d, 1H), 4.69-4.63 (m, 1H), 4.17-4.13 (m, 1H), 4.06-4.03 (m, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 2.30-2.25 (m, 1H), 2.06-2.01 (m, 1H), 1.79-1.74 (m, 1H), 1.42 (d, 3H); MS (ESI) m / z=492.2 (M + H) +

[0184] Example 16: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 Step 1: (S)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a solid (123 mg, 0.347 mmol, yield: 56.61%) in the same manner as in Step 1 of Example 15, except that 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (95.62 mg, 0.612 mmol) was used instead of 1-(difluoromethyl)-4-ethynyl-1H-pyrazole. 1 H-NMR (CD3OD, 400MHz) δ 8.00 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 6.71 (s, 1H), 6.36-6.08 (m, 1H), 4.64-4.56 (m, 2H), 3.93-3.88 (m, 1H), 3.83-3.69 (m, 2H), 1.91-1.82 (m, 2H), 1.30 (d, 3H); MS (ESI) m / z=355.1 (M + H) +

[0185] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a solid in the same manner as in Step 2 of Example 15, except that (S)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (139.51 mg, 0.393 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (101.00 mg, 0.186 mmol, yield: 47.39%). 1H-NMR (CD3OD, 400MHz) δ 8.01 (d, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 6.72 (s, 1H), 6.32-6.04 (m, 2H), 4.58-4.50 (m, 2H), 4.38-4.30 (m, 2H), 4.02-3.98 (m, 1H), 3.60 (s, 3H), 2.36 (s, 3H), 2.16-2.06 (m, 2H), 1.33 (d, 2H); MS (ESI) m / z=542.2 (M + H) +

[0186] Step 3: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 The title compound was prepared as a solid in the same manner as in Step 3 of Example 15, except that (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (117.03 mg, 0.216 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (28.00 mg, 0.055 mmol, yield: 25.65%). 1H-NMR (CD3OD, 400MHz) δ 8.32 (d, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 6.65 (d, 1H), 6.36-6.09 (m, 1H), 4.65-4.57 (m, 2H), 4.21-4.09 (m, 2H), 3.73 (s, 3H), 2.50 (s, 3H), 1.45 (d, 3H); MS (ESI) m / z=506.2 (M + H) +

[0187] Example 17: (S)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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: (S)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a solid (137.00 mg, 0.407 mmol, yield: 66.42%) in the same manner as in Step 1 of Example 15, except that 4-ethynyl-1-(2-fluoroethyl)-1H-pyrazole (95.62 mg, 0.612 mmol) was used instead of 1-(difluoromethyl)-4-ethynyl-1H-pyrazole. 1 H-NMR (CD3OD, 400MHz) δ 7.99-7.97 (m, 2H), 7.75 (s, 1H), 6.70 (s, 1H), 4.84-4.81 (m, 1H), 4.72-4.70 (m, 1H), 4.52-4.43 (m, 2H), 3.92-3.69 (m, 3H), 1.90-1.83 (m, 2H), 1.30 (d, 3H); MS (ESI) m / z=337.1 (M + H) +

[0188] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a solid in the same manner as in Step 2 of Example 15, except that (S)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (132.44 mg, 0.393 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (95.00 mg, 0.181 mmol, yield: 46.10%). 1 H-NMR (CD3OD, 400MHz) δ 8.01 (d, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 6.71 (s, 1H), 6.27 (d, 1H), 4.80-4.78 (m, 1H), 4.69-4.66 (m, 2H), 4.46-4.43 (m, 1H), 4.39-4.30 (m, 4H), 3,60 (s, 3H), 2.36 (s, 3H), 2.16-2.07 (m, 2H), 1.33 (d, 2H); MS (ESI) m / z=524.1 (M + H) +

[0189] Step 3: (S)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 The title compound was prepared as a solid in the same manner as in Step 3 of Example 15, except that (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (113.14 mg, 0.216 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (14.00 mg, 0.029 mmol, yield: 13.30%). 1 H-NMR (CD3OD, 400MHz) δ 8.32 (d, 1H), 8.19 (s, 1H), 7.96 (s, 2H), 7.74 (s, 1H), 6.64 (d, 1H), 4.87-4.82 (m, 1H), 4.74-4.69 (m, 1H), 4.53-4.44 (m, 2H), 4.20-4.08 (m, 2H), 3.73 (s, 3H), 2.50 (s, 3H), 2.35-2.29 (m, 1H), 2.09-2.03 (m, 2H), 1.44 (d, 3H); MS (ESI) m / z=488.3 (M + H) +

[0190] Example 18: (S)-4 5 -((1-isopropyl-1H-pyrazol-4-yl)ethynyl)-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-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (200.00 mg, 0.612 mmol) prepared in Preparation 6, 4-ethynyl-1-isopropyl-1H-pyrazole (82.18 mg, 0.612 mmol), PdCl(PPh) (21.49 mg, 0.031 mmol), CuI (23.34 mg, 0.122 mmol), and TEA (0.17 mL, 1.225 mmol) in DMF (3 mL) was stirred at 50° 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 (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (140.00 mg, 0.420 mmol, yield: 68.68%). 1 H-NMR (CD3OD, 400MHz) δ 7.99-7.97 (m, 2H), 7.71 (s, 1H), 6.70 (s, 1H), 4.59-4.52 (m, 1H), 3.93-3.88 (m, 1H), 3.83-3.70 (m, 2H), 1.93-1.81 (m, 1H), 1.51 (s, 6H), 1.30 (s, 3H); MS (ESI) m / z=333.1 (M + H) +

[0191] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (79.52 mg, 0.239 mmol) prepared in Step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (45.68 mg, 0.239 mmol) prepared in Preparation 7, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.836 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 (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (52.00 mg, 0.103 mmol, yield: 43.01%). 1 H-NMR (CD3OD, 400MHz) δ 7.99 (d, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.51 (s, 1H), 6.74 (s, 1H), 6.27 (d, 1H), 4.54-4.43 (m, 3H), 4.06-4.04 (m, 1H), 3.66 (s, 3H), 2.24-2.15 (m, 2H), 1.45 (d, 6H), 1.39 (d, 3H); MS (ESI) m / z=507.0 (M + H) +

[0192] Step 3: (S)-4 5 -((1-isopropyl-1H-pyrazol-4-yl)ethynyl)-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-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (25.00 mg, 0.049 mmol) prepared in Step 2, CsCO (48.29 mg, 0.148 mmol), XPhos (9.42 mg, 0.020 mmol), and Pd(dba) (9.05 mg, 0.010 mmol) in 1,4-dioxane (4 mL) was stirred at 100 °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 (S)-4 5 -((1-isopropyl-1H-pyrazol-4-yl)ethynyl)-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 (15.10 mg, 0.032 mmol, yield: 65.09%). 1 H-NMR (CD3OD, 400MHz) δ 8.27 (d, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 6.67 (d, 1H), 4.72-4.53 (m, 2H), 4.15-4.11 (m, 2H), 3.81 (s, 3H), 2.37-2.29 (m, 2H), 1.58 (d, 6H), 1.43 (d, 3H); MS (ESI) m / z=470.2 (M + H) +

[0193] Example 19: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-3-yl)ethynyl)-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-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a solid (95.00 mg, 0.312 mmol, yield: 50.90%) in the same manner as in Step 1 of Example 18, except that 3-ethynyl-1-methyl-1H-pyrazole (65.00 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1H-pyrazole. 1 H-NMR (CD3OD, 400MHz) δ 8.00 (d, 1H), 7.64 (d, 1H), 6.73 (s, 1H), 6.53 (d, 1H), 3.94 (s, 3H), 3.93-3.88 (m, 1H), 3.77-3.69 (m, 2H), 1.89-1.84 (m, 2H), 1.30 (d, 3H); MS (ESI) m / z=305.1 (M + H) +

[0194] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a solid (29.00 mg, 0.061 mmol, yield: 25.40%) in the same manner as in Step 2 of Example 18, except that (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (72.82 mg, 0.239 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 8.01-7.97 (m, 2H), 7.83 (s, 1H), 7.57 (s, 1H), 6.77 (s, 1H), 6.36 (s, 1H), 6.26 (d, 1H), 4.53-4.48 (m, 2H), 4.07-4.05 (m, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 2.26-2.17 (m, 2H), 1.47 (d, 3H); MS (ESI) m / z=478.1 (M + H) +

[0195] Step 3: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-3-yl)ethynyl)-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 solid in the same manner as in Step 3 of Example 18, except that (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (23.61 mg, 0.049 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (2.60 mg, 0.006 mmol, yield: 11.92%). 1 H-NMR (CD3OD, 400MHz) δ 8.26 (d, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (s, 1H), 6.70 (d, 1H), 6.44 (d, 1H), 5.95 (s, 1H), 4.88-4.69 (m, 1H), 4.19-4.16 (m, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.23-2.19 (m, 2H), 1.30 (d, 3H); MS (ESI) m / z=442.2 (M + H) +

[0196] Example 20: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a solid (170.00 mg, 0.456 mmol, yield: 74.47%) in the same manner as in Step 1 of Example 18, except that 4-ethynyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole (106.64 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1H-pyrazole. 1 H-NMR (CD3OD, 400MHz) δ 8.06 (s, 1H), 6.76 (s, 1H), 3.99 (s, 3H), 3.95-3.92 (m, 1H), 3.76-3.68 (m, 2H), 1.85-1.81 (m, 2H), 1.30 (d, 3H); MS (ESI) m / z=373.1 (M + H) +

[0197] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a solid (25.00 mg, 0.046 mmol, yield: 19.17%) in the same manner as in Step 2 of Example 18, except that (S)-3-((2-chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (89.06 mg, 0.239 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CD3OD, 400MHz) δ 7.99-7.95 (m, 2H), 7.84 (s, 1H), 7.71 (s, 1H), 6.78 (s, 1H), 6.26 (d, 1H), 4.56-4.46 (m, 2H), 4.08-4.07 (m, 1H), 3.91 (s, 3H), 3.66 (s, 3H), 2.25-2.03 (m, 2H), 1.39 (d, 3H); MS (ESI) m / z=546.1 (M + H) +

[0198] Step 3: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 solid in the same manner as in Step 3 of Example 18, except that (S)-2-(5-(3-((2-chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (26.97 mg, 0.049 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (6.60 mg, 0.013 mmol, yield: 26.22%). 1 H-NMR (CD3OD, 400MHz) δ 8.33 (s, 1H), 8.24 (d, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 6.68 (d, 1H), 4.88-4.67 (m, 1H), 4.19-4.16 (m, 2H), 3.99 (s, 3H), 3.81 (s, 3H), 2.30-2.27 (m, 1H), 2.08-2.03 (m, 1H), 1.44 (d, 3H); MS (ESI) m / z=510.2 (M + H) +

[0199] Example 21: (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol The title compound was prepared as a solid (138.00 mg, 0.400 mmol, yield: 65.34%) in the same manner as in Step 1 of Example 18, except that 3-cyclopropyl-4-ethynyl-1-methyl-1H-pyrazole (89.53 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1H-pyrazole. 1 H-NMR (CD3OD, 400MHz) δ 7.95 (s, 1H), 7.58 (s, 1H), 6.71 (s, 1H), 3.91 (s, 3H), 3.89-3.67 (m, 2H), 1.96-1.82 (m, 3H), 1.30 (d, 3H), 1.18-1.06 (m, 4H); MS (ESI) m / z=345.1 (M + H) +

[0200] Step 2: (S)-2-(5-(3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a solid (22.00 mg, 0.042 mmol, yield: 17.78%) in the same manner as in Step 2 of Example 18, except that (S)-3-((2-chloro-5-((3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (82.39 mg, 0.239 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1 H-NMR (CD3OD, 400MHz) δ 7.98 (d, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 6.76 (s, 1H), 6.26 (d, 1H), 4.59-4.48 (m, 2H), 4.10-4.08 (m, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 2.28-2.24 (m, 2H), 1.41 (d, 3H), 1.02-0.98 (m, 4H); MS (ESI) m / z=518.1 (M + H)+

[0201] Step 3: (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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 solid in the same manner as in Step 3 of Example 18, except that (S)-2-(5-(3-((2-chloro-5-((3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (25.59 mg, 0.049 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (3.10 mg, 0.006 mmol, yield: 13.03%). 1 H-NMR (CD3OD, 400MHz) δ 8.33 (s, 1H), 8.24 (d, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 6.69 (d, 1H), 4.78-4.72 (m, 1H), 4.24-4.18 (m, 2H), 3.92 (s, 3H), 3.81 (s, 3H), 2.29-2.27 (m, 1H), 2.00-1.94 (m, 2H), 1.47 (d, 3H), 1.16-1.12 (m, 4H); MS (ESI) m / z=482.2 (M + H) +

