Macrocyclic aminopyridine compounds as EGFR inhibitors

Abstract

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

Description

MACROCYCLIC AMINOPYRIDINE COMPOUNDS AS EGFR INHIBITORS

[0001] The present invention relates to novel macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moiety or pharmaceutically acceptable salts thereof which exhibit inhibition activity against certain mutated forms of EGFR.

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

[0003] Approximately 10% to 50% of NSCLC patients have EGFR activating mutations, such as in-frame deletions in exon 19 deletion (Del19) or a missense mutation in exon 21 (L858R). (Yang et al., 2018; Shigematsu et al., 2005; Shu et al., 2017; Zhang et al., 2010). These patients respond well to first and second-generation EGFR tyrosine kinase inhibitors (TKI), including gefitinib (IRESSATM), erlotinib (TARCEVATM), and afatinib (GIOTRIFTM) allowing them as the initial therapy for in patients with advanced NSCLC harboring common EGFR mutations (Kashima et al., 2020; Mok et al., 2009; Zhou et al., 2011; Sequist et al., 2013). But ultimately acquired resistance to therapy with gefitinib or erlotinib arises predominantly 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] Several third-generation EGFR TKIs were being explored to overcome this resistance. Currently, osimertinib is the third-generation EGFR-TKI approved by major regulatory agencies for 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 powerful inhibitor that inhibits EGFR mutations and T790M resistant mutations, but it causes ineffective binding and C797S subsequent resistance in NSCLC patients (Arulananda et al., 2017). Unfortunately, it has been reported that acquired resistance mutations occur in lung cancer patients after the treatment with third-generation EGFR-TKIs. The C797S mutation is the frequently arise after the use of third generation EGFR TKIs in 10% to 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 resulting from EGFR triple mutations (Del19 / T790M / C797S and L858R / T790M / C797S) has been reported, requiring the next generation EGFR-TKI to overcome the osimertinib resistant EGFR triple mutations (Kashima et al., 2020).

[0006] In front-line therapy with third generation TKI, 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-mutated NSCLC, regardless of T790M mutation status (Leonetti et al., 2019). When osimertinib was administered as a front-line therapy, the frequency of the C797S mutation was 7%, making it the second most frequent mechanism, behind MET amplification, of drug resistance in this setting (Leonetti et al., 2019; Ramalingam et al., 2018).

[0007] When osimertinib was administered as a front-line therapy, the most common resistance mechanisms resulted to be the C797S mutation (7%) and MET amplification (15%). Other mechanisms included HER2 amplification, PIK3CA and RAS mutations (Ramalingam et al., 2018). Also, selectivity to wild-type (WT) EGFR is important for EGFR-TKIs, because WT EGFR inhibition causes adverse effects such as rashes and / or diarrhea, and these WT EGFR-derived toxicities cause dose-limiting effects (Kashima et al., 2020; Fakih et al., 2010; Takeda et al., 2015).

[0008] The next generation EGFR compounds would need to inhibit Del19 / T790M / C797S, L858R / T790M / C797S, Del19 / C797S and L858R / C797S and be highly selective versus WT EGFR to avoid adverse effects. Recently, mutant selective inhibitors, BI-4020 and BLU-945 were reported as potential therapeutic strategies to overcome the EGFR Del19 / T790M / C797S mutations (Engelhardt et al., 2019; Schalm et al., 2020).

[0009] However, there have been no reports of these compounds inhibiting Del19 / C797S and L858R / C797S. Therefore, novel EGFR-TKIs potently effective against EGFR triple / double mutations are urgently needed.

[0010] To address this unmet need, we are developing a next generation TKI targeting both C797S triple and double mutants. It is necessary to develop a novel selective (next generation) inhibitor for NSCLC patients with advanced or metastatic diseases carrying Del19 / T790M / C797S, L858R / T790M / C797S, Del19 / C797S and L858R / C797S mutation following second-line or upfront use of third-generation EGFR TKIs.

[0011] References

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[0013] 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.

[0014] 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.

[0015] Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr. Oncol. 2010; 17: S18-30.

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[0017] Kashima K, et al. CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19 / T790M / C797S Mutation. Mol Cancer Ther; 19(11) November 2020.

[0018] Leonetti A, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. British Journal of Cancer (2019) 121:725-737.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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).

[0029] 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.

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[0031] 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.

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[0038] SUMMARY OF INVENTION

[0039] The present invention relates to novel macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moietyof Formula (I) shown below, or a pharmaceutically acceptable salt thereof:

[0040]

[0041] wherein

[0042] R1and R2are, independently each other, hydrogen or C1-6alkyl optionally substituted with one or more halogens,

[0043] A is 5-10 membered heteroaryl,

[0044] R3and R4are, independently each other,

[0045] hydrogen;

[0046] halogen;

[0047] C1-6alkyl optionally substituted by one or more substituents selected from the group consisting of halogens, hydroxy, and 4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkyl,hydroxyl-C1-6alkyl, C1-6alkyl substituted by one or more halogens, C1-6alkoxy optionally substituted by one or more halogens, -CH2-S(O)2-C1-6alkyl, oxo, and C3-6cycloalkyl optionally substituted by one or more OH;

[0048] C1-6alkoxy optionally substituted by one or more halogens;

[0049] -S(O)2-C1-6alkyl;

[0050] 4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl optionally substituted by one or more halogens, and mono or di-(C1-6alkyl)amino;

[0051] -O-4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl and halo-C1-6alkyl; and

[0052] -NHC3-6cycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen and C1-6alkoxy optionally substituted by one or more halogens,

[0053] L is a linear or branched C2-6alkylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene,

[0054] R5is hydrogen or C1-6alkyl,

[0055] R6and R7are, independently each other, is hydrogen, halogen or halo-C1-6alkyl, and

[0056] X1is CH or N.

[0057] The present invention also relates to methods of treating protein kinase-mediated disease, particularly mutant EGFR-mediated disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of said compounds of Formula (I) or a pharmaceutically acceptable salt thereof.

[0058] The present invention also relates to pharmaceutically acceptable compositions comprising said compounds of Formula (I) or a pharmaceutically acceptable salt thereof, which exhibit inhibition activity against at least one mutant EGFR selectively as compared to wild type EGFR.

[0059] DETAILED DESCRIPTION OF THE INVENTION

[0060] Hereinafter, the present invention will be described in more detail.

[0061] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, although the invention has been described in conjunction with specific methods and samples, their analogs or equivalents should be within the scope of the present invention. Furthermore, the numerical values set forth herein are considered to include the meaning of "about" unless explicitly stated. All publications and other references mentioned herein are hereby incorporated by reference in their entirety.

[0062] The definition of residues used herein is described in detail. Unless otherwise indicated, each residue has the following definition and is used in the sense as commonly understood by one of ordinary skill in the art.

[0063] As used herein, the term "halo", "halogen", "halide(s)" includes fluoro, chloro, bromo and iodo.

[0064] As used herein, the "alkyl" refers to an aliphatic hydrocarbon radical, and includes both linear and branched hydrocarbon radicals. For example, C1-6alkyl 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, the alkyl refers to C1-6alkyl, preferably C1-4alkyl, more preferably C1-3alkyl.

[0065] As used herein, the "alkenyl" refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon double bond, and includes both linear and branched hydrocarbon radicals. The unlimited example of the "alkenyl" is vinyl, allyl, but-1-enyl or but-2-enyl.

[0066] As used herein, the "alkynyl" refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon triple bond, and includes both linear and branched hydrocarbon radicals. The unlimited example of the "alkynyl" is ethynyl, propargyl, but-1-ynyl or but-2-ynyl.

[0067] As used herein, the "haloalkyl" refers to an alkyl group substituted with one or more halogen atom, and the alkyl group is defined as above. The "halo" refers to F, Cl, Br, or I, and the term is compatibly used with the term "halogen". Unless otherwise defined, the haloalkyl refers tofluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.

[0068] As used herein, the term "alkoxy" refers to-O-alkyl or alkyl-O- group, and the alkyl group is defined as shown above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.

[0069] As used herein, the term "hydroxy"or "hydroxyl" alone or in combination with other terms means -OH.

[0070] As used herein, the term "hydroxyalkyl" refers to any hydroxyl derivative of alkyl radical. The term "hydroxyalkyl" includes any alkyl radical having one or more hydrogen atoms replaced by a hydroxy group.

[0071] As used herein, "amino" refers to -NH2.

[0072] As used herein,the term "cycloalkyl" refers to a cyclic alkyl which may be substituted or unsubstituted, and for example, the C3-20cycloalkyl represents a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, unless otherwise defined, the cycloalkyl may be C3-8cycloalkyl, or C3-6cycloalkyl.

[0073] As used herein, the "heterocycle" refers to an aromatic, saturated or partially unsaturated mono-, bi- or poly- ring system containing the specified number of ring atoms, and include one or more heteroatoms selected from N, O, and S as a ring member, wherein the heterocyclic ring is connected to the base molecule via a ring atom, which may be C or N. Bicyclic systems may be connected via a 1,1-fusion (spiro), a 1,2-fusion (fused) or a 1,>2-fusion (bridgehead).

[0074] As used herein, the "heteroaryl" refers to a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having 1 to 10 carbon ring members containing one or more, preferably one to three, heteroatoms selected among N, O, and S. Examples of the heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazoly, l,1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like. Examples of the bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furopyridinyl and similar groups thereof, but are not limited thereto. Unless otherwise defined, the heteroaryl is 4-12 membered heteroaryl, preferably 4-10 memberedheteroaryl, more preferably 4-7 heteroaryl.

[0075] As used herein, the "heterocycloalkyl" refers to monocyclic, bicyclic, tricyclic or higher cyclic alkyl having 3 to 10 carbon ring members containing one or more, for example, one to four, heteroatoms selected among N, O, and S. In addition, the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl. Examples of non-aromatic rings include 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, teterahydropyrazolopyridinyl, morpholinyl, indolinyl, thiomorpholinyl, azepanyl, diazepanyl, azaadamantanyl, diazamantanyl, and the like, but are not limited thereto. 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 aforementioned groups. Unless otherwise defined, heterocycloalkyl refers to 4-12 membered heterocycloalkyl, preferably 4-10 memberedheterocycloalkyl, more preferably 4-7 heterocycloalkyl.

[0076] The present invention provides novel compounds, a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, and solvates thereof that are useful for inhibiting epidermal growth factor receptor (EGFR) and for treating diseases and disorders that are mediated by the protein kinase, for example, cell proliferative diseases and disorders such as cancer, immune diseases such as arthritis, rheumatoid arthritis or autoimmune diseases, infections, cardiovascular diseases, and neurodegenerative diseases and disorders. Especially, the compounds or pharmaceutically acceptable salts thereof of the present invention exhibit excellent inhibition activity against theEGFR triple / double mutantsas well as excellent kinase selectivity. In addition, the compounds or pharmaceutically acceptable salts thereof of the present invention show excellent bioavailability according to the oral administration, along with improved pharmacokinetic characteristics.

[0077] The present invention also provides pharmaceutical compositions comprising at least one of the compounds of Formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

[0078] The present invention provides compositions and methods for modulating the activity of the epidermal growth factor receptor (EGFR) mutants. In one aspect, the present invention provides compounds which act as inhibitors of EGFR mutants.

[0079] In one embodiment, provided herein is a compound of Formula (I) shown below, a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof:

[0080]

[0081] wherein

[0082] R1and R2are, independently each other, hydrogen or C1-6alkyl optionally substituted with one or more halogens,

[0083] A is 5-10 membered heteroaryl,

[0084] R3and R4are, independently each other,

[0085] hydrogen;

[0086] halogen;

[0087] C1-6alkyl optionally substituted by one or more substituents selected from the group consisting of halogens, hydroxy, and 4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkyl,hydroxyl-C1-6alkyl, C1-6alkyl substituted by one or more halogens, C1-6alkoxy optionally substituted by one or more halogens, -CH2-S(O)2-C1-6alkyl, oxo, and C3-6cycloalkyl optionally substituted by one or more OH;

[0088] C1-6alkoxy optionally substituted by one or more halogens;

[0089] -S(O)2-C1-6alkyl;

[0090] 4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl optionally substituted by one or more halogens, and mono or di-(C1-6alkyl)amino;

[0091] -O-4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl and halo-C1-6alkyl; and

[0092] -NHC3-6cycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen and C1-6alkoxy optionally substituted by one or more halogens,

[0093] L is a linear or branched C2-6alkylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene,

[0094] R5is hydrogen or C1-6alkyl,

[0095] R6and R7are, independently each other, is hydrogen, halogen or halo-C1-6alkyl, and

[0096] X1is CH or N.

[0097] In certain embodiment, R1may be hydrogen or methyl. Preferably, R1may be methyl.

[0098] In certain embodiment, R2may be C1-6alkyl optionally substituted with one or more halogens.

[0099] In certain embodiment, Amay be pyrazolyl, pyrazinyl, thiazolyl, pyridinyl or pyrimidinyl.

[0100] In certain embodiment, the 4-8 membered heterocyclyl may be azetidinyl, oxetanyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[2.3]hexanyl, pyrrolidinyl, 2-thio-6-azaspiro[3.3]heptanyl, hexahydro-1H-thieno[3,4-c]pyrrolyl, or 2-azaspiro[3.3]heptanyl.

[0101] In certain embodiment, L may be ethylene,n-propylene, 1-methylpropylene, 1-ethylpropylene, 3-methylpropylene, 2-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene,n-butylene, 1-methylbutylene, 3-methylbutylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene.

[0102] Representative compounds of Formula (I) are listed below:

[0103] (1) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0104] (2) (S)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0105] (3) (R)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0106] (4) 11-Methyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0107] (5) (R)-11,6-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0108] (6) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0109] (7) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,5-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0110] (8) (S)-2-(6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)propan-2-ol;

[0111] (9) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0112] (10) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;

[0113] (11) (61S,63R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane;

[0114] (12) (R)-45-(3-Fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0115] (13) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0116] (14) 45-(3-Methoxypyridin-2-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0117] (15) (S)-45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0118] (16) 45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;

[0119] (17) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;

[0120] (18) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0121] (19) (S)-45-(3-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0122] (20) (S)-11,6-Dimethyl-45-(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0123] (21) (S)-45-(5-Fluoro-3-methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0124] (22) (S)-45-(3-(2,2-Difluoroethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0125] (23) (S)-11,6-Dimethyl-45-(pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0126] (24) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-7-(trifluoromethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0127] (25) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane;

[0128] (26) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0129] (27) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;

[0130] (28) (S)-11,6-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0131] (29) (6S)-11,6-Dimethyl-45-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0132] (30) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-11-(2,2,2-trifluoroethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0133] (31) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0134] (32) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0135] (33) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0136] (34) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-isopropyl-6-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0137] (35) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0138] (36) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0139] (37) 11,7,7-Trimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0140] (38) 11,7,7-Trimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0141] (39) (S)-11,8-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0142] (40) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0143] (41) (S)-11,6-Dimethyl-45-(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0144] (42) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0145] (43) (S)-N-(3,3-Difluorocyclobutyl)-2-(11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-amine;

[0146] (44) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0147] (45) (S)-45-(3-Fluoro-5-(piperidin-1-ylmethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0148] (46) 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine;

[0149] (47) 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine;

[0150] (48) (3-Fluoro-2-(11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)methanol;

[0151] (49) (S)-(1-((6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methanol;

[0152] (50) (S)-45-(3-Fluoro-5-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0153] (51) 45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0154] (52) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0155] (53) 45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0156] (54) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0157] (55) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0158] (56) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0159] (57) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0160] (58) (S)-45-(5-((3,3-Difluoroazetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0161] (59) (S)-45-(5-((3,3-Difluoroazetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0162] (60) (S)-45-(5-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0163] (61) (S)-45-(5-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0164] (62) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];

[0165] (63) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];

[0166] (64) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[cyclobutane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];

[0167] (65) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[cyclopentane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];