[0202] Example 22: (S)-7-fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1H-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol (155.72 mg, 0.471 mmol) prepared in Preparation 1, 4-ethynyl-1-methylpyrazole (50 mg, 0.471 mmol), PdCl(PPh) (33.07 mg, 0.047 mmol), CuI (17.94 mg, 0.094 mmol), and TEA (131.33 μL, 0.942 mmol) was purged with nitrogen gas for 10 minutes. DMF (1 mL) was added, and the reaction mixture was stirred at 70 °C for 2 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 (EA / n-Hex=0-70%) to produce (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol as a pale pink solid (86.5 mg, 0.28 mmol, yield: 59.49%). MS (ESI) m / z=308.9 (M + H). +

[0203] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A reaction mixture of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (48 mg, 0.251 mmol), (tributylphosphoranylidene)acetonitrile (164.66 μL, 0.628 mmol), and (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (77.51 mg, 0.251 mmol) prepared in Step 1 in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and concentrated. The crude product was purified by silica gel column chromatography (MeOH / EA=0-15%) to produce (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a pale yellow solid (46 mg, 0.095 mmol, yield: 38.02%). 1 H-NMR (DMSO-d6, 400 MHz) δ 8.19 (d, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.60 (s, 1H), 6.19 (d, 1H), 5.85 (t, 1H), 5.13-4.96 (m, 1H), 4.82 (s, 2H), 4.74-4.60 (m, 2H), 3.91 (s, 3H), 3.87-3.69 (m, 5H)

[0204] Step 3: (S)-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane A suspension of Pd(dba) (12.83 mg, 0.014 mmol), XPhos (13.35 mg, 0.028 mmol), CsCO (91.28 mg, 0.28 mmol), and (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.093 mmol) prepared in Step 2 in 1,4-dioxane (1.0 mL) was stirred at 90 °C for 2 h. The mixture was diluted with DCM, filtered through Celite, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex=0-100%), slurried in EA / IPE for 0.5 h (room temperature), filtered, and purified to give (S)-7-fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a pale yellow solid (15.8 mg, 0.035 mmol, yield: 37.98%). 1 H-NMR (DMSO-d6, 400 MHz) δ 10.04 (s, 1H), 8.31 (d, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1 H), 7.98 (s, 1H), 7.70 (s, 1 H), 6.79 (d, 1H), 6.68 (t, 1H), 4.84 (dd, 1H), 4.66 (dd, 1H), 4.40 (t, 1H), 4.17-4.09 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.66-3.56 (m, 1H); MS (ESI) m / z=445.9 (M + H) +

[0205] Example 23: (S)-7-fluoro-1 1 -methyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1H-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as a white solid (1166 mg) in the same manner as in Step 1 of Example 22, except that 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (50 mg, 0.312 mmol) was used instead of 4-ethynyl-1-methylpyrazole. 1 H-NMR (CDCl3, 400 MHz) 8.17 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 6.58 (s, 1H), 5.56 (t, 1H), 4.90-4.73 (m, 1H), 4.02-3.83 (m, 2H), 3.68-3.58 (m, 2H), 2.21 (t, 1H)

[0206] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (41 mg) in the same manner as in Step 2 of Example 22, except that (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (75.88 mg, 0.209 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 6.64 (s, 1H), 6.19 (d, 1H), 6.10 (t, 1H), 5.11-4.81 (m, 1H), 4.81 (s, 2H), 4.68-4.61 (m, 2H), 3.95-3.78 (m, 2H), 3.73 (s, 3H)

[0207] Step 3: (S)-7-Fluoro-1 1 -methyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (9.9 mg) in a similar manner to Step 3 of Example 22, except that (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (35 mg, 0.065 mmol) was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 10.05 (s, 1H), 8.89 (s, 1H), 8.32 (d, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 6.80 (d, 1H), 6.77 (t, 1H), 4.84 (dd, 1H), 4.66 (dd, 1H), 4.40 (t, 1H), 4.19-4.12 (m, 1H), 3.75 (s, 3H), 3.64-3.54 (m, 1H); MS (ESI) m / z=499.8 (M + H) +

[0208] Example 24: (R)-7-fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol The title compound was prepared as a white solid (80 mg) in the same manner as in Step 1 of Example 22, except that (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol (155.72 mg, 0.471 mmol) prepared in Preparation 2 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m / z=308.9 (M + H) +

[0209] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (72 mg) in the same manner as in Step 2 of Example 22, except that (R)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (77.51 mg, 0.251 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.19 (d, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.60 (s, 1H), 6.20 (d, 1H), 5.85 (t, 1H), 5.13-4.96 (m, 1H), 5.01 (s, 2H), 4.96-4.60 (m, 2H), 3.91 (s, 3H), 3.87-3.69 (m, 5H)

[0210] Step 3: (R)-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 in Step 3 of Example 22, except that (R)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.093 mmol) was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine, as an off-white solid (19.2 mg). 1 H-NMR (DMSO-d6, 400 MHz) δ 10.02 (s, 1H), 8.31 (d, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1 H), 7.98 (s, 1H), 7.70 (s, 1 H), 6.79 (d, 1H), 6.67 (t, 1H), 4.84 (dd, 1H), 4.66 (dd, 1H), 4.40 (t, 1H), 4.17-4.09 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.66-3.57 (m, 1H); MS (ESI) m / z=445.9 (M + H) +

[0211] Example 25: (S)-1 1 ,8-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a white solid (80.8 mg) in the same manner as in Step 1 of Example 22, except that (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (153.85 mg, 0.471 mmol) prepared in Preparation 3 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m / z=305.0 (M + H) +

[0212] Step 2: (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)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 (54 mg) in the same manner as in Step 2 of Example 22, except that (R)-4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (76.52 mg, 0.251 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (d, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.33 (s, 1H), 6.94 (s, 1H), 6.70 (dd, 1H), 6.54 (s, 1H), 6.14 (d, 1H), 5.06-5.02 (m, 1H), 4.77 (s, 2H), 3.84 (s, 3H), 3.72-3.54 (m, 2H), 3.62 (s, 3H), 2.32-2.24 (m, 1H), 1.97-1.91 (m, 1H), 1.23 (d, 3H)

[0213] Step 3: (S)-1 1 ,8-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 (7 mg) in the same manner as in Step 3 of Example 22, except that (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (44.63 mg, 0.093 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400 MHz) δ 8.36 (s, 1H), 8.26 (d, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H), 6.69 (d, 1H), 5.44-5.36 (m, 1H), 3.97-3.91 (m, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.62-3.55 (m, 1H), 2.32-2.24 (m, 1H), 1.97-1.91 (m, 1H), 1.11 (d, 3H); MS (ESI) m / z=442.0 (M+H) +

[0214] Example 26: (S)-1 1 ,8-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a white solid (95 mg) in the same manner as in Step 1 of Example 25, except that 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (50 mg, 0.312 mmol) was used instead of 4-ethynyl-1-methylpyrazole. 1 H-NMR (CDCl3, 400 MHz) 8.11 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 6.50 (s, 1H), 6.05 (brs, 1H), 4.09 (brs, 1H), 3.47-3.29 (m, 2H), 1.94-1.76 (m, 2H), 1.33 (d, 3H)

[0215] Step 2: (S)-2-(5-((4-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)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 (35 mg) in the same manner as in Step 2 of Example 22, except that (R)-4-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (75.06 mg, 0.209 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.12 (d, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.44 (d, 1H), 7.13 (dd, 1H), 6.57 (s, 1H), 6.14 (d, 1H), 4.99-4.92 (m, 1H), 4.79 (s, 2H), 3.75-3.57 (m, 2H), 3.65 (s, 3H), 2.24-2.14 (m, 1H), 1.87-1.84 (m, 1H), 1.22 (d, 3H)

[0216] Step 3: (S)-1 1 ,8-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (2.2 mg) in a similar manner to Step 3 of Example 22, except that (S)-2-(5-((4-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (34.74 mg, 0.065 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CD3OD, 400 MHz) δ 8.50 (s, 1H), 8.39 (s, 1H), 8.28 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 6.72 (d, 1H), 5.45-5.41 (m, 1H), 3.99-3.92 (m, 1H), 3.77 (s, 3H), 3.62-3.57 (m, 1H), 2.34-2.32 (m, 1H), 1.99-1.93 (m, 1H), 1.32 (d, 3H); MS (ESI) m / z=495.9 (M + H) +

[0217] Example 27: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a white solid (103 mg) in the same manner as in Step 1 of Example 25, except that 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (47.81 mg, 0.306 mmol) was used instead of 4-ethynyl-1-methylpyrazole. MS (ESI) m / z=354.9 (M + H). +

[0218] Step 2: (S)-2-(5-((4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)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 (52 mg) in the same manner as in Step 2 of Example 22, except that (R)-4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (92.78 mg, 0.262 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m / z=527.9 (M + H) +

[0219] Step 3: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 an off-white solid (9.9 mg) in a similar manner to Step 3 of Example 22, except that (S)-2-(5-((4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50 mg, 0.095 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.35 (d, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 6.37 (d, 1H), 6.13 (tt, 1H), 5.51-5.43 (m, 2H), 4.51 (td, 2H), 4.12-4.05 (m, 1H), 3.77 (s, 3H), 3.58-3.51 (m, 1H), 2.30-2.20 (m, 1H), 1.98-1.92 (m, 1H), 1.12 (d, 3H); MS (ESI) m / z=491.9 (M + H) +

[0220] Example 28: (S)-1 1 ,8-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a white solid (112 mg) in the same manner as in Step 1 of Example 25, except that 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (53.32 mg, 0.306 mmol) was used instead of 4-ethynyl-1-methylpyrazole. MS (ESI) m / z=372.9 (M + H). +

[0221] Step 2: (S)-2-(5-((4-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)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 (58 mg) in the same manner as in Step 2 of Example 22, except that (R)-4-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (97.49 mg, 0.262 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m / z=545.9 (M + H). +

[0222] Step 3: (S)-1 1 ,8-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (9.5 mg) in the same manner as in Step 3 of Example 22, except that (S)-2-(5-((4-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (51.7 mg, 0.095 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.35 (d, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 6.37 (d, 1H), 5.51-5.43 (m, 2H), 475 (q, 2H), 4.12-4.05 (m, 1H), 3.77 (s, 3H), 3.58-3.52 (m, 1H), 2.30-2.22 (m, 1H), 1.98-1.92 (m, 1H), 1.12 (d, 3H); MS (ESI) m / z=509.9 (M+H) +

[0223] Example 29: 1'-methyl-5'-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane] Step 1: (1-(((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methanol The title compound was prepared as a white solid (90.5 mg) in the same manner as in Step 1 of Example 22, except that (1-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)cyclopropyl)methanol (159.51 mg, 0.471 mmol) prepared in Preparation 4 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m / z=316.9 (M + H) +

[0224] Step 2: 2-(5-((1-(((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (47 mg) in the same manner as in Step 2 of Example 22, except that 3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (79.53 mg, 0.251 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.11 (d, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.39 (s, 1H), 6.97 (s, 1H), 6.62 (t, 1H), 6.46 (s, 1H), 6.17 (d, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.78 (s, 3H), 3.64 (s, 3H), 3.41 (d, 2H), 0.86-0.79 (q, 4H)

[0225] Step 3: 1'-methyl-5'-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-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 the same manner as in Step 3 of Example 22, except that 2-(5-((1-(((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.75 mg, 0.093 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 8.26 (d, 1H), 8.05 (s, 1H), 7.95 (s 1H), 7.87 (s, 1H), 7.69 (s, 1H), 6.70 (d, 1H), 4.23 (brs, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.59 (brs, 2H), 0.92 (s, 3H), 0.74 (s, 3H); MS (ESI) m / z=453.9 (M + H) +

[0226] Example 30:1 1 ,7,7-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol The title compound was prepared as a white solid (83 mg) in the same manner as in Step 1 of Example 22, except that 3-((2-chloro-5-iodopyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (160.46 mg, 0.471 mmol) prepared in Preparation 5 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m / z=318.9 (M + H) +

[0227] Step 2: 2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a white solid (46 mg) in the same manner as in Step 2 of Example 22, except that 3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (80.04 mg, 0.251 mmol) prepared in Step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1 H-NMR (CDCl3, 400 MHz) δ 8.11 (d, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.30 (s, 1H), 6.86 (s, 1H), 6.84 (t, 1H), 6.55 (s, 1H), 6.15 (d, 1H), 4.73 (s, 2H), 4.09 (s, 2H), 3.79 (s, 3H), 3.66 (s, 3H), 3.40 (d, 2H), 1.17 (s, 6H)

[0228] Step 3:1 1 ,7,7-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 an off-white solid (10.2 mg) in a similar manner to Step 3 of Example 22, except that 2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.94 mg, 0.093 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (DMSO-d6, 400 MHz) δ 9.93 (s, 1H), 8.29 (d, 1H), 8.17 (s, 1H), 8.05 (s, 1 H), 7.96 (s, 2H), 7.70 (d, 1H), 6.77 (d, 1H), 6.29 (t, 1H), 4.59 (brs, 1H), 3.87 (brs, 4H), 3.78 (s, 3H), 3.67 (brs, 1H), 3.01 (brs, 1H), 1.30 (s, 3H), 0.89 (s, 3H); MS (ESI) m / z=456.0 (M + H) +

[0229] Example 31: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine (300 mg, 1.273 mmol) prepared in Preparation 10 and (S)-3-aminobutan-1-ol (113.4 mg, 1.273 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.44 mL, 2.546 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 MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to give (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (385 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.13-8.12 (d, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 6.54 (s, 1H), 6.17-6.16 (d, 1H), 5.86-5.84 (d, 1H), 4.84 (s, 2H), 4.57-4.53 (q, 1H), 4.46-4.41 (q, 1H), 3.98-3.91 (q, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 2.25-2.20 (m, 1H), 2.10-2.05 (m, 1H), 1.45-1.40 (t, 3H); MS (ESI) m / z=305.1 (M + H) +

[0230] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (224 mg, 1.17 mmol) prepared in Preparation 7, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (385 mg, 1.263 mmol, 1.08 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (1.2 mL, 3.51 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (209 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.12-8.11 (d, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 6.54 (s, 1H), 6.16-6.15 (d, 1H), 5.85-5.83 (d, 1H), 4.91 (s, 2H), 4.56-4.53 (t, 1H), 4.46-4.42 (q, 1H), 3.96-3.92 (t, 1H), 3.81 (s, 3H), 3.64 (s, 3H), 2.22-2.19 (m, 1H), 2.10-2.05 (m, 1H), 1.41-1.39 (d, 3H); MS (ESI) m / z=478.2 (M + H) +

[0231] Step 3: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (209 mg, 0.348 mmol) prepared in Step 2, CsCO (427 mg, 1.31 mmol), XPhos (83 mg, 0.17 mmol), and Pd(dba) (80 mg, 0.087 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-methyl-1H-pyrazol-4-yl)ethynyl)-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 (10.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.32-8.31 (d, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.77-7.73 (d, 1H), 7.65-7.58 (m, 2H), 7.43-7.42 (d, 1H), 7.12-7.08 (d, 1H), 6.37-6.36 (d, 1H), 4.95-4.94 (d, 1H), 4.81-4.76 (t, 1H), 4.29-4.27 (d, 1H), 4.06-4.02 (m, 1H), 3.94-3.91 (d, 3H), 3.80 (s, 3H), 2.20-2.13 (m, 2H), 1.47-1.46 (d, 3H); MS (ESI) m / z=442.2 (M + H) +

[0232] Example 32: (R)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1H-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine (300 mg, 1.273 mmol) prepared in Preparation 10 and (R)-3-aminobutan-1-ol (113.4 mg, 1.273 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.44 mL, 2.546 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 MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to give (R)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (357 mg). 1 H-NMR (CDCl3, 400 MHz) δ 7.98-7.96 (d, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 6.46 (s, 1H), 5.75-5.73 (d, 1H), 3.84 (s, 3H), 3.80-3.76 (m, 3H), 1.90-1.87 (m, 1H), 1.77-1.73 (m, 1H), 1.27-1.21 (q, 3H); MS (ESI) m / z=305.1 (M + H) +

[0233] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (224 mg, 1.17 mmol) prepared in Preparation 7, (R)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (357 mg, 1.171 mmol, 1.0 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (1.2 mL, 3.51 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (158 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.11-8.10 (d, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 6.53 (s, 1H), 6.16-6.14 (d, 1H), 5.85-5.83 (d, 1H), 4.99 (s, 2H), 4.55-4.51 (m, 1H), 4.45-4.41 (m, 1H), 3.95-3.91 (t, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.22-2.18 (m, 1H), 2.09-2.03 (m, 1H), 1.40-1.38 (d, 3H); MS (ESI) m / z=478.2 (M + H) +

[0234] Step 3: (R)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (159 mg, 0.333 mmol) prepared in Step 2, CsCO (427 mg, 1.31 mmol), XPhos (83 mg, 0.17 mmol), and Pd(dba) (80 mg, 0.087 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-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Prepared as a white solid (23.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31-8.30 (d, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.38-6.36 (d, 1H), 4.95-4.94 (d, 1H), 4.81-4.76 (t, 1H), 4.29-4.27 (d, 1H), 4.05-4.03 (t, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.20-2.13 (m, 2H), 1.47-1.45 (d, 3H); MS (ESI) m / z=442.2 (M + H) +

[0235] Example 33: (R)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (150 mg, 0.525 mmol) prepared in Preparation 11 and (R)-3-aminobutan-1-ol (46.8 mg, 0.525 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.18 mL, 1.05 mmol, 2.0 eq) 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (141 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.69-7.68 (d, 2H), 6.51 (s, 1H), 6.23-5.95 (t, 1H), 5.63-5.61 (d, 1H), 4.50-4.43 (m, 2H), 3.88-3.80 (m, 3H), 2.24 (s, 1H), 1.93-1.89 (q, 1H), 1.82-1.77 (q, 1H), 1.30-1.29 (d, 3H); MS (ESI) m / z=355.1 (M + H) +

[0236] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (30.8 mg, 0.161 mmol) prepared in Preparation 7, (R)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (140 mg, 0.395 mmol, 2.45 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.14 mL, 0.402 mmol, 2.5 eq) in toluene (2 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (45.3 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.09-8.08 (d, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 6.53 (s, 1H), 6.15-6.14 (d, 1H), 6.04-5.90 (m, 2H), 5.05 MS (ESI) m / z=528.2 (M + H) +

[0237] Step 3: (R)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.3 mg, 0.087 mmol), CsCO (85 mg, 0.261 mmol), XPhos (17 mg, 0.035 mmol), and Pd(dba) (16 mg, 0.017 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)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (2.7 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.33-8.32 (d, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 6.37-6.36 (d, 1H), 6.25-5.98 (t, 1H), 4.93-4.91 (d, 1H), 4.81-4.76 (t, 1H), 4.53-4.46 (m, 2H), 4.30-4.28 (d, 1H), 4.07-4.05 (d, 1H), 3.81 (s, 3H), 2.20-2.17 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m / z=492.2 (M + H) +

[0238] Example 34: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1H-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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (150 mg, 0.525 mmol) prepared in Preparation 11 and (S)-3-aminobutan-1-ol (46.8 mg, 0.525 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.18 mL, 1.05 mmol, 2.0 eq) 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (141 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.02 (s, 1H), 7.68 (s, 2H), 6.50 (s, 1H), 6.22-5.94 (t, 1H), 5.66-5.64 (d, 1H), 4.49-4.42 (m, 2H), 3.88-3.79 (m, 3H), 1.92-1.89 (q, 1H), 1.82-1.75 (q, 1H), 1.29-1.27 (d, 3H); MS (ESI) m / z=355.1 (M + H) +

[0239] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (30.8 mg, 0.161 mmol) prepared in Preparation 7, (S)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (140 mg, 0.395 mmol, 2.45 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.14 mL, 0.402 mmol, 2.5 eq) in toluene (2 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (70.8 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.12-8.11 (d, 1H), 7.96 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.55 (s, 1H), 6.17 (d, 1H), 6.05-5.92 (m, 2H), 5.05 (s, 2H), 4.87 (s, 2H), 4.56-4.56 (d, 1H), 4.54-4.33 (m, 3H), 3.96-3.93 (t, 1H), 3.64 (s, 3H), 2.23-2.21 (t, 1H), 2.10-2.04 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m / z=528.1 (M + H) +

[0240] Step 3: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (S)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (71.0 mg, 0.087 mmol), CsCO (85 mg, 0.261 mmol), XPhos (17 mg, 0.035 mmol), and Pd(dba) (16 mg, 0.017 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 (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (4.0 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.33-8.32 (d, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 6.37-6.36 (d, 1H), 6.24-5.90 MS (ESI) m / z=492.2 (M + H) +

[0241] Example 35: (6S)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-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: (3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (100 mg, 0.306 mmol), 1-(2,2-difluorocyclopropyl)-4-ethynyl-1H-pyrazole (42.3 mg, 0.306 mmol), PdCl(PPh) (10.8 mg, 0.015 mmol), and CuI (11.7 mg, 0.061 mmol) was purged with nitrogen gas for 10 minutes. DMF (15 mL) and TEA (0.09 mL, 0.612 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as an off-white solid (71.1 mg). 1 H-NMR (CDCl3, 400 MHz) δ 7.55 (s, 1H), 7.50 (s, 2H), 7.22-7.12 (m, 1H), 7.07-7.05 (d, 1H), 6.08 (s, 1H), 5.89-5.87 (d, 1H), 4.35 (s, 1H), 3.84-3.82 (d, 1H), 3.40-3.36 (q, 2H), 3.29 (s, 1H), 1.95-1.86 (m, 1H), 1.75-1.70 (q, 1H), 1.47-1.44 (q, 1H), 1.34-1.30 (q, 1H), 0.85-0.83 (d, 3H); MS (ESI) m / z=367.1 (M + H) +

[0242] Step 2: 2-(5-((3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (30.8 mg, 0.161 mmol) prepared in Preparation 7, (3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (71.1 mg, 0.194 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.17 mL, 0.485 mmol, 2.5 eq) in toluene (2 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-((3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (50.7 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.13-8.08 (q, 2H), 7.96 (s, 1H), 7.49 (s, 1H), 7.33 (s, 1H), 6.55 (s, 1H), 6.17-6.14 (t, 1H), 5.95-5.88 (m, 1H), 4.87 MS (ESI) m / z=540.2 (M + H) +

[0243] Step 3: (6S)-4 5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-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 2-(5-((3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.7 mg, 0.094 mmol) prepared in Step 2, CsCO (92 mg, 0.282 mmol), XPhos (17.9 mg, 0.038 mmol), and Pd(dba) (17.2 mg, 0.019 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 C18 column chromatography (MeCN / water = 0-100%) to give (6S)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-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 (9.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.31-8.30 (d, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.72-7.71 (d, 1H), 6.38-6.37 (d, 1H), 4.94-4.92 MS (ESI) m / z=504.2 (M + H) +

[0244] Example 36:11 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane Step 1: 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of 2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (200 mg, 0.412 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (43.7 mg, 0.412 mmol, 1.0 eq), PdCl(PPh) (14.4 mg, 0.021 mmol, 0.05 eq), and CuI (15.7 mg, 0.082 mmol, 0.2 eq) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.11 mL, 0.824 mmol, 2.0 eq) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to give 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as an off-white solid (191 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.11-8.09 (d, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.55-6.53 (d, 2H), 6.16-6.15 (d, 1H), 5.00 (s, 2H), 4.64-4.62 (d, 2H), 4.42-4.40 (t, 2H), 3.60-3.59 (d, 2H), 3.18-3.14 (t, 2H), 2.16-2.14 (t, 2H), 1.47-1.44 (t, 3H); MS (ESI) m / z=532.1 (M+H) +

[0245] Step 2:1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (191 mg, 0.359 mmol) prepared in Step 1, Cs2CO3 (350 mg, 1.077 mmol), XPhos (68.5 mg, 0.144 mmol), and Pd2(dba)3 (65.7 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 C18 column chromatography (MeCN / water = 0-100%) to give 1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (12.7 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.34-8.32 (d, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.75-7.73 (d, 1H), 6.37-6.36 (d, 1H), 5.54-5.52 (t, 1H), 4.77-4.70 (q, 2H), 4.43-4.40 (t, 2H), 3.79 (s, 3H), 3.77 (s, 2H), 2.23 (s, 2H); MS (ESI) m / z=496.2 (M + H) +

[0246] Example 37: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (500 mg, 1.841 mmol) prepared in Preparation 13 and (S)-3-aminobutan-1-ol (164 mg, 1.841 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.64 mL, 3.681 mmol, 2.0 eq) 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (517 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.33-7.03 (t, 1H), 6.52 (s, 1H), 5.69-5.67 (d, 1H), 3.91 (s, 1H), 3.86-3.81 (m, 2H), 1.94-1.91 (m, 1H), 1.82-1.80 (m, 1H), 1.31-1.29 (d, 3H); MS (ESI) m / z=341.1 (M + H) +