[0168] (66) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0169] (67) (S)-11,6-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0170] (68) (S)-11,8-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0171] (69) (S)-7-Fluoro-11-methyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0172] (70) (R)-7-Fluoro-11-methyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0173] (71) 11,7,7-Trimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0174] (72) (R)-11,8-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0175] (73) (S)-11,8-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0176] (74) (S)-11,6-Dimethyl-45-(2-(trifluoromethyl)thiazol-4-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0177] (75) (R)-11,6-Dimethyl-45-(2-(trifluoromethyl)thiazol-4-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0178] (76) (S)-45-(1,4-Dimethyl-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0179] (77) (S)-45-(1,4-Dimethyl-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0180] (78) (S)-45-(5-(Difluoromethoxy)pyrazin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0181] (79) (S)-2-(6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0182] (80) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0183] (81) (S)-45-(4-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0184] (82) (S)-45-(4-(Difluoromethoxy)pyridin-2-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0185] (83) (S)-45-(4-(Difluoromethoxy)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0186] (84) 45-(4-(Difluoromethoxy)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0187] (85) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0188] (86) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0189] (87) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0190] (88) (R)-45-(5-(Difluoromethoxy)pyridin-2-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0191] (89) 45-(5-(Difluoromethoxy)pyridin-2-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0192] (90) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0193] (91) 45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0194] (92) (S)-45-(4-(Difluoromethoxy)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0195] (93) (S)-11,6-Dimethyl-45-(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0196] (94) (S)-45-(3-Methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0197] (95) 2-(6-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;

[0198] (96) 2-(6-((S)-11,8-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;

[0199] (97) 1,1,1-Trifluoro-2-(6-(11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0200] (98) 1,1,1-Trifluoro-2-(6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0201] (99) (S)-45-(4-(3-(2,2-Difluoroethyl)azetidin-1-yl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0202] (100) (S)-45-(4-(3-(2,2-Difluoropropyl)azetidin-1-yl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0203] (101) (S)-11,6-Dimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0204] (102) (S)-11,13,6-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0205] (103) (S)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0206] (104) 11,13,7,7-Tetramethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0207] (105) (R)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0208] (106) (S)-45-(5-((3-(2,2-Difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0209] (107) (S)-45-(5-((3-(2,2-Difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0210] (108) (S)-45-(5-((3-(Difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0211] (109) (S)-45-(5-((3-(2,2-Difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0212] (110) (S)-45-(5-((3-(2,2-Difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0213] (111) (S)-45-(5-((3-(Difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0214] (112) (S)-46-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4),4(3,5)-dipyrimidina-1(4,5)-pyrazolacyclononaphane;

[0215] (113) (S)-2-(5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0216] (114) (S)-2-(5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0217] (115) (S)-45-(3-Fluoro-5-(methylsulfonyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0218] (116) (S)-45-(3-Fluoro-5-(methylsulfonyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0219] (117) 1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol;

[0220] (118) 1-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol;

[0221] (119) (S)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;

[0222] (120) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0223] (121) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0224] (122) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0225] (123) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0226] (124) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0227] (125) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0228] (126) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0229] (127) (S)-11,13,6-Trimethyl-45-(5-(morpholinomethyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0230] (128) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0231] (129) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0232] (130) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0233] (131) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0234] (132) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0235] (133) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0236] (134) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0237] (135) (S)-2-(5-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;

[0238] (136) (S)-45-(3-Fluoro-5-(((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0239] (137) (S)-45-(3-Fluoro-5-(((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0240] (138) (S)-45-(3-Fluoro-5-(((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0241] (139) (S)-2-(5-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;

[0242] (140) (S)-6-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

[0243] (141) (S)-6-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

[0244] (142) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0245] (143) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0246] (144) 5-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide;

[0247] (145) 5-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide;

[0248] (146) (S)-45-(3-Fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0249] (147) (S)-45-(3-Fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0250] (148) (S)-45-(3-Fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0251] (149) (S)-45-(3-Fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0252] (150) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrimidin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0253] (151) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyrimidin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0254] (152) (R)-2-(5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0255] (153) (R)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0256] (154) (R)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0257] (155) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0258] (156) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;

[0259] (157) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;

[0260] (158) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;

[0261] (159) (S)-1-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;

[0262] (160) (S)-2-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-ol;

[0263] (161) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;

[0264] (162) (S)-1-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;

[0265] (163) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)propan-2-ol;

[0266] (164) (S)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)propan-2-ol;

[0267] (165) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-2-yl)propan-2-ol;

[0268] (166) (S)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-2-yl)propan-2-ol;

[0269] (167) (R)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;

[0270] (168) (R)-1-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;

[0271] (169) (S)-1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-ol;

[0272] (170) (S)-1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-ol;

[0273] (171) (S)-1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol;

[0274] (172) (S)-1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol;

[0275] (173) (R)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-3-ol;

[0276] (174) (S)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-3-ol;

[0277] (175) (S)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0278] (176) (R)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0279] (177) (S)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0280] (178) (S)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0281] (179) (R)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0282] (180) (S)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0283] (181) (R)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0284] (182) (S)-45-(5-(2-Fluoropropan-2-yl)pyrimidin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0285] (183) (S)-45-(5-(2-Fluoropropan-2-yl)pyrimidin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0286] (184) (S)-N,N-Dimethyl-1-(6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;

[0287] (185) (S)-N,N-Dimethyl-1-(6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;

[0288] (186) (S)-45-(5-(Difluoromethyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0289] (187) (S)-45-(5-(Difluoromethyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0290] (188) (S)-11,13,6-Trimethyl-45-(5-(trifluoromethyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0291] (189) (S)-11,13,8-Trimethyl-45-(5-(trifluoromethyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0292] (190) (S)-11,13,6-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and

[0293] (191) (S)-11,13,8-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.

[0294] Further representative compounds of Formula (I) are listed below:

[0295] (51) 45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0296] (52) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0297] (55) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0298] (57) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0299] (61) (S)-45-(5-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0300] (80) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0301] (90) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0302] (91) 45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0303] (98) 1,1,1-Trifluoro-2-(6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0304] (102) (S)-11,13,6-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0305] (103) (S)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0306] (104) 11,13,7,7-Tetramethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0307] (105) (R)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0308] (109) (S)-45-(5-((3-(2,2-Difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0309] (110) (S)-45-(5-((3-(2,2-Difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0310] (111) (S)-45-(5-((3-(Difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.

[0311] (113) (S)-2-(5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0312] (114) (S)-2-(5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0313] (117) 1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol;

[0314] (118) 1-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol;

[0315] (119) (S)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;

[0316] (120) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0317] (121) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0318] (122) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0319] (123) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0320] (124) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0321] (125) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0322] (126) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0323] (127) (S)-11,13,6-Trimethyl-45-(5-(morpholinomethyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0324] (128) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0325] (129) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0326] (130) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0327] (131) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0328] (132) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0329] (133) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0330] (134) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0331] (135) (S)-2-(5-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;

[0332] (136) (S)-45-(3-Fluoro-5-(((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0333] (137) (S)-45-(3-Fluoro-5-(((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0334] (138) (S)-45-(3-Fluoro-5-(((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0335] (139) (S)-2-(5-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;

[0336] (140) (S)-6-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

[0337] (141) (S)-6-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

[0338] (143) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0339] (144) 5-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide;

[0340] (145) 5-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide;

[0341] (146) (S)-45-(3-Fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0342] (147) (S)-45-(3-Fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0343] (148) (S)-45-(3-Fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0344] (149) (S)-45-(3-Fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0345] (150) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrimidin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0346] (152) (R)-2-(5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0347] (153) (R)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0348] (154) (R)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0349] (155) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0350] (156) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;

[0351] (157) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;

[0352] (158) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;

[0353] (159) (S)-1-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;

[0354] (160) (S)-2-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-ol;

[0355] (161) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;

[0356] (162) (S)-1-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;

[0357] (163) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)propan-2-ol;

[0358] (164) (S)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)propan-2-ol;

[0359] (165) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-2-yl)propan-2-ol;

[0360] (166) (S)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-2-yl)propan-2-ol;

[0361] (167) (R)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;

[0362] (168) (R)-1-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;

[0363] (169) (S)-1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-ol;

[0364] (170) (S)-1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-ol;

[0365] (171) (S)-1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol;

[0366] (172) (S)-1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol;

[0367] (173) (R)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-3-ol;

[0368] (174) (S)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-3-ol;

[0369] (175) (S)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0370] (176) (R)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0371] (177) (S)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0372] (178) (S)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0373] (179) (R)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0374] (180) (S)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0375] (181) (R)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0376] (182) (S)-45-(5-(2-Fluoropropan-2-yl)pyrimidin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0377] (183) (S)-45-(5-(2-Fluoropropan-2-yl)pyrimidin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0378] (184) (S)-N,N-Dimethyl-1-(6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;

[0379] (185) (S)-N,N-Dimethyl-1-(6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;

[0380] (186) (S)-45-(5-(Difluoromethyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0381] (187) (S)-45-(5-(Difluoromethyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0382] (188) (S)-11,13,6-Trimethyl-45-(5-(trifluoromethyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0383] (189) (S)-11,13,8-Trimethyl-45-(5-(trifluoromethyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0384] (190) (S)-11,13,6-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and

[0385] (191) (S)-11,13,8-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.

[0386] Further preferable representative compounds of Formula (I) are listed below:

[0387] (52) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0388] (55) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0389] (57) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0390] (80) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0391] (98) 1,1,1-Trifluoro-2-(6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0392] (102) (S)-11,13,6-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0393] (103) (S)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0394] (104) 11,13,7,7-Tetramethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0395] (105) (R)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0396] (109) (S)-45-(5-((3-(2,2-Difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0397] (110) (S)-45-(5-((3-(2,2-Difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0398] (120) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0399] (121) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0400] (127) (S)-11,13,6-Trimethyl-45-(5-(morpholinomethyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0401] (128) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0402] (130) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0403] (131) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0404] (133) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0405] (134) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0406] (135) (S)-2-(5-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;

[0407] (140) (S)-6-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

[0408] (150) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrimidin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0409] (153) (R)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0410] (154) (R)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;

[0411] (155) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;

[0412] (156) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;

[0413] (157) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;

[0414] (158) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;

[0415] (159) (S)-1-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;

[0416] (161) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;

[0417] (176) (R)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;

[0418] (184) (S)-N,N-Dimethyl-1-(6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;

[0419] (185) (S)-N,N-Dimethyl-1-(6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;

[0420] (190) (S)-11,13,6-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and

[0421] (191) (S)-11,13,8-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane or a pharmaceutically acceptable salt thereof.

[0422] Single stereochemical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts of the above exemplified compounds are also within the scope of the present invention. Pharmaceutically acceptable salts may be, for example, derived from suitable inorganic and organic acids and bases.

[0423] Acid addition salts can be prepared by reacting the purified compound in its free-based form, if possible, with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of pharmaceutically acceptable acid addition salts include, without limitations, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as carboxylic acid salt, trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.

[0424] 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 thus formed. Such salts include, without limitations, alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N+(C1-4alkyl)4　salts.

[0425] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.

[0426] The compounds of the present inventionmay be synthesized by methods known in the art or by methods illustrated in Examples 1-191 below.

[0427] PHARMACEUTICAL COMPOSITIONS, METHODS AND USE

[0428] In one embodiment, the present invention relates to a method for treating protein kinase-mediated disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amountof a compound of Formula (I) or a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof In specific embodiment, the protein kinase-mediated disease is a cancer or immune disease.

[0429] As used herein, the term "cancer" refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize. The types of cancer include, but is not limited to, solid tumors, such as those of the bladder cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, endometrium cancer, uterine cancer, heart cancer, kidney cancer, lung cancer, liver cancer, stomach cancer, lymphoma, pancreatic cancer, head and neck cancer, or other endocrine organ (thyroid cancer), prostate cancer, skin (melanoma) or hematological tumors (such as the leukemias). In another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0430] In one embodiment, the method disclosed herein relates to treatment of cancer, wherein the cancer results from at least one mutation of EGFR.

[0431] In one embodiment, the method of treatment of cancer is particularly useful for patient who is resistant to a kinase inhibitor other that a compound of the invention, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. In another embodiment, the kinase inhibitor is a mutated EGFR inhibitor.

[0432] The invention also relates to a method for inhibiting at least one mutant of EGFR selectively as compared to wild type EGFR, in biological sample or in a patient, comprising contacting the biological sample with or administering to the patient a compound to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0433] In one embodiment, the at least one mutant is at least one single mutant selected from Table 1 shown below.

[0434] Number (#)Mutation type1EGFR Del19 (Del E746-A750)2EGFR L858R3EGFR Del19 / T790M4EGFR Del19 / C797S5EGFR Del19 / C797X (X=G, N)6EGFR Del19 / L792X (X=F, H, P, R, V, Y)7EGFR Del19 / L718X (X=Q, V)8EGFR L858R / T790M9EGFR L858R / C797S10EGFR L858R / C797X (X=G, N)11EGFR L858R / L792X (X=F, H, P, R, V, Y)12EGFR L858R / L718X (X=Q, V)13EGFR Del19 / T790M / C797S14EGFR Del19 / T790M / C797X (X=G, N)15EGFR Del19 / T790M / L792X (X=F, H, P, R, V, Y)16EGFR Del19 / T790M / L718X (X=Q, V)17EGFR L858R / T790M / C797S18EGFR L858R / T790M / C797X (X=G, N)19EGFR L858R / T790M / L792X (X=F, H, P, R, V, Y)20EGFR L858R / T790M / L718X (X=Q, V)

[0435] The invention further relates to therapeutic methods and uses comprising administering the compounds of the invention, or a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof alone or in combination with other therapeutic or palliative agents.A further embodiment of the invention relates to a compound of the invention for use as a medicament, and in particular for use in the treatment of diseases where the inhibition of mutated EGFR protein ( e.g., those described in Table 1) activity may induce benefit, such as cancer. A still further embodiment of the present invention relates to the use of the compounds of the invention, or a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof, for the manufacture of a drug having an EGFR inhibitory activity for the treatment of EGFR mediated diseases and / or conditions, in particular the diseases and / or conditions listed above.

[0436] The term "therapeutically effective amount" refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. Regarding the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of reducing the size of the tumor, inhibiting (i.e., slowing or stopping) tumor metastases, inhibiting (i.e. slowing or stopping) tumor growth or tumor invasiveness, and / or relieving to some extent one or more signs or symptoms related to the cancer.

[0437] A therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[0438] The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress 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.

[0439] As used herein, the term "subject" or "patient" encompasses mammals and nonmammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guineapigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like.

[0440] As used herein, the term "biological sample" encompasses cells, tissues, and body fluids obtained (isolated) from mammals, such as humans (e.g., patients having cancers) or nonmammals exemplified hereinabove, and cultures thereof.

[0441] Administration of the compounds of the invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0442] Also provided herein, in other aspects, is a pharmaceutical composition comprising a compound of t Formula (I), a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof as an active ingredient, and pharmaceutically acceptable excipients. 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 of EGFR as compared to wild type EGFR.

[0443] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

[0444] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid.

[0445] Examples of carriers, excipients and diluents that can be included in the composition, may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, arabic gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. When formulated into a preparation, a diluting agent or an excipient, such as commonly-used fillers, stabilizing agents, binding agents, disintegrating agents, and surfactants can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations may be prepared by mixing the compound of the present invention with at least one excipient, for example, starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose or the like. In addition to the simple excipient, a lubricant such as magnesium stearate and talc are also used. Liquid preparations for oral administration include a suspension, a liquid for internal use, an emulsion, a syrup, etc. In addition to a commonly used simple diluent such as water and liquid paraffin, various excipients such as a humectant, a sweetener, an aromatic, a preservative, etc. may also be contained. Formulations for parenteral administration include a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized formulation and a suppository. The non-aqueous solution or suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, etc. As a base of the suppository, witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerogelatin, etc. may be used. In order to formulate the formulation for parenteral administration, the compound of Formula I or a pharmaceutically acceptable salt thereof may be mixed in water together with sterilized and / or contain adjuvants such as preservatives, stabilizers, auxiliary agents such as wettable powder or emulsifying accelerators, salt for controlling osmotic pressure and / or buffers and the like, and other therapeutically useful substances, to prepare a solution or suspension, which is then manufactured in the form of an ampoule or vial unit administration.