[0247] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (56.1 mg, 0.293 mmol) prepared in Preparation 7, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100 mg, 0.293 mmol, 1.0 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.30 mL, 0.88 mmol, 3.0 eq) in toluene (2 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (105.4 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.10-8.08 (t, 2H), 7.95 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.11-6.96 (t, 1H), 6.56 (s, 1H), 6.15-6.13 (d, 1H), 5.96-5.93 (d, 1H), 4.55-4.50 (m, 1H), 4.45-4.41 (m, 1H), 3.97-3.94 (t, 1H), 3.67 (s, 3H), 2.20-2.18 (t, 1H), 2.09-2.03 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m / z=514.1 (M + H) +

[0248] Step 3: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105 mg, 0.204 mmol), CsCO (199 mg, 0.613 mmol, 3.0 eq), XPhos (38.9 mg, 0.082 mmol, 0.4 eq), and Pd(dba) (37 mg, 0.041 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 (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (31.3 mg).1 H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.37 (s, 1H), 8.29-8.28 (d, 1H), 8.12-8.10 (d, 2H), 8.01 (s, 1H), 7.79 (s, 1H), 7.35-7.05 (t, 1H), 6.38-6.36 (d, 1H), 4.91-4.89 (d, 1H), 4.77-4.76 (d, 1H), 4.27 (d, 1H), 4.04-4.02 (t, 1H), 3.79 (s, 3H), 2.20-2.12 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m / z=478.1 (M + H) +

[0249] Example 38: (R)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (500 mg, 1.841 mmol) prepared in Preparation 13 and (R)-3-amino-1-butanol (164 mg, 1.841 mmol) was purged with nitrogen gas for 10 minutes. DMF (6 mL) and DIPEA (0.64 mL, 3.681 mmol, 2.0 eq) 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (535 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.02-8.00 (d, 2H), 7.76 (s, 1H), 7.32-7.02 (t, 1H), 6.49 (s, 1H), 5.76-5.74 (d, 1H), 3.89-3.87 (t, 1H), 3.84-3.80 (q, 2H), 1.96-1.90 (m, 1H), 1.80-1.77 (m, 1H), 1.29-1.28 (d, 3H); MS (ESI) m / z=341.1 (M + H) +

[0250] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (56.1 mg, 0.293 mmol) prepared in Preparation 7, (R)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100 mg, 0.293 mmol, 1.0 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.30 mL, 0.88 mmol, 3.0 eq) in toluene (2 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (88.2 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 8.09-8.08 (d, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.26-6.96 (t, 1H), 6.56 (s, 1H), 6.15-6.14 (d, 1H), 5.95-5.93 (d, 1H), 4.56-4.53 (m, 1H), 4.51-4.40 (m, 1H), 3.98-3.94 (t, 1H), 3.66 (s, 3H), 2.22-2.19 (q, 1H), 2.10-2.04 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m / z=514.1 (M + H) +

[0251] Step 3: (R)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (88 mg, 0.171 mmol) prepared in Step 2, CsCO (199 mg, 0.613 mmol), XPhos (38.9 mg, 0.082 mmol), and Pd(dba) (37 mg, 0.041 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 C18 column chromatography (MeCN / water = 0-100%) to give (R)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (22.9 mg).1 H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.32-8.30 (d, 1H), 8.12-8.10 (m, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.35-7.05 (t, 1H), 6.38-6.37 MS (ESI) m / z=478.2 (M + H) +

[0252] Example 39: (R)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (133.3 mg, 0.766 mmol), PdCl(PPh) (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (R)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as an off-white solid (260 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.73-7.73 (d, 2H), 7.43-7.43 (d, 1H), 6.53 (s, 1H), 5.60-5.59 (d, 1H), 4.75-4.69 (q, 2H), 3.92-3.81 (m, 2H), 1.92-1.90 (m, 1H), 1.83-1.81 (m, 1H), 1.31-1.30 (d, 3H); MS (ESI) m / z=373.1 (M + H) +

[0253] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) prepared in Preparation 7, (R)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (260 mg, 0.697 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (98 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.10-8.09 (d, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 6.54 (s, 1H), 6.16-6.15 (d, 1H), 5.95-5.93 MS (ESI) m / z=546.1 (M + H) +

[0254] Step 3: (R)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (98 mg, 0.180 mmol) prepared in Step 2, CsCO (175 mg, 0.539 mmol), XPhos (34.2 mg, 0.072 mmol), and Pd(dba) (32.8 mg, 0.036 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-4-yl)ethynyl)-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 (28.3 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.33-8.32 (d, 1H), 8.14 (s, 1H), 7.76-7.74 (d, 2H), 6.39-6.38 (d, 1H), 4.94-4.93 (d, 1H), 4.81-4.72 (m, 3H), 4.31-4.29 (q, 1H), 4.15-4.13 (d, 1H), 4.07-4.05 (t, 1H), 3.81 (s, 3H), 2.22-2.21 (m, 2H), 1.49-1.48 (d, 3H); MS (ESI) m / z=510.1 (M + H) +

[0255] Example 40: (R)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol), 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (122.5 mg, 0.766 mmol), PdCl(PPh) (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (R)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as an off-white solid (275 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.02 (s, 2H), 7.86 (s, 1H), 6.50 (s, 1H), 5.84-5.82 (d, 1H), 3.91-3.88 (q, 1H), 3.85-3.80 (m, 2H), 1.95-1.87 (m, 1H), 1.81-1.78 (m, 1H), 1.30-1.28 (d, 3H); MS (ESI) m / z=359.1 (M + H) +

[0256] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) prepared in Preparation 7, (R)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (275 mg, 0.767 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (169 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.10-8.08 (t, 2H), 7.95 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 6.57 (s, 1H), 6.15-6.14 (d, 1H), 6.09-6.07 (d, 1H), 4.86 MS (ESI) m / z=532.1 (M + H) +

[0257] Step 3: (R)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (169 mg, 0.318 mmol), CsCO (175 mg, 0.539 mmol), XPhos (34.2 mg, 0.072 mmol), and Pd(dba) (32.8 mg, 0.036 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 (35.6 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.32-8.31 (d, 1H), 8.13-8.12 (d, 2H), 8.03 (s, 1H), 7.90 (s, 1H), 6.40-6.39 (d, 1H), 4.91-4.89 (d, 1H), 4.78-4.75 (t, 1H), 4.31-4.29 (q, 1H), 4.07-4.04 (t, 1H), 3.80 (s, 3H), 2.22-2.14 (m, 2H), 1.49-1.48 (d, 3H); MS (ESI) m / z=496.1 (M + H) +

[0258] Example 41: (6R)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-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: (3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol), 1-(2,2-difluorocyclopropyl)-4-ethynyl-1H-pyrazole (128.6 mg, 0.766 mmol), PdCl(PPh) (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as an off-white solid (180 mg). 1 H-NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 6.45 (s, 1H), 5.73-5.72 (d, 1H), 4.08-4.06 (q, 1H), 3.86-3.77 (m, 1H), 2.24-2.16 (m, 2H), 2.14-2.06 (m, 1H), 1.93-1.91 (t, 1H), 1.89-1.87 (t, 1H), 1.30-1.28 (d, 3H); MS (ESI) m / z=367.1 (M + H) +

[0259] Step 2: 2-(5-((3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) prepared in Preparation 7, (3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (180 mg, 0.491 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 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-((3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (107 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.13-8.07 (m, 2H), 7.96-7.96 (d, 1H), 7.49-7.48 (d, 1H), 7.33 (s, 1H), 6.55 (s, 1H), 6.17-6.14 (q, 1H), 5.95-5.88 (q, 1H), 4.90-4.88 (d, 2H), 4.60-4.42 (m, 2H), 4.05-4.03 (q, 1H), 3.96-3.93 (t, 1H), 3.65-3.64 (d, 3H), 2.23-2.15 (m, 2H), 2.11-2.04 (m, 2H), 1.42-1.41 (d, 3H); MS (ESI) m / z=540.1 (M + H) +

[0260] Step 3: (6R)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-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 2-(5-((3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (107 mg, 0.198 mmol) prepared in Step 2, CsCO (193 mg, 0.594 mmol), XPhos (37.8 mg, 0.079 mmol), and Pd(dba) (36.2 mg, 0.04 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 C18 column chromatography (MeCN / water = 0-100%) to give (6R)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-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 (22 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31-8.29 (d, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.73-7.72 (d, 2H), 6.39-6.38 (d, 1H), 4.95-4.93 MS (ESI) m / z=504.2 (M + H) +

[0261] Example 42: (R)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol), 4-ethynyl-1-(2-fluoroethyl)-1H-pyrazole (105.6 mg, 0.766 mmol), PdCl(PPh) (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (R)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as an off-white solid (189 mg). 1 H-NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 6.46 (s, 1H), 5.71-5.69 (d, 1H), 4.79-4.77 (t, 1H), 4.67-4.65 (t, 1H), 4.41-4.39 (t, 1H), 4.34-4.32 (t, 1H), 3.84-3.74 (m, 3H), 1.89-1.86 (m, 1H), 1.77-1.75 (m, 1H), 1.26-1.24 (d, 3H); MS (ESI) m / z=337.1 (M+H) +

[0262] Step 2: (R)-2-(5-(3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) prepared in Preparation 7, (R)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (189 mg, 0.561 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 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-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (139 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.11-8.07 (m, 2H), 7.96 (s, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 6.17-6.15 (d, 1H), 5.85-5.83 (d, 1H), 4.79-4.77 (t, 1H), 4.67-4.65 (t, 1H), 4.54-4.51 (q, 2H), 4.46-4.42 (q, 1H), 4.38-4.30 (q, 1H), 3.94 (s, 1H), 3.65 (s, 3H), 2.37-2.19 (t, 1H), 2.10-2.09 (d, 1H), 1.41-1.39 (d, 3H); MS (ESI) m / z=510.1 (M + H) +

[0263] Step 3: (R)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (139 mg, 0.273 mmol), CsCO (193 mg, 0.594 mmol), XPhos (37.8 mg, 0.079 mmol), and Pd(dba) (36.2 mg, 0.04 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)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (50.8 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31-8.29 (d, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.72-7.72 (d, 2H), 6.40-6.38 (d, 1H), 4.97-4.95 (d, 1H), 4.87-4.85 (t, 1H), 4.81-4.73 (m, 2H), 4.50-4.47 (t, 1H), 4.43-4.41 (t, 1H), 4.30-4.28 (t, 1H), 4.06-4.03 (t, 1H), 3.81 (s, 3H), 2.22-2.13 (m, 2H), 1.48-1.47 (d, 3H); MS (ESI) m / z=474.1 (M + H) +

[0264] Example 43: (S)-6-methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 -(2,2,2-trifluoroethyl)-1 1H-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (68 mg, 0.262 mmol) prepared in Preparation 15, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (80 mg, 0.262 mmol, 1.0 eq) prepared in Step 1 of Example 31, and (tributylphosphoranylidene)acetonitrile (0.27 mL, 0.787 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (62 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.14-8.13 (d, 1H), 8.09-8.08 (d, 2H), 7.48 (s, 1H), 6.53 (s, 1H), 6.21-6.20 (d, 1H), 5.63-5.60 (d, 1H), 4.70-4.67 (q, 1H), 4.55-4.48 (m, 3H), 3.93-3.90 (t, 1H), 3.85 (s, 3H), 2.21-2.19 (m, 1H), 2.11-2.08 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m / z=545.8 (M + H) +

[0265] Step 2: (S)-6-Methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (62 mg, 0.114 mmol) prepared in Step 1, CsCO (111 mg, 0.341 mmol), XPhos (21.6 mg, 0.045 mmol), and Pd(dba) (20.8 mg, 0.023 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 C18 column chromatography (MeCN / water = 0-100%) to give (S)-6-methyl-4-pyrimidin-4-amine. 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 was prepared as a white solid (7.5 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36-8.34 (t, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 6.54-6.52 (d, 1H), 5.15 (t, 1H), 5.07-5.06 MS (ESI) m / z=510.9 (M + H) +