[0446] GENERAL REACTION SCHEME AND SUMMARY OF THE SYNTHESIS ROUTE

[0447] The present invention includes, within its scope, a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof, in accordance with the following Scheme 1:

[0448] Scheme 1.

[0449]

[0450] In the Scheme 1, R1, R2, R3, R4,R5, R6, R7,X1, L and A are the same as defined in the above; X is halogen; and M is B(OH)2or BPin.

[0451] Specifically, the compound of formula (I) or its pharmaceutically acceptable salt may be prepared using a process which comprises: reacting a compound of formula (IIa) with AR3R4-M to obtain a compound of formula (IIIa), reacting the compound of formula (IIIa) with NHR5-LR6R7-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (V) to obtain the compound of formula (VI) and cyclizing the compound of formula (VI) to obtain the compound of formula (I).

[0452] In the processes of Scheme 1, the compounds of formula (IIa), AR3R4-M and NHR5-LR6R7-OH are commercially available. The reaction of the compound of formula (IIa) and AR3R4-M may be performed in the presence of a base, such as sodium carbonate, potassium carbonate, etc. and a ligand-coupled palladium catalyst such as Pd(dppf)Cl2,Pd(PPh3)4,etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., DME, THF, 1,4-dioxane, etc. under heating, e.g. at a temperature of 40-120oC.

[0453] The reaction of the compound of formula (IIIa) and NHR5-LR6R7-OH may be performed in the presence of a base, such as potassium carbonate, cesium carbonate, TEA, DIPEA, etc. Further, the reaction may be carried out in an organic solvent, such as anhydrous THF, DMF, DMA, etc. and at room temperature or under heating, e.g., at a temperature of 40-120oC.

[0454] The compound of formula (IV) is coupled with a compound of formula (V) to obtain a compound of formula (VI) by Mitsunobu reaction. The reaction of the compound of formula (IV) and (V) may be performed in the presence of a phosphorane　ylide such as (trimethylphosphoranylidene)acetonitrile, (tributylphosphoranylidene)acetonitrile, etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., 1,4-dioxane or toluene, etc. under heating, e.g. at a temperature of 90-130oC.

[0455] The compound of formula (VI) is cyclized by Buchwald-Hartwig reaction to obtain the compound of formula (I). The cyclization reaction of the compound of formula (VI) may be performed in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. Further, the reaction may be performed in the presence of a palladium catalyst such as Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4,Pd(dppf)Cl2, BrettPhos Pd G1 methylt-butyl ether adduct, etc. and a ligand such as BINAP, SPhos, XPhos, Xantphos, BrettPhos, etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., 1,4-dioxane or toluene, etc. under heating, e.g. at a temperature of 90-130oC.

[0456] Alternately, the compound of formula (IV) may be prepared by reacting a compound of formula (IIa) with NHR5-LR6R7-OH to obtain a compound of formula (IIIb) and reacting the compound of formula (IIIb) with AR3R4-M.

[0457] The reaction of the compound of formula (IIa) and NHR5-LR6R7-OH may be performed in the presence of a base, such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. Further, the reaction may be carried out in an organic solvent, such as anhydrous THF, DMF, DMA, etc. and at room temperature or under heating, e.g., at a temperature of 40-120oC.

[0458] The reaction of the compound of formula (IIIb) and AR3R4-M may be performed in the presence of a base, such as sodium carbonate, potassium carbonate, etc. and a ligand-coupled palladium catalyst such as Pd(dppf)Cl2,Pd(PPh3)4,etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., DME, THF, 1,4-dioxane, etc. under heating, e.g. at a temperature of 40-120oC.

[0459] Alternately, the compound of formula (I) or its pharmaceutically acceptable salt may be prepared in accordance with the following Scheme 2:

[0460] Scheme 2.

[0461]

[0462] In the Scheme 2, R1, R2, R3, R4,R5, R6, R7,X1, L and A are the same as defined in the above; X is halogen; and M is B(OH)2or BPin.

[0463] Specifically, the compound of formula (I) or its pharmaceutically acceptable salt may be prepared using a process which comprises: reacting a compound of formula (IIb) with AR3R4-X to obtain a compound of formula (IIIa), reacting the compound of formula (IIIa) with NHR5-LR6R7-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (V) to obtain the compound of formula (VI) and cyclizing the compound of formula (VI) to obtain the compound of formula (I).

[0464] In the processes of Scheme 2, the compounds of formula (IIb), AR3R4-X, and NHR5-LR6R7-OH are commercially available. The reaction of the compound of formula (IIb) and AR3R4-X may be performed in the presence of a base, such as sodium carbonate, potassium carbonate, etc. and a ligand-coupled palladium catalyst such as Pd(dppf)Cl2,Pd(PPh3)4,etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., DME, THF, 1,4-dioxane, etc. under heating, e.g. at a temperature of 40-120oC.

[0465] The reaction of the compound of formula (IIIa) and NHR5-LR6R7-OH may be performed in the presence of a base, such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. Further, the reaction may be carried out in an organic solvent, such as anhydrous THF, DMF, DMA, etc. and at room temperature or under heating, e.g., at a temperature of 40-140oC.

[0466] The compound of formula (IV) is coupled with a compound of formula (V) to obtain a compound of formula (VI) by Mitsunobu reaction. The reaction of the compound of formula (IV) and (V) may be performed in the presence of a phosphorane　ylide such as (trimethylphosphoranylidene)acetonitrile, (tributylphosphoranylidene)acetonitrile, etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., 1,4-dioxane or toluene, etc. under heating, e.g. at a temperature of 90-130oC.

[0467] The compound of formula (VI) is cyclized by Buchwald-Hartwig reaction to obtain the compound of formula (I). The cyclization reaction of the compound of formula (V) may be performed in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. Further, the reaction may be performed in the presence of a palladium catalyst such as Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4,Pd(dppf)Cl2, BrettPhos Pd G1 methylt-butyl ether adduct, etc. and a ligand such as BINAP, SPhos, XPhos, Xantphos, BrettPhos, etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., 1,4-dioxane or toluene, etc. under heating, e.g. at a temperature of 90-130oC.

[0468] In an embodiment, the compound of formula (IV) may be prepared by reacting a compound of formula (IIb) with NHR5-LR6R7-OH to obtain a compound of formula (IIIc) and reacting the compound of formula (IIIc) with AR3R4-X.

[0469] The reaction of the compound of formula (IIb) and NHR5-LR6R7-OH may be performed in the presence of a base, such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. Further, the reaction may be carried out in an organic solvent, such as anhydrous THF, DMF, DMA, etc. and at room temperature or under heating, e.g., at a temperature of 40-120oC.

[0470] The reaction of the compound of formula (IIIc) and AR3R4-X may be performed in the presence of a base, such as sodium carbonate, potassium carbonate, etc. and a ligand-coupled palladium catalyst such as Pd(dppf)Cl2,Pd(PPh3)4,etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., DME, THF, 1,4-dioxane, etc. under heating, e.g. at a temperature of 40-120oC.

[0471] In another embodiment, the compound of formula (V) may be prepared in accordance with the following Scheme 3:

[0472] Scheme 3.

[0473]

[0474] In the Scheme 3, R1and R2are the same as defined in the above; X is halogen; and M is B(OH)2or BPin.

[0475] Specifically, the compound of formula (V) may be prepared using a process which comprises: reacting a compound of formula (VII) with (VIII) to obtain a compound of formula (IX), and carrying out hydrogenolysis of a compound of formula (IX) to obtain a compound of formula (V).

[0476] In the processes of Scheme 3, the compounds of formula (VII) is commercially available. The reaction of the compound of formula (VII) and (VIII) may be performed in the presence of a base, such as sodium carbonate, potassium carbonate, etc. and a ligand-coupled palladium catalyst such as Pd(dppf)Cl2,Pd(PPh3)4,etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., THF, 1,4-dioxane, etc. under heating, e.g. at a temperature of 40-100oC.

[0477] The hydrogenolysis of the compound of formula (IX) may be carried out in the presence of palladium on carbon catalyst such as Pd / C, Pd(OH)2 / C, etc. under hydrogen atmosphere. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., THF, DCM, or MeOH at room temperature or under heating.

[0478] In still another embodiment, the compound of formula (VIII) may be prepared in accordance with the following Scheme 4:

[0479] Scheme 4.

[0480]

[0481] In the Scheme 4, R1and R2 are the same as defined in the above; X is halogen; and M is B(OH)2or BPin.

[0482] Specifically, the compound of formula (VIII) may be prepared using a process which comprises: reacting a compound of formula (X) with Bn-X to obtain a compound of formula (XI), halogenating a compound of formula (XI) to obtain a compound of formula (XII) and borylating a compound of formula (XII) to obtain a compound of formula (VIII).

[0483] In the processes of Scheme 4, the compounds of formula (X) and Bn-X are commercially available. The reaction of the compound of formula (X) and Bn-X may be performed in the presence of a base, such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc. Further, the reaction may be carried out in an organic solvent, such as anhydrous THF, DMF, DMA, etc. and at room temperature or under heating, e.g., at a temperature of 40-120oC.

[0484] The halogenation of the compound of formula (XI) may be performed in the presence of halogenating agents such as NIS, NBS, halogen acid, elemental halogens, etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., MeCN, DCM, or DCE at a temperature of 0-10oC.

[0485] The borylation of the compound of formula (XII) may be performed in the presence of boron reagent such as B2Pin2, B2Cat2,i-proOBPin, etc. and organometallic reagents such asiPrMgCl·LiCl complex etc. under argon atmosphere. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., THF, hexane or toluene at a temperature of -10-30oC.

[0486] EXAMPLES

[0487] The present invention is further exemplified by the following examples that illustrate the preparation of compounds of Formula (I) according to the invention. The examples are for illustrative purpose only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications can be made without changing the scope of the invention.

[0488] The analyses of the compounds prepared in the following examples were carried out as follows: Nuclear magnetic resonance (NMR) spectrum analysis was carried out using Bruker 400 MHz spectrometer and Agilent 600 MHz spectrometer and chemical shifts thereof were analyzed in ppm. Further, the indicated molecular weights were measured by using liquid chromatography / mass selective detector (MSD) of Agilent 1260 Infinity series equipped with an electrostatic spray interface (by using Single Quadrupole, it indicates a value of m / z in ESI+ (ESI-MS (cation), which is represented by the (M + H)+peak). Column chromatography was carried out on silica gel (Merck, 70-230 mesH) (W.C. Still, J. Org. Chem., 43, 2923, 1978). Further, the starting materials in eachExample are known compounds, which were synthesized according to literatures or obtained from the market such as Sigma-Aldrich. Further, the abbreviations used in the following examples are as follows:

[0489] Table 2

[0490] List of abbreviations

[0491]

[0492] Reference Example 1. 2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine

[0493] The reaction mixture of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol), 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.14 g, 4.661 mmol), Pd(dppf)Cl2(317.23 mg, 0.388 mmol) and 2 M K2CO3soln. (3.88 mL, 11.66 mmol) in 1,4-dioxane (20 mL) was stirred at 90oC for 3 hours. The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-20%) to yield 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (910 mg, 3.675 mmol, 94.61% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 9.02 (d, 1H), 7.93 (d, 1H), 7.29 (t, 1H), 7.20 (d, 1H), 6.88 (t, 1H); MS (ESI) m / z = 248.0 (M + H)+

[0494] Reference Example 2. 2-Chloro-4-fluoro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine

[0495] To a solutioin of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol) in 1,4-dioxane (20 mL) were added 1-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (1.29 g, 4.661 mmol), Pd(dppf)Cl2(317.23 mg, 0.388 mmol) and 3 M K2CO3soln. (3.88 mL, 11.66 mmol). The reaction mixture was stirred at 90oC for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-30%) to give 2-chloro-4-fluoro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine (876 mg, 3.133 mmol, 80.65% yield) as a white solid.1H-NMR (DMSO-d6, 400 MHz) δ 8.89 (d, 1H), 7.77 (d, 1H), 7.31 (s, 1H), 4.06 (s, 3H); MS (ESI) m / z 280.0 = (M + H)+

[0496] Reference Example 3. 2-Chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine

[0497] To a solutioin of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol) in 1,4-dioxane (20 mL) were added (1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)boronic acid (903.95 mg, 4.661 mmol), Pd(dppf)Cl2(317.23 mg, 0.388 mmol) and 3 M K2CO3soln. (3.88 mL, 11.66 mmol). The reaction mixture was stirred at 90oC for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-30 %) to give 2-chloro-4-fluoro-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]pyridine (886 mg, 3.169 mmol, 81.57% yield) as a white solid.1H-NMR (DMSO-d6, 400 MHz) δ 8.89 (d, 1H), 7.77 (d, 1H), 7.31 (s, 1H), 4.06 (s, 3H); MS (ESI) m / z = 280.0 (M + H)+

[0498] Reference Example 4. 4-(6-Chloro-4-fluoro-3-pyridyl)-2-(trifluoromethyl)-1H-thiazole

[0499] The title compound as a white solid (809 mg) was prepared in the same fashion as Reference Example 2 except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)thiazole (1.41 g, 5.050 mmol) was used instead of 1-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 9.24 (d, 1H), 8.01 (s, 1H), 7.24 (d, 1H)

[0500] Reference Example 5. 2-(6-Chloro-4-fluoropyridin-3-yl)-5-(difluoromethoxy)pyrazine

[0501] To a solutioin of 2-bromo-5-(difluoromethoxy)pyrazine (200 mg, 0.889 mmol) in 1,4-dioxane (4.53 mL) were added 2-chloro-4-fluoro-5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (228.9mg, 0.889 mmol), Pd(dppf)Cl2(72.59 mg, 0.089 mmol) and 3 M K2CO3soln. (0.89 mL, 2.667 mmol). The reaction mixture was stirred at 90oC for 2 hours. The reaction mixture was cooled to room temperature, and quenched with water, then extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-40 %) to give 2-(6-Chloro-4-fluoropyridin-3-yl)-5-(difluoromethoxy)pyrazine (201 mg, 0.729 mmol, 82.04% yield) as a pale yellow solid.1H-NMR (CDCl3, 400 MHz) δ 9.05 (d, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 47.47 (t, 1H), 7.25 (s, 1H)

[0502] Reference Example 6. 2-(6'-Chloro-4'-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol

[0503] The title compound as a white solid (545 mg) was prepared in the same fashion as Reference Example 5, except that 2-(6-bromo-3-pyridyl)propan-2-ol (700 mg, 3.24 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine.1H-NMR (CDCl3, 400 MHz) δ 8.99 (d, 1H), 8.85 (d, 1H), 7.93 (dd, 1H), 7.70 (dd, 1H), 7.19 (d, 1H), 2.24 (s, 1H), 1.65 (s, 6H); MS (ESI) m / z = 267.0 (M + H)+

[0504] Reference Example 7. 6'-Chloro-4-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine

[0505] The title compound as a white solid (183 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-4-(difluoromethoxy)pyridine (200 mg, 0.893 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine.1H-NMR (CDCl3, 400 MHz) δ 9.08 (d, 1H), 8.72 (d, 1H), 7.51 (s, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 6.70 (t, 1H); MS (ESI) m / z = 343.9 (M + H)+.

[0506] Reference Example 8. 6'-Chloro-5-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine

[0507] The title compound as a white solid (467 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-5-(difluoromethoxy)pyridine (500 mg, 2.232 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine.1H-NMR CDCl3, 400 MHz) δ 9.05 (d, 1H), 8.64 (s, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.23 (d, 1H), 6.64 (t, 1H); MS (ESI) m / z = 343.9 (M + H)+

[0508] Reference Example 9. 6'-Chloro-4-(difluoromethoxy)-3,4'-difluoro-2,3'-bipyridine

[0509] The title compound as a white solid (272 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-4-(difluoromethoxy)-3-fluoro-pyridine (500 mg, 2.066 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine.1H-NMR (CDCl3, 400 MHz) δ 8.65 (d, 1H), 8.52 (d, 1H), 7.31 9t, 1H), 7.25 (d, 1H), 6.75 (t, 1H)

[0510] Reference Example 10. 2-(6'-Chloro-4'-fluoro-[2,3'-bipyridin]-5-yl)-1,1,1-trifluoropropan-2-ol

[0511] The title compound as an off-white solid (185 mg) was prepared in the same fashion as Reference Example 5, except that 2-(6-bromo-3-pyridyl)-1,1,1-trifluoro-propan-2-ol (542 mg, 2.01 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 321.0 (M + H)+

[0512] Reference Example 11. 6'-Chloro-4'-fluoro-5-((1-methylpiperidin-4-yl)oxy)-2,3'-bipyridine

[0513] The title compound as a white solid (468 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-5-((1-methylpiperidin-4-yl)oxy)pyridine (502.04 mg, 1.852 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 322.0 (M + H)+

[0514] Reference Example 12. 6'-Chloro-4'-fluoro-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-2,3'-bipyridine

[0515] The title compound as a white solid (140 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine (188 mg, 0.554 mmol) was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 390.1 (M + H)+

[0516] Reference Example 13. 6'-Chloro-4'-fluoro-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-2,3'-bipyridine

[0517] Step 1. 2-Bromo-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine

[0518] The reaction mixture of 1-(2,2,2-trifluoroethyl)piperidin-4-yl 4-methylbenzenesulfonate(750 mg, 2.223 mmol), K2CO3(614.52 mg, 4.446 mmol), 6-bromo-5-methoxy-pyridin-3-ol(498.92 mg, 2.445 mmol) in DMF (5 mL) was stirred at　90oC for 3 hours. The reaction mixture was cooled to room temperature, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-80%) to yield 2-bromo-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine (382 mg, 1.035 mmol, 46.54 % yield) as colorless oil. MS (ESI) m / z = 370.0 (M + H)+

[0519] Step 2. 6'-Chloro-4'-fluoro-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-2,3'-bipyridine

[0520] The title compound as a white solid (301 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-3-methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine (380 mg, 1.029 mmol) prepared in step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 420.1 (M + H)+

[0521] Reference Example 14. 6'-Chloro-4-(3-(2,2-difluoroethyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine

[0522] Step 1. 2-Bromo-4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridine

[0523] The reaction mixture of 2-bromo-4-fluoro-pyridine (90 mg, 0.511 mmol), 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate(156.33 mg, 0.665 mmol), DIPEA (0.22 mL, 1.278 mmol) in DMA (1 mL) was stirred at　90oC for 4 hours. The reaction mixture was cooled to room temperature, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-50%) to yield 2-bromo-4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridine (141 mg, 0.509 mmol, 99.5 % yield) as colorless oil. MS (ESI) m / z = 277.9 (M + H)+

[0524] Step 2. 6'-Chloro-4-(3-(2,2-difluoroethyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine

[0525] The title compound as a white solid (65 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-4-(3-(2,2-difluoroethyl)azetidin-1-yl)pyridine (129.14 mg, 0.466 mmol) prepared in step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 327.9 (M + H)+

[0526] Reference Example 15. 6'-Chloro-4-(3-(2,2-difluoropropyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine

[0527] Step 1. 2-Bromo-4-(3-(2,2-difluoropropyl)azetidin-1-yl)pyridine

[0528] The title compound as a white solid (145 mg) was prepared in the same fashion as step 1 in Reference Example 14, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (114.09 mg, 0.665 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate. MS (ESI) m / z = 292.9 (M + H)+

[0529] Step 2. 6'-Chloro-4-(3-(2,2-difluoropropyl)azetidin-1-yl)-4'-fluoro-2,3'-bipyridine

[0530] The title compound as a white solid (68 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-4-(3-(2,2-difluoropropyl)azetidin-1-yl)pyridine (135.68 mg, 0.466 mmol) prepared in step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 341.9 (M + H)+

[0531] Reference Example 16. 6'-Chloro-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0532] Step 1. 2-Bromo-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridine

[0533] The reaction mixture of 6-bromo-5-fluoronicotinaldehyde (200 mg, 0.98 mmol), 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate(230.54 mg, 0.98 mmol), sodium triacetoxyborohydride(623.35 mg, 2.941 mmol) in DCM (5 mL) was stirred at　room temperature for 20 hours. The reaction mixture diluted in DCM, quenched by NaHCO3soln., washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex=0-70%) to yield 2-bromo-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridine (168 mg, 0.543 mmol, 55.43 % yield) as pale yellow solid. MS (ESI) m / z = 310.8 (M + H)+

[0534] Step 2. 6'-Chloro-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0535] The title compound as a white solid (151 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-5-((3-(2,2-difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridine (150 mg, 0.485 mmol) prepared in step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 359.9 (M + H)+

[0536] Reference Example 17. 6'-Chloro-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0537] Step 1. 2-Bromo-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridine

[0538] The title compound as a white solid (214 mg) was prepared in the same fashion as step 1 in Reference Example 16, except that 3-(2,2-difluoropropyl)azetidine hydrochloride (168.25 mg, 0.98 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate.1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.43 (dd, 1H), 3.58 (s, 2H), 3.54 (t, 2H), 2.87 (t, 2H), 2.83-2.76 (m, 1H), 2.12 (td, 2H), 1.58 (t, 3H)

[0539] Step 2. 6'-Chloro-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0540] The title compound as a white solid (151 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-5-((3-(2,2-difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridine (156.8 mg, 0.485 mmol) prepared in step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 374.0 (M + H)+

[0541] Reference Example 18. 6'-Chloro-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0542] Step 1. 2-Bromo-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridine

[0543] The title compound as a white solid (159 mg) was prepared in the same fashion as step 1 in Reference Example 16, except that 3-(difluoromethoxy)azetidine hydrochloride (156.43 mg, 0.98 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate.1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.43 (dd, 1H), 6.20 (t, 1H), 4.84-4.78 (m, 1H), 3.70 (td, 2H), 3.66 (s, 3H), 3.14 (td, 2H)

[0544] Step 2. 6'-Chloro-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0545] The title compound as a white solid (152 mg) was prepared in the same fashion as Reference Example 5, except that 2-bromo-5-((3-(difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridine (150.96 mg, 0.485 mmol) prepared in step 1 was used instead of 2-bromo-5-(difluoromethoxy)pyrazine. MS (ESI) m / z = 361.9 (M + H)+

[0546] Reference Example 19. (S)-3-((2-Chloro-5-iodopyridin-4-yl)amino)butan-1-ol

[0547] The 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 90oC for 3hours. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / Hex = 0-50%) to yield (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (399 mg, 1.222 mmol, 89.87% yield) as an off-white solid.1H-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)

[0548] Reference Example 20. (R)-4-((2-Chloro-5-iodopyridin-4-yl)amino)butan-2-ol

[0549] The title compound as an off-white solid (406 mg) was prepared in the same fashion as Reference Example 19 except that (R)-4-aminobutan-2-ol (89.14 mg, 1.36 mmol) was used instead of (S)-3-aminobutan-1-ol.1H-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)

[0550] Reference Example 21. (S)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol

[0551] To the solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (500.00 mg, 2.019 mmol) prepared in Reference Example 1 in DMA (6 mL) was added (S)-3-aminobutan-1-ol (216.01mg, 2.423 mmol) and DIPEA (564.48 uL, 4.039 mmol). The reaction mixture was heated at 80oC for 3 hours. The reaction mixture was cooled to room temperature, added to water and extracted with EA. The combined organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography (EA / n-Hex = 30-100%) to give (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (500 mg, 1.759 mmol, 78.17% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 7.91-8.68 (m, 2H), 7.20 (t, 1H), 6.81 (d, 1H), 6.68 (s, 1H), 3.90-3.83 (t, 3H), 1.89 (q, 2H), 1.67 (s, 1H), 1.33 (d, 3H)

[0552] Reference Example 22. 6'-Chloro-4'-fluoro-3-methoxy-2,3'-bipyridine

[0553] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.00 g, 7.767 mmol), 2-bromo-3-methoxypyridine (1.46 g, 7.767 mmol), 1 M K2CO3soln. (23.30 mL, 23.301 mmol) and Pd(dppf)Cl2(951.43 mg, 1.165 mmol) in 1,4-dioxane (30 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (1000 mg, 4.190 mmol, 53.95% yield).1H-NMR (CD3OD, 400MHz) δ 8.47 (d, 1H), 8.26 (d, 1H), 7.64 (d, 1H), 7.51-4-7.46 (m, 2H), 3.89 (s, 3H); MS (ESI) m / z = 239.1 (M + H)+

[0554] Reference Example 23. 4-(4-Aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol

[0555] Step 1. 5-(Benzyloxy)-1-methyl-1H-pyrazole

[0556] To a solution of 1-methyl-1H-pyrazol-5-ol (50.0 g, 0.51 mol) in DMF (500 mL) were added K2CO3(106 g, 0.76 mol) and benzyl bromide (72.6 mL, 0.61 mol). The mixture was stirred at 60 ℃ for 6 hours. Ice cold water (500 mL) was added into the mixture to quench the reaction and then it was extracted with EA. The combined organic layers were washed several times with ice cold water and brine to remove DMF. Then it was 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(36.4 g) as a colorless oil.1H 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)+

[0557] Step 2. 5-(Benzyloxy)-4-iodo-1-methyl-1H-pyrazole

[0558] To a solution of 5-(benzyloxy)-1-methyl-1H-pyrazole(44.4 g, 236 mmol) prepared in step 1 in MeCN (675 mL) was addedN-iodosuccinimide (53.1 g, 236 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3solution and then extracted by EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. It was then purified by use of flash column chromatography (EA / n-Hex = 0-25%) to give 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole (41.5 g) as a pale yellow liquid.1H 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)+

[0559] Step 3. 5-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0560] To a stirred solution 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole (41.5 g, 132 mmol) in THF (420 mL), was slowly added a solution ofiPrMgCl LiCl complex in THF (1.3 M, 112 mL, 145 mmol) at -10-0 ℃ under argon atmosphere. The mixture was stirred at 0 ℃ for 1 hour and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.3 mL, 159 mmol) was added dropwise to the solution at 0 ℃. After the reaction mixture was stirred for another 1.5 hours at room temperature, the reaction was quenched by slow addition of sat. NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by use of flash column chromatography (EA / n-Hex = 0-20%) to obtain 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(32.5 g) as a white solid.1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 7.40-7.35 (m, 5H), 5.39 (s, 2H), 3.55 (s, 3H), 1.32 (s, 12H); MS (ESI)m / z = 315.2 (M + H)+

[0561] Step 4. 2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0562] To a solution of 2-bromopyrimidin-4-amine(16.0 g, 91.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(28.9 g, 91.9 mmol) in 1,4-dioxane (460 mL) were added 3 M K2CO3soln. (91.9 mL, 276 mmol) and Pd(dppf)Cl2dichloromethane complex (7.51 g, 9.19 mmol). The mixture was degassed by argon and then heated to 90 ℃ for 5-6 hours under argon atmosphere. 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 use of flash column chromatography (MeOH / DCM = 0-5%) to give 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(11.2 g) as a yellow solid.1H 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)+

[0563] Step 5. 4-(4-Aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol

[0564] To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(12.3 g, 43.7 mmol) in methanol (120 mL) was added Pd(OH)2on carbon (20% Pd, 120 mg) and stirred under H2atmosphere at 25 ℃ for 6-8 hours. After completion, the reaction mixture was filtered through a celite pad and washed thoroughly with MeOH. Solvent was evaporated under reduced pressure to obtain 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)+

[0565] Reference Example 24. 4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol

[0566] Step 1. 5-(Benzyloxy)-1,3-dimethyl-1H-pyrazole

[0567] To a solution of 1,3-dimethyl-1H-pyrazol-5-ol (13.0 g, 116 mmol) in THF (500 mL) were added K2CO3(24.0 g, 174 mmol) and benzyl bromide (16.5 mL, 139 mol). The mixture was stirred at 60 ℃ for 8 hours. Ice cold water (500 mL) was added into the mixture to quench the reaction and then it was extracted with EA. The combined organic layers were washed several times with ice cold water and brine to remove DMF. Then it was 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(9.20 g) as a colorless oil.1H 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)+

[0568] Step 2. 5-(Benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole

[0569] 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 addedN-iodosuccinimide (10.2 g, 45.5 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3solution and then extracted by EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. It was then purified by use of 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.1H 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)+

[0570] Step 3. 5-(Benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0571] To a stirred solution 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole (7.40 g, 22.6 mmol) in THF (75 mL), was slowly added a solution ofiPrMgCl LiCl complex in THF (1.3 M, 26 mL, 33.8 mmol) at -10-0 ℃ under argon atmosphere. The mixture was stirred at 0 ℃ for 1 hour and then 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 ℃. After the reaction mixture was stirred for another 1.5 hours at room temperature, the reaction was quenched by slow addition of sat. NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by use of flash column chromatography (EA / n-Hex = 0-20%) to obtain 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.48 g) as a white solid.1H 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)+

[0572] Step 4. 2-(5-(Benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0573] To a solution of 2-bromopyrimidin-4-amine(530 mg, 3.05 mmol) and 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 3.05 mmol) in 1,4-dioxane (15 mL) were added 3 M K2CO3soln. (3.05 mL, 9.14 mmol) and Pd(dppf)Cl2dichloromethane complex (249 mg, 0.31 mmol). The mixture was degassed by argon and then heated to 90 ℃ for overnight under argon atmosphere. 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 use of flash column chromatography (MeOH / DCM = 0-5%) to give 2-(5-(benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine(160 mg) as a yellow solid.1H 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)+

[0574] Step 5. 4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol

[0575] To a solution of 2-(5-(benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine(1.26 g, 4.27 mmol) in methanol (15 mL) was added Pd(OH)2on carbon (20% Pd, 126 mg) and stirred under H2atmosphere at 25 ℃ for 6 hours. After completion, the reaction mixture was filtered through a celite pad and washed thoroughly with MeOH. Solvent was evaporated under reduced pressure to obtain 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol(710 mg) as gray solid.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)+

[0576] Reference Example 25. (R)-3-((2-Chloro-5-iodopyridin-4-yl)amino)butan-1-ol

[0577] The 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 charged nitrogen gas for 10 minutes. After DMF (15 mL) and DIPEA (4.06 mL, 23.307 mmol, 2.0 eq) were added, the reaction mixture was stirred at 80oC overnight. The reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-40%) to yield (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (2.56 g) as an off-white solid.1H-NMR (CDCl3, 400MHz) δ 8.20 (s, 1H), 6.44 (s, 1H), 5.13-5.11 (d, 1H), 3.85-3.80 (q, 2H), 1.91-1.88 (q, 1H), 1.82-1.78 (t, 1H), 1.29-1.25 (d, 3H); MS (ESI) m / z = 327.0 (M + H)+

[0578] Reference Example 26. 2-(6-Chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine

[0579] Step 1. 2-Bromo-5-(oxetan-3-yloxy)pyrazine

[0580] To a solution of sodium hydride (15.13 mg, 0.631mmol) in THF (2 mL) was added 3-hydroxyoxetane (26.69 uL, 0.42 mmol) at room temperature. The reaction mixture was stirred for 5 minutes and 2,5-dibromopyrazine (100 mg, 0.42 mmol) was added to the mixture. The reaction mixture was stirred at 50oC for 4 hours and quenched by water. The aqueous phase was extracted with DCM. The combined organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EA / n-Hex = 0-40%) to give 2-bromo-5-(oxetan-3-yloxy)pyrazine (86 mg, 0.382 mmol, 88.54% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 8.10 (s, 1H), 5.58 (quin, 1H), 4.99 (t, 2H), 4.74 (t, 2H)