[0266] Example 44: (S)-1 1 -ethyl-6-methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol (53.8 mg, 0.262 mmol) prepared in Preparation 16, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (80 mg, 0.262 mmol, 1.0 eq) prepared in Step 1 of Example 31, and (tributylphosphoranylidene)acetonitrile (0.27 mL, 0.787 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (91 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.12-8.10 (d, 1H), 8.07 (s, 2H), 7.99 (s, 1H), 7.44 (s, 1H), 7.20 (s, 1H), 6.54 (s, 1H), 6.17-6.15 (d, 1H), 5.80-5.78 (d, 1H), 5.02 (s, 2H), 4.53-4.50 (q, 1H), 4.45-4.41 (m, 1H), 4.00-3.93 (m, 3H), 3.81 (s, 3H), 2.26-2.20 (m, 2H), 2.09-2.04 (m, 1H), 1.41-1.39 (d, 3H); MS (ESI) m / z=491.9 (M + H) +

[0267] Step 2: (S)-1 1 -ethyl-6-methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (91 mg, 0.185 mmol) prepared in Step 1, CsCO (180 mg, 0.555 mmol), XPhos (35.2 mg, 0.074 mmol), and Pd(dba) (33.8 mg, 0.037 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 -ethyl-6-methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 (40.5 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.28-8.27 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.44-6.42 (d, 1H), 5.00-4.98 MS (ESI) m / z=455.9 (M + H) +

[0268] Example 45: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (57 mg, 0.22 mmol) prepared in Preparation 15, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (75 mg, 0.22 mmol, 1.0 eq) prepared in Step 1 of Example 37, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.66 mmol, 3.0 eq) in toluene (2 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (82 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.13-8.11 (t, 2H), 8.07 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.30-7.00 (t, 1H), 6.56 (s, 1H), 6.20-6.19 (d, 1H), 5.67-5.64 (d, 1H), 4.95 (s, 2H), 4.69-4.67 (q, 1H), 4.56-4.49 (m, 3H), 3.94-3.94 (q, 1H), 2.29-2.21 (m, 2H), 2.12-2.11 (m, 1H), 1.43-1.42 (d, 3H); MS (ESI) m / z=581.8 (M + H) +

[0269] Step 2: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (82 mg, 0.141 mmol) prepared in Step 1, CsCO (137 mg, 0.423 mmol), XPhos (26.8 mg, 0.056 mmol), and Pd(dba) (25.8 mg, 0.028 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)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 was prepared as a white solid (4.5 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36-8.35 (d, 1H), 8.32-8.30 (d, 2H), 8.11 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.37-7.22 (t, 1H), 6.43-6.42 (d, 1H), 5.16-5.13 (d, 1H), 4.96-4.95 (d, 1H), 4.72-4.68 (t, 1H), 4.60-4.56 (t, 1H), 4.36-4.34 (d, 1H), 4.03-4.01 (q, 1H), 2.30-2.21 (m, 2H), 2.13-2.11 (d, 1H), 1.30-1.28 (d, 3H); MS (ESI) m / z=545.9 (M + H) +

[0270] Example 46: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -ethyl-6-methyl-1 1H-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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol (45.1 mg, 0.22 mmol) prepared in Preparation 16, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (75 mg, 0.22 mmol, 1.0 eq) prepared in Step 1 of Example 37, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.66 mmol, 3.0 eq) in toluene (2 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (29 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.11-8.09 (t, 2H), 7.97 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.28-7.12 (t, 1H), 6.57 (s, 1H), 6.16-6.15 (d, 1H), 5.88-5.86 (d, 1H), 4.53-4.53 (q, 1H), 4.44-4.42 (m, 1H), 4.01-3.96 (q, 3H), 2.22-2.20 (m, 2H), 2.09-2.07 (m, 1H), 1.43-1.41 (d, 3H), 1.36-1.34 (d, 3H); MS (ESI) m / z=527.9 (M + H) +

[0271] Step 2: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -ethyl-6-methyl-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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (29 mg, 0.055 mmol), CsCO (53.7 mg, 0.165 mmol), XPhos (10.5 mg, 0.022 mmol), and Pd(dba) (10.1 mg, 0.011 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 (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -ethyl-6-methyl-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 (5.2 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.36-8.34 (d, 1H), 8.18 (s, 1H), 8.03-8.00 (d, 2H), 7.80 (s, 1H), 7.37-7.07 (t, 1H), 6.53-6.52 (d, 1H), 5.00-4.99 (d, 1H), 4.88-4.83 (q, 1H), 4.35-4.34 (d, 1H), 4.17-4.01 (m, 4H), 2.22-2.14 (m, 2H), 1.54-1.49 (q, 3H), 1.29-1.26 (t, 3H); MS (ESI) m / z=492.9 (M + H) +

[0272] Example 47: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol (48.2 mg, 0.22 mmol) prepared in Preparation 17, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (75 mg, 0.22 mmol, 1.0 eq) prepared in Step 1 of Example 37, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.66 mmol, 3.0 eq) in toluene (2 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (73 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.14-8.12 (t, 2H), 8.01 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.28-7.12 (t, 1H), 6.59 (s, 1H), 6.17-6.16 (d, 1H), 5.86-5.84 (d, 1H), 4.81 (s, 2H), 4.54-4.49 (m, 2H), 4.45-4.41 (m, 1H), 4.02-3.99 (t, 1H), 2.29-2.22 (m, 1H), 2.10-2.06 (m, 1H), 1.45-1.44 (d, 6H), 1.43-1.39 (q, 3H); MS (ESI) m / z=541.9 (M + H) +

[0273] Step 2: (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg, 0.135 mmol), CsCO (131.6 mg, 0.404 mmol), XPhos (25.7 mg, 0.054 mmol), and Pd(dba) (24.7 mg, 0.027 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 (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -isopropyl-6-methyl-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (20.6 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.31-8.30 (d, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.37-7.07 (t, 1H), 6.40-6.39 (d, 1H), 4.93-4.88 (q, 2H), 4.50-4.46 (t, 1H), 4.33-4.32 (d, 1H), 3.94-3.92 (t, 1H), 2.12-2.10 (m, 2H), 1.59-1.57 (d, 3H), 1.50-1.48 (d, 6H); MS (ESI) m / z=506.9 (M + H) +

[0274] Example 48: (S)-1 1 ,2 5 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine A suspension of 4-(4-amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (101 mg, 0.492 mmol) prepared in Preparation 18, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (150 mg, 0.492 mmol, 1.0 eq) prepared in Step 1 of Example 31, and (tributylphosphoranylidene)acetonitrile (0.50 mL, 1.477 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine as a yellow solid (164 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.97-7.96 (d, 2H), 7.45 (s, 1H), 7.16 (s, 1H), 6.55 (s, 1H), 5.89-5.87 (d, 1H), 4.88 (s, 2H), 4.56-4.52 MS (ESI) m / z=491.9 (M + H) +

[0275] Step 2: (S)-1 1 ,2 5 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine (164 mg, 0.333 mmol) prepared in Step 1, CsCO (325 mg, 1.00 mmol), XPhos (63.5 mg, 0.133 mmol), and Pd(dba) (61 mg, 0.067 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 ,2 5 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 (39.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 4.96-4.94 (d, 1H), 4.80-4.74 (m, 1H), 4.28-4.27 (d, 1H), 4.05-4.01 (m, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 2.23 (s, 3H), 2.21-2.18 (m, 1H), 2.13-2.10 (m, 1H), 1.47-1.45 (d, 3H); MS (ESI) m / z=456.0 (M + H) +

[0276] Example 49: (S)-1 1 ,2 6 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1H-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine A suspension of 4-(4-amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (101 mg, 0.492 mmol) prepared in Preparation 19, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (150 mg, 0.492 mmol, 1.0 eq) prepared in Step 1 of Example 31, and (tributylphosphoranylidene)acetonitrile (0.50 mL, 1.477 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine as a yellow solid (135 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.23 (s, 1H), 6.55 (s, 1H), 6.07-6.07 (d, 1H), 4.77 (s, 2H), 4.55-4.49 MS (ESI) m / z=491.9 (M + H) +

[0277] Step 2: (S)-11 ,2 6 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine (135 mg, 0.274 mmol), CsCO (325 mg, 1.00 mmol), XPhos (63.5 mg, 0.133 mmol), and Pd(dba) (61 mg, 0.067 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 (S)-1 1 ,2 6 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 (33.7 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 6.23 (s, 1H), 4.94-4.92 (d, 1H), 4.81-4.75 (m, 1H), 4.29-4.27 (m, 1H), 4.05-4.01 (m, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 2.40 (s, 3H), 2.20-2.12 (m, 2H), 1.47-1.45 (d, 3H); MS (ESI) m / z=455.9 (M + H) +

[0278] Example 50: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (101 mg, 0.492 mmol) prepared in Preparation 8, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (150 mg, 0.492 mmol, 1.0 eq) prepared in Step 1 of Example 31, and (tributylphosphoranylidene)acetonitrile (0.50 mL, 1.477 mmol, 3.0 eq) in toluene (2 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (118 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.17-8.16 (d, 1H), 8.08 (s, 1H), 7.48-7.48 (d, 1H), 7.22 (s, 1H), 6.53 (s, 1H), 6.18-6.16 (d, 1H), 5.81-5.79 (d, 2H), 4.83 (s, 2H), 4.45-4.41 (m, 1H), 4.34-4.30 (m, 1H), 3.93-3.90 (t, 1H), 3.83 (s, 3H), 3.60 (s, 3H), 2.48 (s, 3H), 2.17-2.15 (m, 1H), 2.07-2.04 (m, 1H), 1.38-1.36 (d, 3H); MS (ESI) m / z=491.9 (M + H) +

[0279] Step 2: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (118 mg, 0.240 mmol) prepared in Step 1, CsCO (325 mg, 1.00 mmol), XPhos (63.5 mg, 0.133 mmol), and Pd(dba) (61 mg, 0.067 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 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (27.7 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36-8.35 (d, 1H), 8.30 (s, 1H), 8.11-8.09 (brs, 2H), 7.66 (s, 1H), 7.59 (s, 1H), 6.37-6.36 (d, 1H), 4.95-4.93 (d, 1H), 4.82-4.77 (t, 1H), 4.28-4.26 (d, 1H), 4.00-3.97 (m, 1H), 3.95 (s, 3H), 3.74-3.72 (d, 3H), 2.59 (s, 3H), 2.26-2.06 (m, 2H), 1.46-1.45 (d, 3H); MS (ESI) m / z=456.0 (M + H) +

[0280] Example 51: 1'-methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-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-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol A mixture of (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (160 mg, 0.451 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (78.6 mg, 0.451 mmol), PdCl(PPh) (15.8 mg, 0.023 mmol), and CuI (17.2 mg, 0.09 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.13 mL, 0.903 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (3-(((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol as an off-white solid (172 mg). 1 H-NMR (CDCl3, 400 MHz) δ 7.75-7.72 (d, 1H), 7.68-7.63 (m, 1H), 7.50-7.45 (m, 1H), 6.59 (s, 1H), 6.30 (s, 1H), 4.73-4.67 (q, 2H), 4.57-4.56 (d, 1H), 4.52-4.50 (d, 1H), 4.14-4.08 (t, 2H), 3.62-3.60 (d, 2H); MS (ESI) m / z=400.9 (M + H) +

[0281] Step 2: 2-(5-((3-(((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (97.1 mg, 0.508 mmol) prepared in Preparation 7, (3-(((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (172 mg, 0.429 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.44 mL, 1.287 mmol) in toluene (2 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-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (148 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.11-8.10 (d, 2H), 7.99 (s, 1H), 7.42 (s, 1H), 7.06 (s, 1H), 6.64 (s, 1H), 6.42-6.42 (t, 1H), 6.19-6.17 (d, 1H), 5.19 (s, 2H), 4.87 (s, 2H), 4.81-4.79 (d, 2H), 4.67-4.57 (m, 4H), 3.82-3.81 (d, 2H), 3.66 (s, 3H); MS (ESI) m / z=573.8 (M + H) +

[0282] Step 3: 1'-methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-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-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (148 mg, 0.258 mmol) prepared in Step 2, CsCO (252 mg, 0.774 mmol), XPhos (49.2 mg, 0.103 mmol), and Pd(dba) (47.2 mg, 0.052 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 C18 column chromatography (MeCN / water=0-100%) to produce 1'-methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane] as a white solid (25.3 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.33-8.31 (t, 2H), 8.20 (s, 1H), 8.10 (s, 1H), 7.78-7.77 (d, 2H), 6.39-6.37 (d, 1H), 5.65-5.62 (t, 1H), 4.79-4.68 (m, 5H), 4.58-4.56 (d, 2H), 4.06-4.04 (d, 2H), 3.86 (s, 3H); MS (ESI) m / z=537.9 (M + H) +