[0581] Step 2. 2-(6-Chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine

[0582] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (115.01mg, 0.447 mmol), Pd(dppf)Cl2(30.4mg, 0.037 mmol), 2-bromo-5-(oxetan-3-yloxy)pyrazine (86 mg, 0.372 mmol) prepared in step 1, and 3 M K2CO3soln. (0.37 mL, 1.117 mmol) in 1,4-dioxane (2.5 mL) was stirred at 80 ℃ for 2 hours. And the reaction mixture was cooled to room temperature, concentrated, and extracted with DCM / water. The organic layer was dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (EA / n-Hex = 0-50%) to give 2-(6-chloro-4-fluoro-3-pyridyl)-5-(oxetan-3-yloxy)pyrazine (60 mg, 0.213 mmol, 57.23% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 9.01 (d, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.23 (d, 1H), 5.69 (quin, 1H), 5.04 (t, 2H), 4.79 (t, 1H)

[0583] Reference Example 27. 6'-Chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine

[0584] Step 1. 1-((6-Bromo-5-fluoropyridin-3-yl)methyl)-4-methylpiperazine

[0585] To the solution of 1-methylpiperazine (119.62 uL, 1.078 mmol) in DCM (5 mL) was added 6-bromo-5-fluoro-pyridine-3-carbaldehyde (200 mg, 0.980 mmol) and sodium triacetoxyborohydride (623.35 mg, 2.941 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and poured into sat. NaHCO3sol.. The aqueous phase was extracted with DCM. The combined organic layer was washed with water, dried over MgSO4, concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / EA = 0-30%) to give 1-((6-bromo-5-fluoropyridin-3-yl)methyl)-4-methylpiperazine (232 mg, 0.805 mmol, 82.12% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 7.50 (dd, 1H), 3.52 (s, 2H), 2.43 (brs, 8H), 2.32 (s, 3H)

[0586] Step 2. 6'-Chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine

[0587] The title compound as a brown solid (190 mg) was prepared in the same fashion as Reference Example 1, except that 1-((6-bromo-5-fluoropyridin-3-yl)methyl)-4-methylpiperazine (230 mg, 0.798 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (246.63 mg, 0.958 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.51 (s, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 3.63 (s, 2H), 2.56-2.49 (m, 8H), 2.32 (s, 3H)

[0588] Reference Example 28. (S)-3-((6'-Chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0589] To the solution of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine (189 mg, 0.558 mmol) prepared in Reference Example 27 in DMA (3 mL) was added (S)-3-aminobutan-1-ol (59.68 mg, 0.669 mmol) and DIPEA (0.16 mL, 1.116 mmol). The reaction mixture was heated at 80 ℃ for 19 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / EA = 0-70%) to give (S)-3-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (129 mg, 0.316 mmol, 56.69% yield) as a pale brown solid.1H-NMR (CDCl3, 400 MHz) δ 8.38 (d, 1H), 8.35 (s, 1H), 7.93 (d, 1H), 7.58 (dd, 1H), 6.69 (s, 1H), 3.80-3.57 (m, 3H), 3.57 (s, 2H), 2.52 (brs, 8H), 2.29 (s, 3H), 1.90-1.74 (m, 2H), 1.31 (d, 3H)

[0590] Reference Example 29. 3-((6'-Chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)-2,2-dimethylpropan-1-ol

[0591] The title compound as a beige solid (315 mg) was prepared in the same fashion as Reference Example 28, except that 3-amino-2,2-dimethylpropan-1-ol (138.85 mg, 1.346 mmol) was used instead of (S)-3-aminobutan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.58 (d, 1H), 6.66 (s, 1H), 3.58 (s, 2H), 3.46 (s, 2H), 3.09 (d, 2H), 2.51 (brs, 8H), 2.31 (s, 3H), 1.03 (s, 6H)

[0592] Reference Example 30. (R)-4-((6'-Chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-2-ol

[0593] The title compound as a brown solid (160 mg) was prepared in the same fashion as Reference Example 28, except that (R)-4-aminobutan-2-ol (119.98 mg, 1.346 mmol) was used instead of (S)-3-aminobutan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.42 (d, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.62 (d, 1H), 6.66 (s, 1H), 4.03-3.98 (m, 1H), 3.59 (s, 2H), 3.51-3.33 (m, 2H), 2.54 (brs, 8H), 2.33 (s, 3H), 1.88-1.76 (m, 2H), 1.29 (d, 3H)

[0594] Reference Example 31. (S)-3-((5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0595] Step 1. 6-((6-Bromo-5-fluoropyridin-3-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane

[0596] The title compound as a colorless liquid (366.6 mg) was prepared in the same fashion as step 1 in Reference Example 27, except that 2-oxa-6-azaspiro[3.3]heptane (189.02 mg, 1.907 mmol) was used instead of 1-methylpiperazine.1H-NMR (CDCl3, 400 MHz) δ 8.10 (d, 1H), 7.40 (dd, 1H), 4.77 (s, 4H), 3.55 (s, 2H), 3.40 (s, 4H)

[0597] Step 2. 6-((6'-Chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane

[0598] The title compound as a brown liquid (330 mg) was prepared in the same fashion as Reference Example 1, except that 6-((6-bromo-5-fluoropyridin-3-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (304.43 mg, 1.06 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.31 mg, 1.166 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.46 (s, 1H), 7.52 (d, 1H), 7.24 (d, 1H), 4.79 (s, 4H), 3.66 (s, 2H), 3.46 (s, 4H)

[0599] Step 3. (S)-3-((5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0600] The title compound as a pale yellow solid (228 mg) was prepared in the same fashion as Reference Example 28, except that 6-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (292.69 mg, 0.867 mmol) prepared in step 2 was used instead of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine.1H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.32 (s, 1H), 7.92 (d, 1H), 7.51 (d, 1H), 6.71 (s, 1H), 4.79 (s, 4H), 3.83-3.80 (m, 3H), 3.61 (s, 2H), 3.45 (s, 4H), 1.86-1.84 (m, 2H), 1.29 (d, 3H)

[0601] Reference Example 32. (S)-3-((6'-Chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0602] Step 1. 2-Bromo-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridine

[0603] The title compound as a white solid (298.1 mg) was prepared in the same fashion as step 1 in Reference Example 27, except that 3,3-difluoroazetidine hydrochloride (247 mg, 1.907 mmol) was used instead of 1-methylpiperazine.1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 7.48 (dd, 1H), 3.77 (s, 2H), 3.65 (t, 4H)

[0604] Step 2. 6'-Chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine

[0605] The title compound as a yellow liquid (300 mg) was prepared in the same fashion as Reference Example 1, except that 2-bromo-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoropyridine (298 mg, 1.06 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.31 mg, 1.166 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.51 (s, 1H), 7.59 (d, 1H), 7.25 (d, 1H), 3.87 (s, 2H), 3.70 (t, 4H)

[0606] Step 3. (S)-3-((6'-Chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0607] The title compound as a pale yellow solid (314 mg) was prepared in the same fashion as Reference Example 28, except that 6'-chloro-5-((3,3-difluoroazetidin-1-yl)methyl)-3,4'-difluoro-2,3'-bipyridine (287.44 mg, 0.867 mmol) prepared in step 2 was used instead of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine.1H-NMR (CDCl3, 400 MHz) δ 8.41-8.38 (m, 2H), 7.95 (d, 1H), 7.57 (dd, 1H), 6.71 (s, 1H), 3.86-3.81 (m, 4H), 3.69 (t, 4H), 1.95-1.80 (m, 3H), 1.30 (d, 3H)

[0608] Reference Example 33. (S)-3-((6'-Chloro-5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0609] Step 1. 5-((6-Bromo-5-fluoropyridin-3-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane

[0610] The title compound as a colorless liquid (536.8 mg) was prepared in the same fashion as step 1 in Reference Example 27, except that 1,1-difluoro-5-azaspiro[2.3]hexane (227.11 mg, 1.907 mmol) was used instead of 1-methylpiperazine.1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.47 (dd, 1H), 3.75 (s, 2H), 3.54 (d, 2H), 3.37-3.35 (m, 2H), 1.40 (t, 2H)

[0611] Step 2. 5-((6'-Chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane

[0612] The title compound as a yellow liquid (310 mg) was prepared in the same fashion as Reference Example 1, except that 5-((6-bromo-5-fluoropyridin-3-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane (325.61 mg, 1.06 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.31 mg, 1.166 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.51 (s, 1H), 7.58 (d, 1H), 7.24 (d, 1H), 3.85 (s, 2H), 3.59 (d, 2H), 3.42-3.40 (m, 2H), 1.42 (t, 2H)

[0613] Step 3. (S)-3-((6'-Chloro-5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0614] The title compound as a pale yellow solid (228 mg) was prepared in the same fashion as Reference Example 28, except that 5-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)-1,1-difluoro-5-azaspiro[2.3]hexane (310 mg, 0.867 mmol) prepared in step 2 was used instead of 6'-chloro-3,4'-difluoro-5-((4-methylpiperazin-1-yl)methyl)-2,3'-bipyridine.1H-NMR (CDCl3, 400 MHz) δ 8.40-8.38 (m, 2H), 7.94 (d, 1H), 7.57 (d, 1H), 6.71 (s, 1H), 3.85-3.80 (m, 5H), 3.58 (d, 2H), 3.41-3.39 (m, 2H), 1.88-1.78 (m, 3H), 1.41 (m, 2H), 1.30 (d, 3H)

[0615] Reference Example 34. 4-(4-Aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol

[0616] Step 1. 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-ol

[0617] To a solution of(2,2,2-trifluoroethyl)hydrazine hydrochloride (20.0 g, 133 mmol) in ethanol (200 mL) at 60-65 ℃ was added methyl 3-methoxyacrylate (15.5 g, 132.86 mmol) dropwise in a 1 hour. After addition was completed, the mixture was heated to reflux for 2 hours. After cooling to room temperature, 30% sodium methoxide in methanol solution was added and pH was adjusted to 5.0. The mixture was filtered and the filtrate was concentrated to get the crude product, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol(33 g). This crude was used in the next step without further purification.

[0618] Step 2. 5-(Benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0619] To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (30.0 g, 180.6 mmol) in DMF prepared in step 1 (300 mL) were added K2CO3(37.5 g, 270.9 mmol) and benzyl bromide (25.8 mL, 216.7 mmol). The mixture was stirred at 60 ℃ for 6 hours. Ice cold water (500 mL) was added into the mixture to quench the reaction and then it was extracted with EA. The combined organic layers were washed several times with ice cold water and brine to remove DMF. Then it was 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.1H 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)+

[0620] Step 3. 5-(Benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0621] 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 addedN-iodosuccinimide (7.02 g, 31.2 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3solution and then extracted by EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. It was then purified by use of flash column chromatography (EA / n-Hex = 0-20%) to give 5-(benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g) as a pale yellow liquid.1H NMR (CDCl3, 400 MHz) δ7.46-7.40 (m, 6H), 5.33 (s, 2H), 4.36 (q, 2H); MS (ESI)m / z = 383.0 (M + H)+

[0622] Step 4. 5-(Benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0623] To a stirred solution 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 ofiPrMgCl LiCl complex in THF (1.3 M, 17.7 mL, 23.1 mmol) at -10-0 ℃ under argon atmosphere. The mixture was stirred at 0 ℃ for 1 hour and then 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 ℃. After the reaction mixture was stirred for another 1.5 hours at room temperature, the reaction was quenched by slow addition of sat. NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by use of flash column chromatography (EA / n-Hex = 0-20%) to obtain 5-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.5 g) as a white solid.1H 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)+

[0624] Step 5. 2-(5-(Benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

[0625] 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) were added 3 M K2CO3soln. (12.0 mL, 36.1 mmol) and Pd(dppf)Cl2dichloromethane complex (983 mg, 1.2 mmol). The mixture was degassed by argon and then heated to 90 ℃ for 5-6 hours under argon atmosphere. 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 use of flash column chromatography (MeOH / DCM = 0-5%) to give 2-(5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (450 mg) as a yellow solid.1H NMR (CD3OD, 400 MHz) δ 8.10 (d, 1H), 7.98 (s, 1H), 7.38-7.35 (m, 5H), 6.36 (d, 1H), 5.49 (s, 2H), 4.53 (q, 2H); MS (ESI)m / z = 350.2 (M + H)+

[0626] Step 6. 4-(4-Aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol

[0627] 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)2on carbon (20% Pd, 45 mg) and stirred under H2atmosphere at 25 ℃ for 6-8 hours. After completion, the reaction mixture was filtered through a celite pad and washed thoroughly with MeOH. Solvent was evaporated under reduced pressure to obtain 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (300 mg) as a gray solid.1H 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)+

[0628] Reference Example 35. 4-(4-Aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol

[0629] Step 1. 5-(Benzyloxy)-1-isopropyl-1H-pyrazole

[0630] To a solution of 1-isopropyl-1H-pyrazol-5-ol (2.0 g, 15.8 mmol) in DMF (20 mL) were added K2CO3(3.29 g, 23.8 mmol) and benzyl bromide (2.26 mL, 19.0 mmol). The mixture was stirred at 60 ℃ for 6 hours. Ice cold water (500 mL) was added into the mixture to quench the reaction and then it was extracted with EA. The combined organic layers were washed several times with ice cold water and brine to remove DMF. Then it was 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.1H 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)+

[0631] Step 2. 5-(Benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole

[0632] 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 addedN-iodosuccinimide (2.15 g, 9.57 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3solution and then extracted by EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. It was then purified by use of flash column chromatography (EA / n-Hex = 0-20%) to give 5-(benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole (2.30 g) as a colorless liquid.1H 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)+

[0633] Step 3. 5-(Benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0634] To a stirred solution 5-(benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole (2.30 g, 6.72 mmol) prepared in step 2 in THF (23 mL), was slowly added a solution ofiPrMgCl LiCl complex in THF (1.3 M, 5.69 mL, 7.39 mmol) at -10-0 ℃ under argon atmosphere. The mixture was stirred at 0 ℃ for 1 hour and then 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 ℃. After the reaction mixture was stirred for another 1.5 hours at room temperature, the reaction was quenched by slow addition of sat. NH4Cl solution and extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by use of flash column chromatography (EA / n-Hex = 0-20%) to obtain 5-(benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.91 g) as a white solid.1H 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)+

[0635] Step 4. 2-(5-(Benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0636] To a solution of 2-bromopyrimidin-4-amine(1.0 g, 5.75 mmol) and 5-(benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.97 g, 5.75 mmol) prepared in step 3 in 1,4-dioxane (30 mL) were added 3 M K2CO3soln. (5.75 mL, 17.2 mmol) and Pd(dppf)Cl2dichloromethane complex (470 mg, 0.57 mmol). The mixture was degassed by argon and then heated to 90 ℃ for 5-6 hours under argon atmosphere. 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 use of flash column chromatography (MeOH / DCM = 0-5%) to give 2-(5-(benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (570 mg) as a brown solid.1H 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)+

[0637] Step 5. 4-(4-Aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol

[0638] To a solution of 2-(5-(benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (570 mg, 1.84 mmol) prepared in step 4 in methanol (10 mL) was added Pd(OH)2on carbon (20% Pd, 57 mg) and stirred under H2atmosphere at 25 ℃ for 6-8 hours. After completion, the reaction mixture was filtered through a celite pad and washed thoroughly with MeOH. Solvent was evaporated under reduced pressure to obtain 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)+

[0639] Example 1. (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0640] Step 1. (R)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0641] To the solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine prepared in Reference Example 1 (250 mg, 1.010 mmol) in DMA (6mL) was added (R)-3-amino-1-butanol (108 mg, 1.212 mmol) and DIPEA (0.28 mL, 2.020 mmol). The reaction mixture was heated at 80oC for 3 hours. The reaction mixture was cooled to room temperature, added to water and extracted with EA. The combined organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography (EA / n-Hex = 30-100%) to give (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (250 mg) as a white solid. The mixture of (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (90 mg, 0.284 mmol), 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.2 mg, 0.381 mmol) prepared in Reference Example 23, and (tributylphosphoranylidene)acetonitrile (1.0 mL, 0.995 mmol, 3.5 eq) in toluene (2 mL) was stirred at 100oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-30%) to yield (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.5 mg) as a yellow solid.1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 8.10-8.09 (d, 1H), 7.95-7.94 (d, 2H), 7.83-7.82 (d, 1H), 7.26-6.95 (t, 1H), 6.78-6.77 (d, 1H), 6.65 (s, 1H), 6.15-6.14 (d, 1H), 5.06 (s, 2H), 4.53-4.49 (m, 1H), 4.44-4.40 (m, 1H), 3.97-3.93 (t, 1H), 3.65 (s, 3H), 3.44 (s, 2H), 2.15-2.09 (m, 2H), 1.38-1.36 (d, 3H); MS (ESI) m / z = 490.2 (M + H)+

[0642] Step 2. (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0643] The suspension of (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.5 mg, 0.215 mmol) prepared in step 1, Cs2CO3(210.5 mg, 0.646 mmol), XPhos (41.1 mg, 0.086 mmol), and Pd2(dba)3(39.4 mg, 0.043 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by C18 column chromatography (MeCN / water = 0-100%) to yield (R)-45-(1-(difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (63 mg) as an white solid.1H-NMR (CDCl3, 400MHz) δ 8.40 (s, 1H), 8.32-8.30 (d, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.36-7.06 (t, 1H), 6.81 (s, 1H), 6.44-6.43 (d, 1H), 4.81-4.76 (t, 1H), 4.34-4.34 (d, 1H), 4.12-4.09 (t, 1H), 3.81 (s, 3H), 2.23-2.14 (m, 2H), 2.03 (s, 1H), 1.50-1.49 (d, 3H); MS (ESI) m / z = 454.2 (M + H)+

[0644] Example 2. (S)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0645] Step 1. (S)-3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol

[0646] The mixture of 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (2630 mg, 9.406 mmol) prepared in Reference Example 3, and (S)-3-aminobutan-1-ol (838.4 mg, 9.406 mmol) was charged nitrogen gas for 10 minutes. After DMF (20 mL) and DIPEA (3.28 mL, 18.811 mmol) were added, the reaction mixture was stirred at 80oC for 12 hours. The reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to yield (S)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (1840 mg) as a yellow solid.1H-NMR (CDCl3, 400MHz) δ 8.19 (s, 1H), 8.00-7.98 (d, 1H), 7.49 (s, 1H), 6.60-6.57 (d, 1H), 4.74-4.67 (q, 2H), 3.87-3.76 (m, 3H), 1.93-1.90 (m, 1H), 1.88-1.85 (m, 1H), 1.28-1.26 (d, 3H)

[0647] Step 2. (S)-2-(5-(3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0648] The mixture of (S)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (500 mg, 1.434 mmol) prepared in step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (274.1 mg, 1.434 mmol) prepared in Reference Example 23, and 2.0 M (0.98 mL, 2.867 mmol, 2 eq) in toluene (10 mL) was stirred at 100oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-30%) to yield (S)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (445 mg) as a yellow solid.1H-NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 8.14-8.09 (m, 2H), 7.96 (s, 1H), 7.53 (s, 1H), 6.69 (s, 1H), 6.64 (s, 1H), 6.17-6.16 (d, 1H), 4.68-4.62 (q, 2H), 4.51-4.50 (t, 1H), 4.43-4.41 (d, 1H), 3.94 (s, 1H), 3.66 (s, 3H), 2.12-2.07 (m, 3H), 1.25-1.24 (d, 3H); MS (ESI) m / z = 522.2 (M + H)+

[0649] Step 3. (S)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0650] The suspension of (S)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (189 mg, 0.362 mmol) prepared in step 2, Cs2CO3(353.9 mg, 1.086 mmol), XPhos (69 mg, 0.145 mmol), and Pd2(dba)3(66.3 mg, 0.072 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by C18 column chromatography (MeCN / water = 0-100%) to yield (S)-11,6-dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (27 mg) as an white solid.1H-NMR (CDCl3, 400MHz) δ 8.37 (s, 1H), 8.32-8.30 (d, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 8.05-8.03 (d, 1H), 7.54 (brs, 2H), 6.7 (s, 1H), 6.37-6.35 (d, 1H), 4.84-4.81 (t, 1H), 4.77-4.69 (m, 2H), 4.33-4.30 (t, 1H), 4.10-4.08 (t, 1H), 3.82 (s, 3H), 2.21-2.20 (d, 2H), 1.47-1.45 (d, 3H); MS (ESI) m / z = 486.2 (M + H)+

[0651] Example 3. (R)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0652] Step 1. (R)-3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol

[0653] The mixture of 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (450 mg, 1.609 mmol) prepared in Reference Example 3, and (R)-3-amino-1-butanol (142.4 mg, 1.609 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.56 mL, 3.219 mmol) were added, the reaction mixture was stirred at 80oC for 12 hours. The reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to yield (R)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (267 mg) as a yellow solid.1H-NMR (CDCl3, 400MHz) δ 8.22 (s, 1H), 8.00-7.98 (d, 1H), 7.50 (s, 1H), 6.61 (s, 1H), 4.74-4.68 (q, 2H), 3.85-3.81 (m, 3H), 2.31 (s, 1H), 1.91-1.81 (m, 2H), 1.30-1.28 (d, 3H) ); MS (ESI) m / z = 349.1 (M + H)+

[0654] Step 2. (R)-2-(5-(3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0655] The mixture of (R)-3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (99 mg, 0.284 mmol) prepared in step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (54.2 mg, 0.284 mmol) prepared in Reference Example 23, and (tributylphosphoranylidene)acetonitrile (0.34 mL, 0.994 mmol, 3.5 eq) in toluene (1 mL) was stirred at 100oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-30%) to yield (R)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (86 mg) as a yellow solid.1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.10-8.07 (m, 2H), 7.93 (s, 1H), 7.50-7.50 (d, 1H), 6.64-6.63 (d, 1H), 6.61 (s, 1H), 6.14-6.13 (d, 1H), 4.67-4.61 (q, 2H), 4.50-4.46 (q, 1H), 4.42-4.38 (q, 1H), 3.93-3.89 (t, 1H), 3.68 (s, 3H), 2.10-2.05 (q, 2H), 1.34-1.32 (d, 3H); MS (ESI) m / z = 522.1 (M + H)+

[0656] Step 3. (R)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0657] The suspension of (R)-2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (86 mg, 0.165 mmol) prepared in step 2, Cs2CO3(161 mg, 0.494 mmol), XPhos (31.4 mg, 0.066 mmol), and Pd2(dba)3(30.2 mg, 0.033 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by C18 column chromatography (MeCN / water = 0-100%) to yield (R)-11,6-dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (14.1 mg) as an white solid.1H-NMR (CDCl3, 400MHz) δ 8.91-8.89 (d, 1H), 8.49 (s, 1H), 8.36-8.35 (d, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.59 (s, 1H), 6.84-6.83 (d, 1H), 6.66 (s, 1H), 4.77-4.64 (m, 3H), 4.34 (s, 1H), 4.14-4.12 (t, 1H), 3.77 (s, 3H), 2.26-2.24 (d, 1H), 2.18-2.15 (t, 1H), 1.50-1.49 (d, 3H); MS (ESI) m / z = 486.2 (M + H)+

[0658] Example 4. 11-Methyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0659] Step 1. 3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol

[0660] The mixture of 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (450 mg, 1.609 mmol) prepared in Reference Example 3, and 3-amino-1-propanol (120.9 mg, 1.609 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.56 mL, 3.219 mmol) were added, the reaction mixture was stirred at 80oC for 12 hours. The reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to yield 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (295 mg) as a yellow solid.1H-NMR (CDCl3, 400MHz) δ 8.30 (s, 1H), 8.06 (s, 1H), 7.54 (s, 1H), 6.69 (s, 1H), 6.58 (s, 1H), 4.75-4.69 (q, 2H), 3.84-3.83 (d, 2H), 3.40-3.36 (q, 2H), 2.00-1.94 (m, 2H), 1.83 (s, 1H) ; MS (ESI) m / z = 335.1 (M + H)+

[0661] Step 2. 2-(5-(3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0662] The mixture of 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (90 mg, 0.269 mmol) prepared in step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (51.4 mg, 0.269 mmol) prepared in Reference Example 23, and (tributylphosphoranylidene)acetonitrile (0.32 mL, 0.941 mmol, 3.5 eq) in toluene (1 mL) was stirred at 100oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-30%) to yield 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (96 mg) as a yellow solid.1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 8.13-8.09 (m, 2H), 7.96 (s, 1H), 7.49 (s, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 6.15-6.14 (d, 1H), 5.11 (brs, 2H), 4.60-4.54 (q, 2H), 4.46-4.43 (t, 2H), 3.69 (s, 3H), 3.52-3.48 (q, 2H), 2.49 (s, 1H), 2.21-2.15 (q, 2H); MS (ESI) m / z = 508.1 (M + H)+

[0663] Step 3. 11-Methyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0664] The suspension of 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (96 mg, 0.189 mmol) prepared in step 2, Cs2CO3(184.7 mg, 0.567 mmol), XPhos (36.0 mg, 0.076 mmol), and Pd2(dba)3(34.6 mg, 0.038 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by C18 column chromatography (MeCN / water = 0-100%) to yield 11-methyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (5.4 mg) as an white solid.1H-NMR (CDCl3, 400MHz) δ 9.10 (s, 1H), 8.55-8.53 (d, 2H), 8.40-8.39 (d, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 6.88-6.86 (d, 1H), 6.70 (s, 1H), 4.81-4.75 (q, 2H), 4.42 (s, 2H), 3.84 (s, 2H), 3.80 (s, 3H), 2.29 (s, 2H); MS (ESI) m / z = 472.2 (M + H)+

[0665] Example 5. (R)-11,6-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0666] Step 1. (R)-2-(5-(3-((2-Chloro-5-iodopyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0667] The mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (270 mg, 0.827 mmol) prepared in Reference Example 25, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (158.1 mg, 0.827 mmol) prepared in Reference Example 23, and (tributylphosphoranylidene)acetonitrile (0.79 mL, 2.894 mmol, 3.5 eq) in toluene (2 mL) was stirred at 100oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-30%) to yield (R)-2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(209 mg) as a yellow solid.1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.21 (s, 1H), 8.15-8.14 (d, 1H), 8.00 (s, 1H), 6.48 (s, 1H), 6.26-6.25 (d, 1H), 5.08-5.06 (d, 1H), 4.44 (s, 2H), 3.93-3.90 (t, 1H), 3.71 (s, 3H), 2.13-2.10 (t, 2H), 1.39-1.37 (d, 3H); MS (ESI) m / z = 500.0 (M + H)+

[0668] Step 2. (R)-2-(5-(3-((2-Chloro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0669] The mixture of (R)-2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(209 mg, 0.418 mmol) prepared in step 1, 1-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (115.4 mg, 0.418 mmol) were added a 3 M K2CO3soln. (0.42 mL, 1.255 mmol, 3 eq) and Pd(dppf)Cl2dichloromethane complex (17.1 mg, 0.021 mmol, 0.05 eq). The mixture was degassed by argon and then heated to 80 ℃ for 3 hours under argon atmosphere. Upon completion, the mixture was diluted with water and extracted several times with CH2Cl2. The combined organic layers were dried over MgSO4,and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 0-100%) to yield (R)-2-(5-(3-((2-chloro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47.3 mg) as a yellow solid.1H-NMR (CDCl3, 400MHz) δ 8.29 (s, 1H), 8.23 (s, 1H), 8.12-8.11 (d, 1H), 8.03-8.01 (d, 1H), 7.98 (s, 1H), 6.95 (s, 1H), 6.64 (s, 1H), 6.22-6.21 (d, 1H), 5.44 (brs, 1H), 4.50-4.42 (dt, 2H), 3.96 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 2.15-2.12 (t, 2H), 1.40-1.38 (d, 3H) ); MS (ESI) m / z = 522.2 (M + H)+

[0670] Step 3. (R)-11,6-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0671] The suspension of (R)-2-(5-(3-((2-chloro-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47.3 mg, 0.091 mmol) prepared in step 2, Cs2CO3(88.6 mg, 0.272 mmol), XPhos (17.3 mg, 0.036 mmol), and Pd2(dba)3(16.6 mg, 0.018 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through Celite, and then concentrated. The crude product was purified by C18 column chromatography (MeCN / water = 0-100%) to yield (R)-11,6-dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (2.8 mg) as an white solid.1H-NMR (CDCl3, 400MHz) δ 8.77-8.75 (d, 1H), 8.54 (s, 1H), 8.44-8.40 (m, 1H), 8.14 (s, 1H), 6.98 (s, 1H), 6.87-6.85 (d, 1H), 4.73-4.68 (t, 1H), 4.41 (s, 1H), 4.18-4.14 (q, 1H), 4.07 (s, 3H), 3.82 (s, 3H), 2.31-2.27 (t, 1H), 2.21-2.18 (t, 1H), 1.56-1.54 (d, 3H); MS (ESI) m / z = 486.2 (M + H)+

[0672] Example 6. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0673] Step 1. 2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine

[0674] The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.0 g, 3.88 mmol), 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.23 g, 5.05 mmol), 3 M K2CO3soln. (3.88 mL, 11.65 mmol), and Pd(dppf)Cl2(158.61 mg, 0.19 mmol) in 1,4-dioxane (20.0 mL) was stirred at 70oC for 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with DCM. The organic layer was dried with MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-20%) to yield 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (943.40 mg, 3.81 mmol, 98.1% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 9.04 (d, 1H), 7.95 (d, 1H), 7.30 (t, 1H), 7.22 (d, 1H), 6.90 (t, 1H); MS (ESI) m / z = 248.0 (M + H)+

[0675] Step 2. (S)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol

[0676] To a solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (550.0 mg, 2.22 mmol) prepared in step 1 in DMF (6.0 mL) was added (S)-3-aminobutan-1-ol (198.01 mg, 2.22 mmol) and DIPEA (0.77 mL, 4.44 mmol). The reaction mixture was stirred at 80oC for overnight. The reaction mixture was added to water and extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-100% → MeOH / DCM = 0-35%) to yield (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (583.0 mg, 1.84 mmol, 82.9% yield).1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.85 (d, 1H), 7.77 (d, 1H), 7.19 (t, 1H), 6.59 (d, 1H), 6.57 (s, 1H), 4.12-3.78 (m, 3H), 3.74 (s, 1H), 1.96-1.78 (m, 2H), 1.27 (d, 3H); MS (ESI) m / z = 317.1 (M + H)+

[0677] Step 3. (S)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino) butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0678] To a solution of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (75.0 mg, 0.24 mmol) prepared in step 2 in toluene (1.0 mL) was added (tributylphosphoranylidene)acetonitrile (0.19 mL, 0.71 mmol) and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (48.60 mg, 0.24 mmol) prepared in Reference Example 24. The reaction mixture was stirred at 100oC 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 yield (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (95.0 mg, 0.19 mmol, 79.6% yield).1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.85 (s, 1H), 7.23 (t, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.24 (d, 1H), 5.53 (s, 2H), 4.27 (q, 2H), 3.89 (quin, 1H), 3.62 (s, 3H), 2.38 (s, 3H), 2.07 (q, 2H), 1.33 (d, 3H); MS (ESI) m / z = 504.2 (M + H)+