[0283] Example 52: 1'-methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane] Step 1: (3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol A mixture of (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (160 mg, 0.451 mmol), 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (72.3 mg, 0.451 mmol), PdCl(PPh) (15.8 mg, 0.023 mmol), and CuI (17.2 mg, 0.09 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.13 mL, 0.903 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol as an off-white solid (148 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 6.67-6.65 (t, 1H), 6.54 (s, 1H), 4.56-4.55 (d, 2H), 4.48-4.47 (d, 2H), 4.11-4.06 (t, 2H), 3.61-3.60 (d, 2H); MS (ESI) m / z=386.9 (M + H) +

[0284] Step 2: 2-(5-((3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (97.1 mg, 0.508 mmol) prepared in Preparation 7, (3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (148 mg, 0.383 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.44 mL, 1.287 mmol) in toluene (2 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (81 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.12-8.10 (t, 2H), 7.99 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 6.71 (s, 1H), 6.68-6.66 (t, 1H), 6.17-6.16 (d, 1H), 4.99 (s, 2H), 4.79-4.78 (d, 4H), 4.67-4.65 (d, 2H), 3.88-3.86 (d, 2H), 3.74 (s, 3H); MS (ESI) m / z=559.8 (M + H) +

[0285] Step 3: 1'-methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (81 mg, 0.145 mmol) prepared in Step 2, CsCO (252 mg, 0.774 mmol), XPhos (49.2 mg, 0.103 mmol), and Pd(dba) (47.2 mg, 0.052 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 C18 column chromatography (MeCN / water=0-100%) to produce 1'-methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane] as a white solid (19.3 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.36-8.33 (t, 2H), 8.21 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 6.40-6.39 (d, 1H), 5.61-5.58 (t, 1H), 4.75 (s, 2H), 4.70-4.68 (d, 2H), 4.58-4.57 (d, 2H), 4.07-4.05 (d, 2H), 3.87 (s, 3H); MS (ESI) m / z=524.9 (M + H) +

[0286] Example 53: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridine A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.42 g, 5.52 mmol), 3-ethynyl-1-methyl-1,2,4-triazole (0.563 g, 5.257 mmol), PdCl(PPh) (184.5 mg, 0.263 mmol), and CuI (200.3 mg, 1.051 mmol) was purged with nitrogen gas for 10 min. DMF (50 mL) and TEA (1.47 mL, 10.514 mmol) were added, and the reaction mixture was stirred at 50 °C for 12 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 / n-Hex=0-40%) to produce 2-chloro-4-fluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridine as an off-white solid (669 mg). MS (ESI) m / z=237.0 (M + H). +

[0287] Step 2: (S)-3-((2-chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridine (120 mg, 0.507 mmol) prepared in Step 1 and (S)-3-aminobutan-1-ol (45.2 mg, 0.507 mmol) was purged with nitrogen gas for 10 minutes. DMF (20 mL) and DIPEA (0.18 mL, 1.014 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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (177 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.78 (s, 1H), 6.68-6.66 (d, 1H), 6.45 (s, 1H), 4.48 (s, 1H), 3.95 (s, 3H), 3.91-3.88 (q, 1H), 3.83-3.78 (m, 2H), 2.00-1.94 (m, 1H), 1.74-1.68 (m, 1H), 1.26-1.26 (d, 3H); MS (ESI) m / z=306.0 (M + H) +

[0288] Step 3: (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (110 mg, 0.579 mmol) prepared in Preparation 7, (S)-3-((2-chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (177 mg, 0.579 mmol, 1.0 eq) prepared in Step 2, and (tributylphosphoranylidene)acetonitrile (0.59 mL, 1.737 mmol, 3.0 eq) in toluene (2 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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (73 mg). 1H-NMR (CDCl3, 600 MHz) δ 8.16 (s, 1H), 8.09-8.08 (d, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 6.62 (s, 1H), 6.15-6.14 (d, 1H), 5.95-5.93 (d, 1H), 5.07 (s, 2H), 4.47-4.42 (m, 2H), 3.99-3.97 (d, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.18-2.12 (m, 2H), 1.44-1.40 (d, 3H); MS (ESI) m / z=479.0 (M + H) +

[0289] Step 4: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg, 0.152 mmol), CsCO (148.9 mg, 0.457 mmol), XPhos (29 mg, 0.061 mmol), and Pd(dba) (27.9 mg, 0.03 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 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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-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 (4.3 mg). 1H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.38-8.37 (d, 1H), 8.17-8.15 (d, 2H), 7.96 (s, 1H), 7.63-7.63 (m, 1H), 6.42-6.40 (d, 1H), 5.01-4.99 (d, 1H), 4.77-4.74 (q, 1H), 4.35-4.32 (q, 1H), 4.05 (s, 3H), 3.82 (s, 3H), 2.22-2.16 (m, 2H), 1.51-1.49 (d, 3H)

[0290] Example 54: (S)-1 1 ,6-dimethyl-4 5 -((5-methylpyrazin-2-yl)ethynyl)-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-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of 2-chloro-4-fluoro-5-iodopyridine (1.097 g, 4.262 mmol), 2-ethynyl-5-methylpyrazine (479 mg, 4.059 mmol), PdCl(PPh) (142.5 mg, 0.203 mmol), and CuI (154.6 mg, 0.812 mmol) was purged with nitrogen gas for 10 minutes. After adding DMF (50 mL) and TEA (1.13 mL, 8.118 mmol), the reaction mixture was stirred at 50 °C for 12 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 (EA / n-Hex = 0-40%) to give 2-((6-chloro-4-fluoropyridin-3-yl)ethynyl)-5-methylpyrazine as an off-white solid (821 mg). A mixture of 2-((6-chloro-4-fluoropyridin-3-yl)ethynyl)-5-methylpyrazine (126 mg, 0.507 mmol) and (S)-3-aminobutan-1-ol (45.2 mg, 0.507 mmol) was purged with nitrogen gas for 10 minutes. DMF (20 mL) and DIPEA (0.18 mL, 1.014 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 MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-100%) to give (S)-3-((2-chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a yellow solid (136 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.64-8.64 (d, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 6.53 (s, 1H), 6.45-6.43 (d, 1H), 3.98-3.95 (q, 1H), 3.90-3.84 (m, 2H), 2.59 (s, 3H), 2.05-1.97 (m, 2H), 1.36-1.35 (d, 3H); MS (ESI) m / z=317.0 (M + H) +

[0291] Step 2: (S)-2-(5-(3-((2-chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (110 mg, 0.579 mmol) prepared in Preparation 7, (S)-3-((2-chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (136 mg, 0.429 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.59 mL, 1.737 mmol) in toluene (2 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-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (45 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.43-8.43 (d, 1H), 8.32-8.31 (d, 1H), 8.18 (s, 1H), 8.10-8.09 (d, 1H), 7.88 (s, 1H), 6.59 (s, 1H), 6.16-6.15 (d, 1H), 5.98-5.96 (d, 1H), 5.05 (s, 2H), 4.52-4.49 (q, 1H), 4.46-4.42 (m, 1H), 3.99-3.96 (t, 1H), 3.73 (s, 3H), 2.57 (s, 3H), 2.23-2.20 (q, 1H), 2.14-2.12 (q, 1H), 1.42-1.41 (d, 3H); MS (ESI) m / z=490.0 (M + H)

[0292] Step 3: (S)-1 1 ,6-dimethyl-4 5 -((5-methylpyrazin-2-yl)ethynyl)-1 1H-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-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.092 mmol) prepared in Step 2, Cs2CO3 (148.9 mg, 0.457 mmol), XPhos (29 mg, 0.061 mmol), and Pd2(dba)3 (27.9 mg, 0.03 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 C18 column chromatography (MeCN / water = 0-100%) to give (S)-1 1 ,6-dimethyl-4 5 -((5-methylpyrazin-2-yl)ethynyl)-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 (4.4 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.66-8.66 (d, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.37-8.36 (d, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 6.41-6.39 (d, 1H), 5.09-5.08 (d, 1H), 4.79-4.78 (d, 1H), 4.34-4.32 (q, 1H), 4.15-4.09 (m, 1H), 3.82 (s, 3H), 2.63 (s, 2H), 2.22-2.19 (q, 2H), 1.52-1.50 (d, 3H)

[0293] Example 55: (S,E)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (S)-1 prepared in Example 31 in methanol (4 mL) 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 To a solution of H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (55 mg, 0.125 mmol), Lindlar's catalyst (15 mg) was added and stirred under H2 atmosphere at 25 °C for 6-8 h. After completion, the reaction mixture was filtered through a pad of Celite and washed thoroughly with MeOH. The solvent was evaporated under reduced pressure to give (S,E)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a grey solid (7.1 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.30-8.29 (d, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 7.18 (s, 1H), 6.63-6.60 (d, 1H), 6.39-6.38 (d, 1H), 6.18-6.16 (d, 1H), 4.81-4.75 (q, 1H), 4.31-4.29 (d, 1H), 4.21-4.20 (d, 1H), 4.06-4.01 (m, 1H), 3.79 (s, 6H), 2.09-2.06 (t, 1H), 1.95-1.92 (m, 1H), 1.22-1.21 (s, 3H)

[0294] Example 56: (S)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (S)-1 prepared in Example 31 in methanol (4 mL) 1 ,6-dimethyl-4 5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 To a solution of H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (55 mg, 0.125 mmol), Pd / C (15 mg) was added and stirred under H2 atmosphere at 25 °C for 6-8 h. After completion, the reaction mixture was filtered through a pad of Celite and washed thoroughly with MeOH. The solvent was evaporated under reduced pressure to give (S)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane was prepared as a grey solid (3.0 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.31-8.29 (d, 2H), 8.14 (s, 1H), 7.73 (s, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 6.35-6.34 (d, 1H), 4.77-4.75 (t, 1H), 4.23-4.21 (t, 1H), 4.09-4.06 (t, 1H), 3.92-3.90 (d, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 2.81-2.76 (m, 2H), 2.68-2.63 (m, 2H), 2.11-2.04 (m, 2H), 1.39-1.37 (s, 3H)

[0295] Example 57: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (500 mg, 1.531 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (266.6 mg, 1.531 mmol), PdCl(PPh) (53.7 mg, 0.077 mmol), and CuI (58.4 mg, 0.306 mmol) was purged with nitrogen gas for 10 minutes. DMF (5 mL) and TEA (0.43 mL, 3.062 mmol) were added, and the reaction mixture was stirred at 50 °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 (EA / n-Hex=0-40%) to produce (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as an off-white solid (495 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.74 (s, 2H), 6.55 (s, 1H), 5.61-5.59 (d, 1H), 4.77-4.70 (q, 2H), 3.91-3.82 (m, 3H), 1.93-1.91 (m, 1H), 1.85-1.84 (m, 1H), 1.33-1.31 (d, 3H); MS (ESI) m / z=372.9 (M + H) +

[0296] Step 2: (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (110.1 mg, 0.537 mmol) prepared in Preparation 8, (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (200 mg, 0.537 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.55 mL, 1.61 mmol, 3 eq) in toluene (2 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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a yellow solid (134 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.17-8.15 (d, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 7.33 (s, 1H), 6.54 (s, 1H), 6.18-6.17 (d, 1H), 5.92-5.90 (d, 1H), 4.81 (s, 2H), 4.67-4.61 (q, 2H), 4.49-4.44 (q, 1H), 4.36-4.32 (q, 1H), 3.94-3.91 (t, 1H), 3.60 (s, 3H), 2.48 (s, 3H), 2.20-2.18 (t, 1H), 2.07-2.03 (q, 1H), 1.39-1.38 (d, 3H); MS (ESI) m / z=559.9 (M + H) +

[0297] Step 3: (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1H-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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (134 mg, 0.239 mmol) prepared in Step 2, CsCO (233 mg, 0.718 mmol), XPhos (45.6 mg, 0.096 mmol), and Pd(dba) (43.8 mg, 0.048 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 ,1 3 ,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 (34.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.37-8.34 (t, 2H), 8.31 (s, 1H), 8.10 (s, 1H), 7.75-7.74 (d, 1H), 6.38-6.36 (d, 1H), 4.92-4.91 (d, 1H), 4.82-4.72 (m, 3H), 4.29-4.27 (d, 1H), 4.00-3.98 (q, 1H), 3.74 (s, 3H), 2.59 (s, 3H), 2.26 (m, 1H), 2.09-2.04 (m, 1H), 1.47-1.43 (t, 3H); MS (ESI) m / z=523.9 (M+H) +