[0679] Step 4. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0680] To a solution of (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (90.0 mg, 0.18 mmol) prepared in step 3 in 1,4-dioxane (5.95 mL) was added cesium carbonate (174.57 mg, 0.54 mmol), Pd2(dba)3(32.71 mg, 0.04 mmol) and XPhos (34.06 mg, 0.07 mmol). The reaction mixture was stirred at 120oC for 3 hours. The reaction mixture was added to water and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-100% → MeOH / DCM = 0-10%) to yield (S)-45-(1-(difluoromethyl)-1H-pyrazol-3-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (37.90 mg, 0.081 mmol, 45.4% yield).1H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.97 (d, 1H), 7.87 (s, 1H), 7.21 (t, 1H), 6.82 (s, 1H), 6.43-6.39 (m, 1H), 4.84-4.79 (m, 1H), 4.20 (dd, 2H), 3.75 (s, 3H), 2.58 (s, 3H), 2.25-2.06 (m, 2H), 1.48 (d, 3H); MS (ESI) m / z = 468.0 (M + H)+

[0681] Example 7. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,5-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0682] Step 1. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol

[0683] The title compound (629.0 mg) was prepared in the same fashion as step 2 in Example 6 except that 3-amino-1-propanol (75.11 mg, 2.22 mmol) was used instead of (S)-3-aminobutan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.01 (s, 1H), 7.84 (d, 1H), 7.21 (t, 1H), 6.74 (d, 1H), 6.56 (s, 1H), 3.86 (t, 2H), 3.39 (q, 2H), 2.67 (s, 1H), 1.98 (quin, 2H); MS (ESI) m / z = 303.1 (M + H)+

[0684] Step 2.N-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-amine

[0685] To a solution of 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (629.0 mg, 2.08 mmol) prepared in step 1 in DCM (6.0 mL) was addedtert-butyldimethylchlorosilane (375.82 mg, 2.49 mmol), 4-dimethylaminopyridine (25.39 mg, 0.21 mmol) and triethylamine (0.58 mL, 4.16 mmol) at ice bath. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was concentrated, added to water and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-70%) to yieldN-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-amine (866.0 mg, 2.01 mmol, 99.9% yield).1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.28 (t, 1H), 6.84 (d, 1H), 6.64 (s, 1H), 3.75 (t, 2H), 3.40 (q, 2H), 1.90 (quin, 2H), 0.92 (s, 9H), 0.06 (s, 6H); MS (ESI) m / z = 417.1 (M + H)+

[0686] Step 3.N-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-methylpyridin-4-amine

[0687] To a solution ofN-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-amine (500.0 mg, 1.20 mmol) prepared in step 2 in THF (5.99 mL) was added sodium hydride (95.93 mg, 2.40 mmol) at 0oC and stirred for 20 minutes at 0oC. To this mixture was added iodomethane (0.22 mL, 3.60 mmol) and then stirred for 3 hours at room temperature. The reaction mixture was quenched with sat. NH4Cl and diluted with EA. The aqueous phase was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 0-30%) to yieldN-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-methylpyridin-4-amine (269.78 mg, 0.63 mmol, 2.2% yield).1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.86 (s, 1H), 7.23 (t, 1H), 6.80 (s, 1H), 6.61 (s, 1H), 3.52 (t, 2H), 3.16 (t, 2H), 2.71 (s, 3H), 1.71-1.65 (m, 2H), 0.86 (s, 9H), 0.00 (s, 6H); MS (ESI) m / z = 431.2 (M + H)+

[0688] Step 4. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propan-1-ol

[0689] To a solution ofN-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-N-methylpyridin-4-amine (267.54 mg, 0.62 mmol) prepared in step 3 in THF (3.10 mL) was added tetrabutylammonium fluoride (1 M in THF, 1.24 mL, 1.24 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (EA / n-Hex = 0-100% → MeOH / DCM = 0-30%) to yield 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propan-1-ol (206.0 mg, 0.65 mmol, 104.7% yield).1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.87 (s, 1H), 7.30 (t, 1H), 6.82 (s, 1H), 6.60 (s, 1H), 3.57 (t, 2H), 3.20 (t, 2H), 2.68 (s, 3H), 2.94 (s, 1H), 1.76 (quin, 2H)

[0690] Step 5. 2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0691] The title compound (105.0 mg) was prepared in the same fashion as step 3 in Example 6 except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propan-1-ol (100.0 mg, 0.32 mmol) prepared in step 4 and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (60.36 mg, 0.32 mmol) prepared in Reference Example 23 were used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol, respectively.1H-NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.21 (t, 1H), 6.81 (s, 1H), 6.57 (s, 1H), 6.19 (d, 1H), 4.97 (s, 2H), 4.23 (t, 2H), 3.63 (s, 3H), 3.30 (t, 2H), 2.75 (s, 3H), 2.03-1.98 (m, 2H)

[0692] Step 6. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,5-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0693] The title compound (45.0 mg) was prepared in the same fashion as step 4 in Example 6 except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)(methyl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.0 mg, 0.12 mmol) prepared in step 5 was used instead of (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.26 (t, 1H), 6.57 (s, 1H), 6.36 (d, 1H), 4.45 (t, 2H), 3.81 (s, 3H), 3.76-3.74 (m, 2H), 2.60 (s, 3H), 2.26-2.24 (m, 2H); MS (ESI) m / z = 454.2 (M + H)+

[0694] Example 8. (S)-2-(6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)propan-2-ol

[0695] Step 1. 2-(6-Bromo-5-fluoropyridin-3-yl)propan-2-ol

[0696] To a solution of methyl 6-bromo-5-fluoropyridine-3-carboxylate (500 mg, 2.137 mmol) in THF (5 mL) was added methylmagnesium bromide solution (3 mL, 10.2 mmol, 3.4 M in 2-MeTHF) dropwise at -30oC. The reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. The reaction mixture was quenched by sat. NH4Cl. The reaction mixture was diluted in water, extracted by DCM, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA / n-Hex = 10-70%) to yield 2-(6-Bromo-5-fluoropyridin-3-yl)propan-2-ol (362.7 mg, 1.5495 mmol, 72.525% yield) as a colorless oil.1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.62 (d, 1H), 1.89 (s, 1H), 1.63 (s, 6H); MS (ESI) m / z = 234.0, 236.0 (M + H)+

[0697] Step 2. 2-(6'-Chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)propan-2-ol

[0698] To a solution of 2-chloro-4-fluoropyridine-5-boronic acid pinacol ester (398.2 mg, 1.547 mmol) in 1,4-dioxane (5 mL) were added 2-(6-bromo-5-fluoropyridin-3-yl)propan-2-ol (362 mg, 1.547 mmol) prepared in step 1, Pd(dppf)Cl2(189.5 mg, 0.232 mmol) and 3 M K2CO3soln. (1.55 mL, 4.640 mmol). The reaction mixture was stirred at 90 ℃ for 2 hours. The reaction mixture was cooled to room temperature, and diluted with water and DCM, then extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA / n-Hex = 10-60%) to give 2-(6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)propan-2-ol (296.9 mg, 1.0429 mmol, 67.433% yield) as a pale brown oil.1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.54 (d, 1H), 7.68 (d, 1H), 7.19 (d, 1H), 3.48 (s, 1H), 1.61 (s, 6H); MS (ESI) m / z = 285.1 (M + H)+

[0699] Step 3. (S)-3-((6'-Chloro-3-fluoro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0700] To the reaction mixture of (3S)-3-aminobutan-1-ol (82 mg, 0.92 mmol) and 2-(6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)propan-2-ol (174.6 mg, 0.613 mmol) prepared in step 2 in DMA (2.5 mL) was added DIPEA (0.32 mL, 1.84 mmol) and the reaction mixture was stirred at 90oC for 4 hours. The reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by silica gel column chromatography (EA / n-Hex = 30-100%) to yield (S)-3-((6'-chloro-3-fluoro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (209.7 mg, 0.5927 mmol, 96.637% yield) as an off-white solid.1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.56 (d, 1H), 6.50 (s, 1H), 4.98-4.80 (m, 2H), 3.84-3.73 (m, 3H), 1.90-1.80 (m, 1H), 1.70-1.60 (m, 1H), 1.62 (s, 3H), 1.54 (s, 3H), 1.16 (d, 3H); MS (ESI) m / z = 354.1 (M + H)+

[0701] Step 4. (S)-2-(4'-((4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol

[0702] The reaction mixture of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (112.94 mg, 0.591 mmol) prepared in Reference Example 23, (S)-3-((6'-chloro-3-fluoro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (209 mg, 0.591 mmol) prepared in step 3 and (tributylphosphoranylidene)acetonitrile (464.38 uL, 1.772 mmol) in toluene (2 mL) was stirred at 110oC for 3 hours. The reaction mixture was cooled, diluted in EA, and extracted in 0.1N hydrochloride solution. The aqueous layer was basified by sat. NaHCO3, extracted in EA, dried over MgSO4, and then concentrated. The crude product was purified by silica gel column chromatography (EA / n-Hex = 30-100%, MeOH / DCM = 0-10%) to yield (S)-2-(4'-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol (207.7 mg, 0.3941 mmol, 66.722% yield) as a brown foam.1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 2H), 8.04-8.03 (m, 1H), 7.95-7.93 (m, 2H), 7.45 (d, 1H), 6.68 (s, 1H), 6.13 (d, 1H), 4.71 (s, 2H), 4.53-4.50 (m, 1H), 4.39-4.35 (m, 1H), 3.98-3.95 (m, 1H), 3.69 (s, 3H), 2.31-2.27 (m, 1H), 2.03-2.00 (m, 1H), 1.51 (d, 6H), 1.33 (d, 3H); MS (ESI) m / z = 527.2 (M + H)+

[0703] Step 5. (S)-2-(6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)propan-2-ol

[0704] The suspension of (S)-2-(4'-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-5-yl)propan-2-ol (50 mg, 0.095 mmol) prepared in step 4, Cs2CO3(92.74 mg, 0.285 mmol), Pd2(dba)3(17.38 mg, 0.019 mmol), XPhos (18.09 mg, 0.038 mmol) in 1,4-dioxane (1 mL) was stirred at room temperature for 30 minutes and then stirred at 130oC for 3 hours. The reaction mixture was cooled, diluted in DCM, filtered through Celite, and then concentrated. The crude product was purified by silica gel column chromatography (MeOH / EA = 0-10%) and triturated by EA / iPro2O to yield (S)-2-(6-(11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)propan-2-ol (12.1 mg, 0.0247 mmol, 25.999% yield) as an off-white solid.1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.42 (s, 2H), 8.34 (d, 1H), 8.27 (m, 1H), 8.16 (s, 1H), 7.72 (d, 1H), 7.57 (brs, 1H), 6.40 (d, 1H), 4.85 (t, 1H), 4.40-4.20 (m, 1H), 4.13-4.11 (m, 1H), 3.83 (s, 3H), 2.23-2.15 (m, 2H), 1.70 (s, 6H), 1.45 (d, 3H); MS (ESI) m / z = 491.2 (M + H)+

[0705] Example 9. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0706] Step 1. (S)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0707] The mixture of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (90.00 mg, 0.284 mmol) prepared in Reference Example 21, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (54.33 mg, 0.284 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.27 mL, 0.882 mmol) in　toluene (1 mL) was stirred at 100oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (120.00 mg, 0.245 mmol, 86.02% yield).1H-NMR (CD3OD, 400MHz) δ 8.36 (s, 1H), 8.31 (d, 1H), 8.11 (s, 1H), 7.93 (d, 1H), 7.82 (s, 1H), 7.52 (t, 1H), 7.00 (s, 1H), 6.81 (s, 1H), 6.23 (d, 1H), 4.51-4.48 (m, 2H), 4.05-4.02 (m, 1H), 3.65 (s, 3H), 2.20-2.12 (m, 2H), 1.37 (d, 3H); MS (ESI) m / z = 490.1 (M + H)+

[0708] Step 2. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0709] The mixture of (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (136.10 mg, 0.278 mmol) prepared in step 1, cesium carbonate (271.56 mg, 0.833 mmol), XPhos (52.98 mg, 0.111 mmol), and Pd2(dba)3(50.88 mg, 0.056 mmol) in 1,4-dioxane (3 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (33.00 mg, 0.073 mmol, 26.20% yield).1H-NMR (CD3OD, 400MHz) δ 8.33 (d, 2H), 8.25 (d, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.58 (t, 1H), 6.96 (s, 1H), 6.69 (d, 1H), 4.75-4.70 (m, 1H), 4.27-4.22 (m, 2H), 3.81 (s, 3H), 2.30-2.20 (m, 2H), 1.49 (d, 3H); MS (ESI) m / z = 454.0 (M + H)+

[0710] Example 10. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0711] Step 1. 4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol

[0712] The mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (500.00 mg, 2.019 mmol) prepared in Reference Example 1, 4-aminopentan-1-ol (208.32 mg, 2.019 mmol), and DIPEA (0.56 mL, 4.039 mmol) in DMA (5 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol (400.00 mg, 1.209 mmol, 59.89% yield).1H-NMR (CD3OD, 400MHz) δ 8.37 (s, 1H), 8.31 (d, 1H), 7.60 (t, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 3.79-3.73 (m, 1H), 3.61-3.58 (m, 2H), 1.74-1.63 (m, 4H), 1.29 (d, 3H); MS (ESI) m / z = 331.1 (M + H)+

[0713] Step 2. 2-(5-((4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0714] The mixture of 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol (93.00 mg, 0.281 mmol) prepared in step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (64.51 mg, 0.337 mmol) prepared in Reference Exmaple 23, DEAD (244.83 mg, 0.562 mmol) and PPh3(110.62 mg, 0.422 mmol) in THF (4 mL) was stirred at 80oC for 4 hours. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (7.00 mg, 0.014 mmol, 4.94% yield). MS (ESI) m / z = 504.1 (M + H)+

[0715] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0716] The mixture of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (19.00 mg, 0.038 mmol) prepared in step 2, cesium carbonate (36.85 mg, 0.113 mmol), XPhos (7.19 mg, 0.015 mmol), and Pd2(dba)3(6.91 mg, 0.008 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 5 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield 45-(1-(difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane (3.30 mg, 0.007 mmol, 18.72% yield).1H-NMR (CD3OD, 400MHz) δ 8.36-8.34 (m, 2H), 8.29 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.60 (t, 1H), 6.98 (s, 1H), 6.76 (d, 1H), 4.54-4.44 (m, 2H), 4.13-4.11 (m, 1H), 3.80 (s, 3H), 2.13-2.00 (m, 3H), 1.48 (d, 3H); MS (ESI) m / z = 468.1 (M + H)+

[0717] Example 11. (61S,63R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane

[0718] Step 1. ((1R,3S)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methanol

[0719] The title compound as a white solid (130.00 mg, 0.379 mmol, 93.91% yield) was prepared in the same fashion as step 1 in Example 10 except that ((1R,3S)-3-aminocyclopentyl)methanol (46.51 mg, 0.404 mmol) was used instead of 4-aminopentan-1-ol.1H-NMR (CD3OD, 400MHz) δ 8.41 (d, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 7.59 (t, 1H), 7.02 (s, 1H), 6.75 (s, 1H), 4.05-4.00 (m ,1H), 3.54 (d, 2H), 2.41-2.2 3(m, 2H), 2.14-2.07 (m, 1H), 1.93-1.86 (m, 1H), 1.73-1.68 (m, 1H), 1.62-1.54 (m, 1H), 1.42-1.35 (m, 1H); MS (ESI) m / z = 343.1 (M + H)+

[0720] Step 2. 2-(5-(((1R,3S)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0721] The title compound as a white solid (41.00 mg, 0.079 mmol, 54.48% yield) was prepared in the same fashion as step 1 in Example 9 except that ((1R,3S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methanol (50.00 mg, 0.146 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol.1H-NMR (CD3OD, 400MHz) δ 8.39 (d, 1H), 8.34 (s, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.84 (s, 1H), 7.48 (t, 1H), 6.97 (s, 1H), 6.75 (s, 1H), 6.26 (d, 1H), 4.32-4.25 (m, 2H), 4.08-4.05 (m, 1H), 3.65 (s, 3H), 2.63-2.59 (m, 1H), 2.46-2.39 (m, 1H), 2.17-2.13 (m, 1H), 2.05-1.98 (m, 1H), 1.82-1.74 (m, 1H), 1.63-1.56 (m, 1H); MS (ESI) m / z = 516.1 (M + H)+