[0298] Example 58: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-Oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane Step 1: (S)—N-(4-((4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine A suspension of 4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol (71.8 mg, 0.377 mmol) prepared in Preparation 21, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (115 mg, 0.377 mmol, 1.0 eq) prepared in Step 1 of Example 31, and (tributylphosphoranylidene)acetonitrile (0.34 mL, 1.0 mmol, 2.65 eq) in toluene (4 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)—N-(4-((4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine as a yellow solid (34 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.13-8.11 (d, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 6.69 (s, 1H), 6.52 (s, 1H), 6.35-6.34 (d, 1H), 5.72-5.70 (d, 1H), 4.33 (s, 3H), 4.27-4.25 (t, 1H), 3.90-3.87 (t, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.14-2.13 (d, 1H), 2.05-2.02 (t, 1H), 1.36-1.34 (d, 3H); MS (ESI) m / z=476.9 (M + H) +

[0299] Step 2: (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane A suspension of (S)-N-(4-((4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine (34 mg, 0.071 mmol), CsCO (69.7 mg, 0.214 mmol), XPhos (13.6 mg, 0.029 mmol), and Pd(dba) (13.0 mg, 0.014 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 (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane was prepared as a white solid (2.9 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.41-8.39 (d, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.06-7.03 (m, 1H), 6.72 (s, 1H), 6.64 (s, 1H), 4.95-4.92 (d, 1H), 4.35-4.31 (t, 1H), 4.27-4.25 (d, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.70 (m, 1H), 2.46 (s, 1H), 2.06-1.98 (m, 2H), 1.47-1.46 (d, 3H)

[0300] Example 59: (S)-(4-hydroxypiperidin-1-yl)(4-((1 1 ,13 ,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)ethynyl)phenyl)methanone Step 1: (S)-(4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone A mixture of (4-((6-chloro-4-fluoropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (152 mg, 0.424 mmol) prepared in Preparation 22 and (S)-3-aminobutan-1-ol (37.8 mg, 0.424 mmol) was purged with nitrogen gas for 10 minutes. DMF (20 mL) and DIPEA (0.15 mL, 0.847 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)-(4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone as a yellow solid (163 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.57-7.55 (d, 1H), 7.42-7.40 (d, 1H), 6.56 (s, 1H), 5.77-5.76 (d, 1H), 4.02-3.94 (m, 1H), 3.88-3.84 (m, 3H), 3.72 (s, 1H), 3.49-3.23 (brs, 4H), 1.96-1.94 (d, 2H), 1.85-1.84 (d, 2H), 1.34-1.33 (d, 3H); MS (ESI) m / z=427.9 (M + H) +

[0301] Step 2: (S)-(4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (78.2 mg, 0.381 mmol) prepared in Preparation 8, (S)-(4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (163 mg, 0.381 mmol, 1.0 eq) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.143 mmol, 3.0 eq) in toluene (2 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)-(4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone as a yellow solid (96.2 mg). 1 H-NMR (CDCl3, 400 MHz) δ 8.13-8.11 (t, 2H), 7.34-7.32 (d, 2H), 7.26 (s, 2H), 6.56 (s, 1H), 6.11-6.10 (d, 1H), 5.79-5.77 (d, 1H), 4.93 (s, 1H), 4.43-4.40 (q, 1H), 4.35-4.31 (m, 1H), 4.00-3.92 (m, 2H), 3.61 (s, 3H), 3.57 (s, 3H), 3.48-3.10 (m, 2H), 2.17-2.15 (q, 1H), 2.09-2.04 (q, 1H), 1.64-1.62 (m, 2H), 1.54 (brs, 2H), 1.40-1.38 (d, 3H); MS (ESI) m / z=617.9 (M + H) +

[0302] Step 3: (S)-(4-hydroxypiperidin-1-yl)(4-((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)ethynyl)phenyl)methanone A suspension of (S)-(4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (96.2 mg, 0.156 mmol) prepared in Step 2, CsCO (152.8 mg, 0.469 mmol), XPhos (29.8 mg, 0.063 mmol), and Pd(dba) (28.6 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 Celite, and concentrated. The crude product was purified by C18 column chromatography (MeCN / water=0-100%) to give (S)-(4-hydroxypiperidin-1-yl)(4-((1 1 ,1 3 ,6-trimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 The resulting mixture was purified by filtration to give 24.3 mg of 1,3-dimethyl-2,4-trimethyl-1,3-trimethyl ... 1H-NMR (CDCl3, 400 MHz) δ 8.38-8.37 (d, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.57-7.55 (d, 1H), 7.44-7.42 (d, 1H), 6.40-6.38 (d, 1H), 5.00-4.98 (d, 1H), 4.83-4.78 (t, 1H), 4.32-4.27 (m, 2H), 4.04-3.99 (m, 2H), 3.76-3.75 (d, 3H), 3.46-3.23 (brs, 2H), 2.60 (s, 3H), 2.28-2.25 (d, 1H), 2.11-2.05 (m, 5H), 1.50-1.48 (d, 3H); MS (ESI) m / z=578.9 (M + H) +

[0303] Example 60: (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a dark yellow solid (282.3 mg) in the same manner as in Step 2 of Example 3, except that 4-ethynyl-1-methyl-1H-pyrazole (120.0 mg, 1.13 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1 H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.49 (s, 1H), 5.91 (t, 1H), 4.10-4.03 (m, 1H), 3.94 (s, 3H), 3.44-3.31 (m, 2H), 1.89-1.78 (m, 2H), 1.62 (d, 1H), 1.32 (d, 3H); MS (ESI) m / z=304.9 (M+H) +

[0304] Step 2: (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine To a solution of (R)-4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (74.25 mg, 0.24 mmol) prepared in Step 1 in toluene (1.0 mL) was added 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50.0 mg, 0.24 mmol) prepared in Preparation 8 and cyanomethylenetributylphosphorane (0.15 mL, 0.56 mmol). The reaction mixture was stirred at 110° C. for 6 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (MeOH / DCM=0-20%), slurried with DCM / IPE for 0.5 hours, and then filtered to prepare (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a light brown solid (50.10 mg, 0.10 mmol, yield: 41.8%). 1 H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.08 (s, 1H), 7.32 (s, 1H), 6.94 (s, 1H), 6.77 (d, 1H), 6.53 (s, 1H), 6.16 (d, 1H), 4.82-4.79 (m, 1H), 4.74 (s, 2H), 3.83 (s, 3H), 3.68-3.60 (m, 1H), 3.58 (s, 3H), 3.56-3.48 (m, 1H), 2.48 (s, 3H), 2.16-2.04 (m, 2H), 1.20 (d, 3H); MS (ESI) m / z=491.9 (M+H) +

[0305] Step 3: (S)-1 1 ,1 3 ,8-trimethyl-4 5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-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 (18.2 mg) in the same manner as in Step 4 of Example 2, except that (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.0 mg, 0.10 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1 H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.37 (d, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 6.35 (d, 1H), 5.49 (t, 1H), 5.30 MS (ESI) m / z=456.0 (M+H) +

[0306] Example 61: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 Step 1: (R)-4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol The title compound was prepared as a dark yellow solid (135.5 mg) in the same manner as in Step 2 of Example 3, except that 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (71.72 mg, 0.46 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1 H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 6.50 (s, 1H), 6.11 (tt, 1H), 5.91 (s, 1H), 4.50 (td, 2H), 4.07 (sex, 1H), 3.45-3.31 (m, 2H), 1.89-1.79 (m, 2H), 1.53 (d, 1H), 1.31 (d, 3H); MS (ESI) m / z=354.9 (M+H) +

[0307] Step 2: (S)-2-(5-((4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine The title compound was prepared as a pale yellow solid (75.8 mg) in the same manner as in Step 2 of Example 60, except that (R)-4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (86.44 mg, 0.24 mmol) prepared in Step 1 was used instead of (R)-4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 8.08 (s, 1H), 7.36 (s, 1H), 7.04 (s, 1H), 6.81 (d, 1H), 6.53 (s, 1H), 6.16 (d, 1H), 6.06 (tt, 1H), 4.83-4.79 (m, 1H), 4.76 (s, 2H), 4.38 (td, 2H), 3.63-3.60 (m, 1H), 3.55 (s, 3H), 3.53-3.47 (m, 1H), 2.47 (s, 3H), 2.16-2.12 (m, 1H), 1.93-1.89 (m, 1H), 1.20 (d, 3H); MS (ESI) m / z=541.9 (M+H) +

[0308] Step 3: (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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 The title compound was prepared as an off-white solid (27.1 mg) in the same manner as in Step 4 of Example 2, except that (S)-2-(5-((4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (71.8 mg, 0.13 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.38 (d, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.07 (s, 1H), 7.22 (s, 1H), 6.34 (d, 1H), 6.12 (tt, 1H), 5.47 (t, 1H), 5.30-5.28 (m, 1H), 4.50 (td, 2H), 4.07-4.03 (m, 1H), 3.72 (s, 3H), 3.61-3.58 (m, 1H), 2.63 (s, 3H), 2.22-2.18 (m, 1H), 1.98-1.92 (m, 1H), 1.11 (d, 3H); MS (ESI) m / z=505.9 (M+H) +

[0309] Example 62: (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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: (S)-3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (223.38 mg, 0.68 mmol), 5-cyclopropyl-4-ethynyl-1-methyl-1H-pyrazole (100 mg, 0.68 mmol), PdCl(PPh) (48.1 mg, 0.068 mmol), CuI (26.05 mg, 0.14 mmol), and TEA (190.69 μL, 1.37 mmol) was purged with nitrogen gas for 10 minutes. DMF (1 mL) was added, and the reaction mixture was stirred at 70 °C for 2 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 (EA / n-Hex=0-70%) to produce (S)-3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a pale yellow solid (221 mg, 0.64 mmol, yield: 93.69%). 1 H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.51 (s, 1H), 6.54 (s, 1H), 5.41 (d, 1H), 3.91 (s, 3H), 3.87-3.81 (m, 3H), 2.25 (s, 1H), 1.94-1.74 (m, 3H), 1.31 (d, 3H), 1.13-1.04 (m, 4H); MS (ESI) m / z=345.0 (M+H) +

[0310] Step 2: (S)-2-(5-(3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Preparation 8, (S)-3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (168.03 mg, 0.49 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (319.58 μL, 1.22 mmol) in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and then concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-90%) to prepare (S)-2-(5-(3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a pale yellow solid (94 mg, 0.18 mmol, yield: 36.26%). 1 H-NMR (CDCl3, 400 MHz) δ 8.20 (d, 1H), 8.10 (s, 1H), 7.38 (s, 1H), 6.56 (s, 1H), 6.18 (d, 1H), 5.41 (d, 1H), 4.75 (s, 2H), 4.41-4.29 MS (ESI) m / z=532.0 (M+H) +

[0311] Step 3: (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-(3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75 mg, 0.14 mmol), Pd2(dba)3 (25.82 mg, 0.028 mmol), XPhos (26.88 mg, 0.056 mmol), and Cs2CO3 (137.79 mg, 0.42 mmol) prepared in Step 2 in 1,4-dioxane (1 mL) was stirred at 95 °C for 2 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by amine column chromatography (EA / n-Hex = 0-100%) to give (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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 as a pale yellow solid (26 mg, 0.052 mmol, yield: 37.22%). 1 H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.54 (s, 1H), 7.53 (d, 1H), 6.35 (d, 1H), 4.96 (d, 1H), 4.83 (t, 1H), 4.32-4.26 (m, 1H), 4.02-3.98 (m, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.60 (s, 3H), 2.30-2.24 (m, 1H), 2.09-2.03 (m, 1H), 1.86-1.80 (m, 1H), 1.47 (d, 3H), 1.18-1.06 (m, 4H); MS (ESI) m / z=496.0 (M+H) +

[0312] Example 63: (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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 Step 1: (R)-4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol A mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (223.38 mg, 0.68 mmol), 5-cyclopropyl-4-ethynyl-1-methyl-1H-pyrazole (100 mg, 0.68 mmol), PdCl(PPh) (48.1 mg, 0.068 mmol), CuI (26.05 mg, 0.14 mmol), and TEA (190.69 μL, 1.37 mmol) was purged with nitrogen gas for 10 minutes. DMF (1 mL) was added, and the reaction mixture was stirred at 70 °C for 2 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 (EA / n-Hex=0-70%) to produce (R)-4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol as a pale yellow solid (216 mg, 0.63 mmol, yield: 91.57%). 1 H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.51 (s, 1H), 6.50 (s, 1H), 5.78 (s, 1H), 4.04 (brs, 1H), 3.91 (s, 3H), 3.45-3.30 (m, 2H), 1.91-1.74 (m, 3H), 1.30 (d, 3H), 1.13-1.04 (m, 4H); MS (ESI) m / z=345.0 (M+H) +

[0313] Step 2: (S)-2-(5-((4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Preparation 8, (R)-4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (168.03 mg, 0.49 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (319.58 μL, 1.22 mmol) in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and then concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-90%) to prepare (S)-2-(5-((4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a pale yellow solid (75 mg, 0.14 mmol, yield: 28.93%). 1 H-NMR (CDCl3, 400 MHz) δ 8.19 (d, 1H), 8.07 (s, 1H), 7.06 (s, 1H), 6.59 (t, 1H), 6.54 (s, 1H), 6.16 (d, 1H), 4.77 (s, 3H), 3.84 (s, 3H), 3.67-3.53 (m, 2H), 3.59 (s, 3H), 2.42 (s, 3H), 2.19-2.07 (m, 1H), 1.89-1.85 (m, 1H), 1.62-1.55 (m, 1H), 1.19 (d, 3H), 0.93-0.89 (m, 4H); MS (ESI) m / z=532.0 (M+H) +

[0314] Step 3: (S)-4 5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-((4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75 mg, 0.14 mmol) prepared in Step 2, Pd(dba) (25.82 mg, 0.028 mmol), XPhos (26.88 mg, 0.056 mmol), and CsCO (137.79 mg, 0.42 mmol) in 1,4-dioxane (1 mL) was stirred at 95 °C for 2 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by amine column chromatography (EA / n-Hex = 0-100%) to give (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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 was prepared as a pale yellow solid (22 mg, 0.044 mmol, yield: 31.49%). 1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.37 (d, 1H), 8.07 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.35 (d, 1H), 5.50 (t, 1H), 5.34-5.30 (m, 1H), 4.11-4.03 (m, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 3.60-3.54 (m, 1H), 2.63 (s, 3H), 2.26-2.19 (m, 1H), 1.98-1.92 (m, 1H), 1.85-1.79 (m, 1H), 1.17-1.05 (m, 6H); MS (ESI) m / z=496.0 (M+H) +

[0315] Example 64: (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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: (S)-3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol A mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (173.56 mg, 0.53 mmol), 4-ethynyl-3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazole (100 mg, 0.53 mmol), PdCl(PPh) (37.31 mg, 0.053 mmol), CuI (20.24 mg, 0.11 mmol), and TEA (148.16 μL, 1.06 mmol) was purged with nitrogen gas for 10 minutes. DMF (1 mL) was added, and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-50%) to produce (S)-3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol as a pale yellow solid (197 mg, 0.51 mmol, yield: 95.83%). 1 H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 6.58 (s, 1H), 5.45 (d, 1H), 3.91-3.81 (m, 3H), 3.51 (s, 1H), 2.53 (s, 3H), 2.37 (s, 3H), 1.96-1.77 (m, 2H), 1.33 (d, 3H); MS (ESI) m / z=386.9 (M+H) +

[0316] Step 2: (S)-2-(5-(3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Preparation 8, (S)-3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (188.48 mg, 0.49 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (319.58 μL, 1.22 mmol) in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and then concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-40%) to prepare (S)-2-(5-(3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a pale yellow solid (42 mg, 0.073 mmol, yield: 15.02%). 1 H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 8.13 (s, 1H), 6.60 (s, 1H), 6.16 (d, 1H), 5.79 (d, 1H), 4.70 (s, 2H), 4.47-4.41 (m, 1H), 4.33-4.28 MS (ESI) m / z=573.9 (M+H) +

[0317] Step 3: (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-(3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (40 mg, 0.07 mmol), Pd2(dba)3 (12.76 mg, 0.014 mmol), XPhos (13.29 mg, 0.028 mmol), and Cs2CO3 (68.12 mg, 0.21 mmol) prepared in Step 2 in 1,4-dioxane (1 mL) was stirred at 95 °C for 2 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-50%) to give (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 as a white solid (19 mg, 0.035 mmol, yield: 50.72%). 1 H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.33 (s, 1H), 6.36 (d, 1H), 4.91 (d, 1H), 4.82 (t, 1H), 4.33-4.28 MS (ESI) m / z=537.9 (M+H) +

[0318] Example 65: (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 Step 1: (R)-4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol A mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (223.38 mg, 0.68 mmol), 4-ethynyl-3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazole (100 mg, 0.53 mmol), PdCl(PPh) (37.31 mg, 0.053 mmol), CuI (20.24 mg, 0.11 mmol), and TEA (148.16 μL, 1.063 mmol) was purged with nitrogen gas for 10 minutes. After adding DMF (1 mL), the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-50%) to produce (R)-4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol as a pale yellow solid (193 mg, 0.50 mmol, yield: 93.88%). 1 H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 6.52 (s, 1H), 5.82 (s, 1H), 4.08-4.04 (m, 1H), 3.47-3.31 (m, 2H), 2.53 (d, 3H), 2.37 (s, 3H), 1.93-1.75 (m, 2H), 1.56 (d, 1H), 1.31 (d, 3H); MS (ESI) m / z=386.9 (M+H) +

[0319] Step 2: (S)-2-(5-((4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Preparation 8, (R)-4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (188.48 mg, 0.49 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (319.58 μL, 1.22 mmol) in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and then concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-40%) to prepare (S)-2-(5-((4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine as a pale yellow solid (102 mg, 0.18 mmol, yield: 36.47%). 1 H-NMR (CDCl3, 400 MHz) δ 8.14 (d, 1H), 8.09 (s, 1H), 6.98 (dd, 1H), 6.57 (s, 1H), 6.13 (d, 1H), 4.77 (s, 2H), 4.77-4.74 (m, 1H), 3.70-3.63 MS (ESI) m / z=573.9 (M+H) +

[0320] Step 3: (S)-4 5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 A suspension of (S)-2-(5-((4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (90 mg, 0.16 mmol) prepared in Step 2, Pd(dba) (28.72 mg, 0.031 mmol), XPhos (29.9 mg, 0.026 mmol), and CsCO (153.26 mg, 0.47 mmol) in 1,4-dioxane (1 mL) was stirred at 95 °C for 2 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-50%) to give (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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 was prepared as a pale yellow solid (15.4 mg, 0.029 mmol, yield: 18.27%). 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 8.39 (d, 1H), 8.10 (s, 1H), 7.35 (s, 1H), 6.36 (d, 1H), 5.43 (t 1H), 5.33-5.29 (m, 1H), 4.11-4.03 MS (ESI) m / z=537.9 (M+H) +

[0321] Example 66: (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile Step 1: (R)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile A mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (249.04 mg, 0.76 mmol), 4-ethynyl-1-methyl-1H-pyrazole-3-carbonitrile (100 mg, 0.76 mmol), PdCl(PPh) (53.53 mg, 0.076 mmol), CuI (29.05 mg, 0.15 mmol), and TEA (212.59 μL, 1.53 mmol) was purged with nitrogen gas for 10 minutes. DMF (1 mL) was added, and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water, dried over MgSO, and concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-70%) to produce (R)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile as a pale yellow solid (141 mg, 0.43 mmol, yield: 56.07%). MS (ESI) m / z=329.9 (M+H). +

[0322] Step 2: (S)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile A suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (85 mg, 0.41 mmol) prepared in Preparation 8, (R)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (136.59 mg, 0.41 mmol) prepared in Step 1, and (tributylphosphoranylidene)acetonitrile (271.64 μL, 1.035 mmol) in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled and then concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-80%) to prepare (S)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile as a pale yellow solid (76 mg, 0.15 mmol, yield: 35.49%). 1 H-NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.87 (d, 1H), 6.57 (s, 1H), 6.19 (d, 1H), 4.83-4.79 (m, 1H), 4.77 (s, 2H), 3.91 (s, 1H), 3.67-3.63 (m, 1H), 3.62 (s, 3H), 3.56-3.48 (m, 1H), 2.44 (s, 3H), 2.20-2.12 (m, 1H), 1.95-1.89 (m, 1H), 1.21 (d, 3H); MS (ESI) m / z=516.9 (M+H) +

[0323] Step 3: (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile A suspension of (S)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (90 mg, 0.16 mmol) prepared in Step 2, Pd(dba) (24.8 mg, 0.027 mmol), XPhos (25.82 mg, 0.054 mmol), and CsCO (132.35 mg, 0.41 mmol) in 1,4-dioxane (1 mL) was stirred at 95 °C for 2 h. The reaction mixture was cooled, filtered through Celite, and concentrated. The crude product was purified by amine column chromatography (EA / n-Hex=0-80%) to give (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile was prepared as a pale yellow solid (15.4 mg, 0.032 mmol, yield: 23.67%). 1 H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.38 (d, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 6.36 (d 1H), 5.70 (t, 1H), 5.32-5.26 MS (ESI) m / z=480.9 (M+H) +

[0324] Example 67: (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyri...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R １ is hydrogen, halogen, C １－６ Alkyl, or halo-C １－６ is alkyl, R ２ and R ３ are each independently hydrogen or C optionally substituted with one or more halogens. １－６ is alkyl, B is C ２－３ Alkylene, C ２－３ Alkenylene, or C ２－３ is alkynylene, A is C ６－１０ aryl or 5-10 membered heteroaryl; R ４ teeth, hydrogen, halogen, -C.N., -S(O) ２ -C １－６ Alkyl, 4-7 membered heterocyclyl optionally substituted with one or more halogen or OH; -CO-4 to 7 membered heterocyclyl optionally substituted with one or more halogen or OH; C optionally substituted with one or more halogens １－６ Alkoxy; C optionally substituted with one or more halogens １－６ alkyl; and C optionally substituted with one or more halogens ３－６ cycloalkyl is selected from the group consisting of n is 0, 1, 2, or 3; L is a linear or branched C ３－６ alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene; R ５ is hydrogen or halogen, Y is CH or N.

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

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

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

5. B is -CH ２ CH ２ 2. The compound of claim 1, wherein the aryl group is -, -CH=CH-, or -C≡C-, or a pharmaceutically acceptable salt thereof.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, pyrazolyl, triazolyl, pyrazinyl, or pyridinyl.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is n-propylene, 1-methylpropylene, 3-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene.

8. (1) (S)-2 5 -Fluoro-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (3) (S)-1 1 ,8-dimethyl-4 5 -((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (4) (S)-1 1 ,6-dimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (5) (S)-1 1 ,8-dimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (6) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (7) 1 1 ,7,7-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (8) 1 1 ,6,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (9) (R)-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (10) (S)-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (11) (S)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (12) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (13) (S)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (14) (S)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (15) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (16) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (17) (S)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (18) (S)-4 5 -((1-isopropyl-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (19) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-3-yl)ethynyl)-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 -((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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)-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (23) (S)-7-Fluoro-1 1 -methyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (24) (R)-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (25) (S)-1 1 ,8-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (26) (S)-1 1 ,8-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (27) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,8-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (28) (S)-1 1 ,8-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (29) 1′-methyl-5′-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (30) 1 1 ,7,7-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (31) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (32) (R)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (33) (R)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-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-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (35) (6S)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (36) 1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (37) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (38) (R)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (39) (R)-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (40) (R)-1 1 ,6-dimethyl-4 5 -((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (41) (6R)-4 5 -((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (42) (R)-4 5 -((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (43) (S)-6-Methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (44) (S)-1 1 -ethyl-6-methyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (45) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (46) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 -ethyl-6-methyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (47) (S)-4 5 -((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (48) (S)-1 1 ,2 5 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (49) (S)-1 1 ,2 6 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (50) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (51) 1′-methyl-5′-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (52) 1′-methyl-5′-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7′-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]; (53) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (54) (S)-1 1 ,6-dimethyl-4 5 -((5-methylpyrazin-2-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (55) (S,E)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (56) (S)-1 1 ,6-dimethyl-4 5 -(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (57) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (58) (S)-1 1 ,6-dimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane; (59) (S)-(4-hydroxypiperidin-1-yl)(4-((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)ethynyl)phenyl)methanone; (60) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (61) (S)-4 5 -((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-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; (62) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (63) (S)-4 5 -((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (64) (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (65) (S)-4 5 -((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-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; (66) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (67) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (68) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((4-(methylsulfonyl)phenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (69) (S)-1 1 ,1 3 ,6-trimethyl-4 5 -((4-morpholinophenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (70) (S)-1 1 ,1 3 ,8-trimethyl-4 5 -((4-morpholinophenyl)ethynyl)-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; (71) (S)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; (72) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (73) (S)-4 5 -((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-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; (74) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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; (75) (S)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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; (76) (R)-1-methyl-4-((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)ethynyl)-1H-pyrazole-3-carbonitrile; and (77) (R)-4 5 -((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-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 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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