[0722] Step 3. (61S,63R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane

[0723] The title compound as a white solid (2.50 mg, 0.005 mmol, 4.48% yield) was prepared in the same fashion as step 3 in Example 10 except that 2-(5-(((1R,3S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)cyclopentyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (60.00 mg, 0.116 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CD3OD, 400MHz) δ 8.37 (s, 1H), 8.30 (d, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.60 (t, 1H), 7.29 (s, 1H), 6.98 (s, 1H), 6.74 (d, 1H), 4.60-4.55 (m, 1H), 4.26-4.21 (m, 1H), 4.13-4.09 (m, 1H), 3.73 (s, 3H), 2.72-2.67 (m, 2H), 2.44-2.39 (m, 1H), 2.15-2.04 (m, 2H), 1.87-1.80 (m, 1H), 1.75-1.70 (m, 2H); MS (ESI) m / z = 480.1 (M + H)+

[0724] Example 12. (R)-45-(3-Fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0725] Step 1. 6'-Chloro-3,4'-difluoro-2,3'-bipyridine

[0726] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-fluoropyridine (170.86 mg, 0.971 mmol), 1 M K2CO3soln. (2.91 mL, 2.913 mmol) and Pd(dppf)Cl2(118.93 mg, 0.046 mmol) in 1,4-dioxane (3 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 6'-chloro-3,4'-difluoro-2,3'-bipyridine (99.00 mg, 0.437 mmol, 45.00% yield).1H-NMR (CD3OD, 400MHz) δ 8.64-8.58 (m, 2H), 7.83-7.78 (m, 1H), 7.63-7.54 (m, 2H); MS (ESI) m / z = 227.1 (M + H)+

[0727] Step 2. (R)-3-((6'-Chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0728] The mixture of 6'-chloro-3,4'-difluoro-2,3'-bipyridine (104.45 mg, 0.461 mmol) prepared in step 1, (R)-3-aminobutan-1-ol (49.30 mg, 0.553 mmol), and DIPEA (0.13 mL, 0.922 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (R)-3-((6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (90 mg, 0.034 mmol, 66.02% yield).1H-NMR (CD3OD, 400MHz) δ 8.49 (s, 1H), 8.14 (s, 1H), 7.80-7.73 (m, 1H), 7.49-7.45 (m, 1H), 6.83 (s, 1H), 3.89-3.84 (m, 1H), 3.71-3.62 (m, 2H), 1.80-1.75 (m, 2H), 1.25 (d, 3H); MS (ESI) m / z = 296.1 (M + H)+

[0729] Step 3. (R)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-amine

[0730] The title compound as a white solid (136.00 mg, 0.290 mmol, 89.27% yield) was prepared in the same fashion as step 1 in Example 9 except that (R)-3-((6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (96.09 mg, 0.325 mmol) prepared in step 2 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol.1H-NMR (CD3OD, 400MHz) δ 8.29 (d, 1H), 8.08 (s, 1H), 7.91 (d, 1H), 7.84 (s, 1H), 7.63-7.58 (m ,1H), 7.34-7.30 (m, 1H), 6.87 (s, 1H), 6.24 (d, 1H), 4.49-4.38 (m, 2H), 4.06-4.03 (m, 1H), 3.66 (s, 3H), 2.23-2.01 (m, 2H), 1.33 (d, 3H); MS (ESI) m / z = 469.1 (M + H)+

[0731] Step 4. (R)-45-(3-Fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0732] The title compound as a white solid (18.70 mg, 0.043 mmol, 14.86% yield) was prepared in the same fashion as step 3 in Example 10 except that (R)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4'-amine (136.50 mg, 0.291 mmol) prepared in step 3 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CD3OD, 400MHz) δ 8.52 (d, 1H), 8.30-8.28 (m, 3H), 8.20 (d, 1H), 7.92 (s, 1H), 7.89-7.84 (m, 1H), 7.75 (d, 1H), 7.46-7.43 (m, 1H), 6.78 (d, 1H), 4.55-4.51 (m, 1H), 4.32-4.30 (m, 1H), 4.06-4.03 (m, 1H), 2.16-1.97 (m, 2H), 1.34 (d, 3H); MS (ESI) m / z = 433.1 (M + H)+

[0733] Example 13. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0734] Step 1. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropan-1-ol

[0735] The mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (150.00 mg, 0.606 mmol) prepared in Reference Example 1, 3-amino-2-methylpropan-1-ol (64.80 mg, 0.727 mmol), and DIPEA (0.17 mL, 1.212 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropan-1-ol (130.00 mg, 0.410 mmol, 67.75% yield).1H-NMR (CD3OD, 400MHz) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.59 (t, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 3.63-3.52 (m, 2H), 3.41-3.18 (m, 3H), 1.06 (d, 3H); MS (ESI) m / z = 317.1 (M + H)+

[0736] Step 2. 2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0737] The title compound as a white solid (104.00 mg, 0.212 mmol, 65.34% yield) was prepared in the same fashion as step 1 in Example 9 except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropan-1-ol (102.91 mg, 0.325 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol.1H-NMR (CD3OD, 400MHz) δ 8.35 (s, 1H), 8.09 (s, 1H), 7.92 (d, 1H), 7.84 (s, 1H), 7.42 (t, 1H), 6.98 (s, 1H), 6.78 (s, 1H), 6.23 (d, 3H), 4.37-4.29 (m, 2H), 3.67 (s, 3H), 3.56-3.35 (m, 2H), 2.50-2.42 (m, 1H), 1.20 (d, 3H); MS (ESI) m / z = 490.1 (M + H)+

[0738] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0739] The title compound as a white solid (23.30 mg, 0.051 mmol, 17.65% yield) was prepared in the same fashion as step 3 in Example 10 except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (142.61 mg, 0.291 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400MHz) δ 8.45 (s, 1H), 8.34-8.24 (m, 3H), 7.94 (s, 1H), 7.88 (t, 1H), 7.14 (s, 1H), 6.78 (d, 1H), 4.37-4.32 (m, 1H), 4.13-4.11 (m, 1H), 3.78 (s, 3H), 3.70-3.32 (m, 2H), 1.99 (d, 3H); MS (ESI) m / z = 454.1 (M + H)+

[0740] Example 14. 45-(3-Methoxypyridin-2-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0741] Step 1. 3-((6'-Chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)propan-1-ol

[0742] The mixture of 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (100.00 mg, 0.419 mmol) prepared in Reference Example 22, 3-aminopropan-1-ol (31.47 mg, 0.419 mmol), and DIPEA (0.12 mL, 0.838 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield 3-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)propan-1-ol (90.00 mg, 0.306 mmol, 73.12% yield). MS (ESI) m / z = 294.0 (M + H)+

[0743] Step 2.N-(3-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)-6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-amine

[0744] The title compound as a white solid (100.00 mg, 0.214 mmol, 59.91% yield) was prepared in the same fashion as step 1 in Example 9 except that 3-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)propan-1-ol (105.02 mg, 0.358 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z = 467.0 (M + H)+

[0745] Step 3. 45-(3-Methoxypyridin-2-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0746] The title compound as a white solid (10.00 mg, 0.023 mmol, 32.81% yield) was prepared in the same fashion as step 3 in Example 10 except thatN-(3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)-6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-amine (33.06mg, 0.071 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400MHz) δ 8.26 (s, 1H), 8.23-8.21 (m, 2H), 8.00 (s, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.43-7.39 (m, 1H), 6.66 (d, 1H), 4.43-4.41 (m, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.58-3.57 (m, 2H), 2.14-2.13 (m, 2H); MS (ESI) m / z = 431.0 (M + H)+

[0747] Example 15. (S)-45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0748] Step 1. (S)-3-((6'-Chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0749] The mixture of 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (100.00 mg, 0.419 mmol) prepared in Reference Example 22, (S)-3-aminobutan-1-ol (37.35 mg, 0.419 mmol), and DIPEA (0.12 mL, 0.838 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (S)-3-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (113.00 mg, 0.367 mmol, 87.62% yield). MS (ESI) m / z = 308.0 (M + H)+

[0750] Step 2. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-amine

[0751] The title compound as a white solid (137.00 mg, 0.285 mmol, 79.68% yield) was prepared in the same fashion as step 1 in Example 9 except that (S)-3-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (110.03 mg, 0.358 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z = 481.0 (M + H)+

[0752] Step 3. (S)-45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0753] The title compound as a white solid (10.08 mg, 0.024 mmol, 34.31% yield) was prepared in the same fashion as step 3 in Example 10 except that (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-amine (34.06 mg, 0.071 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CD3OD, 400MHz) δ 8.28 (s, 1H), 8.22-8.20 (m, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.59 (d, 1H), 7.41-7.38 (m, 1H), 6.65 (d, 1H), 4.71-4.66 (m, 1H), 4.18-4.08 (m, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 2.17-2.01 (m, 2H), 1.31 (d, 3H); MS (ESI) m / z = 445.1 (M + H)+

[0754] Example 16. 45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0755] Step 1. 4-((6'-Chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)pentan-1-ol

[0756] The mixture of 6'-chloro-4'-fluoro-3-methoxy-2,3'-bipyridine (100.00 mg, 0.419 mmol) prepared in Reference Example 22, 4-aminopentan-1-ol (43.23 mg, 0.419 mmol), and DIPEA (0.12 mL, 0.838 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield 4-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)pentan-1-ol (89.00 mg, 0.277 mmol, 66.00% yield). MS (ESI) m / z = 322.0 (M + H)+

[0757] Step 2.N-(5-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentan-2-yl)-6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-amine

[0758] The title compound as a white solid (32.00 mg, 0.065 mmol, 18.08% yield) was prepared in the same fashion as step 1 in Example 9 except that 4-((6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)pentan-1-ol (115.04 mg, 0.358 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z = 495.0 (M + H)+

[0759] Step 3. 45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0760] The title compound as a white solid (4.01 mg, 0.009 mmol, 12.63% yield) was prepared in the same fashion as step 3 in Example 10 except thatN-(5-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)pentan-2-yl)-6'-chloro-3-methoxy-[2,3'-bipyridin]-4'-amine (35.05 mg, 0.071 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CD3OD, 400MHz) δ 8.28 (d, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.60 (d, 1H), 7.43-7.40 (m, 1H), 6.75 (d, 1H), 4.59-4.55 (m, 1H), 4.35-4.09 (m, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 2.07-2.00 (m, 2H), 1.94-1.92 (m, 1H), 1.62-1.55 (m, 1H), 1.31 (d, 3H); MS (ESI) m / z = 459.1 (M + H)+

[0761] Example 17. (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0762] Step 1. (R)-4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutan-1-ol

[0763] The mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (150.00 mg, 0.606 mmol) prepared in Reference Example 1, (R)-4-amino-2-methylbutan-1-ol (75.00 mg, 0.727 mmol), and DIPEA (0.17 mL, 1.212 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutan-1-ol (190.00 mg, 0.574 mmol, 94.82% yield).1H-NMR (CD3OD, 400MHz) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.59 (t, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 3.63-3.52 (m, 2H), 3.41-3.18 (m, 3H), 1.06 (d, 3H); MS (ESI) m / z = 331.1 (M + H)+

[0764] Step 2. (R)-2-(5-(4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0765] The title compound as a white solid (15.00 mg, 0.030 mmol, 4.48% yield) was prepared in the same fashion as step 1 in Example 9 except that (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutan-1-ol (220.00 mg, 0.665 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z = 504.1 (M + H)+

[0766] Step 3. (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0767] The title compound as a white solid (7.90 mg, 0.017 mmol, 13.52% yield) was prepared in the same fashion as step 3 in Example 10 except that (R)-2-(5-(4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (63.00 mg, 0.125 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CD3OD, 400MHz) δ 8.28 (s, 1H), 8.24-8.22 (m, 2H), 8.09 (s,1H), 7.94 (s, 1H), 7.58 (t, 1H), 6.92 (s, 1H), 6.70 (d, 1H), 4.12-4.08 (m, 2H), 3.94-3.92 (m, 1H), 3.78 (s, 3H), 3.70-3.66 (m, 1H), 2.23-2.21 (m, 1H), 2.04-2.00 (m, 1H), 1.91-1.76 (m, 2H), 1.01 (d, 3H); MS (ESI) m / z = 468.1 (M + H)+

[0768] Example 18. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0769] Step 1. (R)-4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-ol

[0770] The mixture of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (130.00 mg, 0.525 mmol) prepared in Reference Example 1, (R)-4-aminobutan-2-ol (56.16 mg, 0.630 mmol), and DIPEA (0.15 mL, 1.050 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-ol (95.00 mg, 0.300 mmol, 57.13% yield). MS (ESI) m / z = 317.1 (M + H)+

[0771] Step 2. (S)-2-(5-((4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0772] The title compound as a white solid (75.00 mg, 0.153 mmol, 37.30% yield) was prepared in the same fashion as step 1 in Example 9 except that (R)-4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-ol (130.00 mg, 0.410 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol. MS (ESI) m / z = 490.1 (M + H)+

[0773] Step 3. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0774] The title compound as a white solid (12.10 mg, 0.027 mmol, 17.43% yield) was prepared in the same fashion as step 3 in Example 10 except that (S)-2-(5-((4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75.00 mg, 0.153 mmol) prepared in step 2 was used instead of 2-(5-((4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400MHz) δ 8.42 (s, 1H), 8.32-8.30 (m, 2H), 8.23 (s, 1H), 8.17-8.13 (m, 1H), 7.86 (d, 1H), 7.27 ( t, 1H), 6.81 (d, 1H), 6.37 (d, 1H), 5.55-5.50 (m, 1H), 4.12-4.08 (m, 1H), 3.76 (s, 3H), 3.60-3.56 (m, 1H), 2.30-2.26 (m, 1H), 1.98-1.91 (m, 1H), 1.10 (d, 3H); MS (ESI) m / z = 454.1 (M + H)+

[0775] Example 19. (S)-45-(3-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0776] Step 1. 6'-Chloro-3-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine

[0777] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-(difluoromethoxy)pyridine (231.1 mg, 0.971 mmol), 1 M K2CO3soln. (2.91 ml, 2.913 mmol) and Pd(dppf)Cl2(118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 6'-chloro-3-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine (121.00 mg, 0.441 mmol, 45.38% yield).1H-NMR (CDCl3, 400MHz) δ 8.63-8.56 (m, 2H), 7.68 (d, 1H), 7.46-7.43 (m, 1H), 7.22 (d, 1H), 6.50 (t, 1H); MS (ESI) m / z = 275.1 (M + H)+

[0778] Step 2. (S)-3-((6'-Chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0779] The mixture of 6'-chloro-3-(difluoromethoxy)-4'-fluoro-2,3'-bipyridine (121.00 mg, 0.441 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (39.27 mg, 0.441 mmol), and DIPEA (0.12 mL, 0.881 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (S)-3-((6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (150.00 mg, 0.436 mmol, 99.04% yield). MS (ESI) m / z = 344.0 (M + H)+

[0780] Step 3. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-amine

[0781] The mixture of (S)-3-((6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (141.09 mg, 0.410 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.47 mg, 0.410 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.437 mmol) in　toluene (1 mL) was stirred at 130oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-amine (75.00 mg, 0.153 mmol, 37.30% yield). MS (ESI) m / z = 490.1 (M + H)+

[0782] Step 4. (S)-45-(3-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0783] The mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(difluoromethoxy)-[2,3'-bipyridin]-4'-amine (75.00 mg, 0.153 mmol) prepared in step 3, cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3(28.04 mg, 0.031 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield (S)-45-(3-(difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (9.7 mg, 0.020 mmol, 13.19% yield).1H-NMR (CDCl3, 400MHz) δ 8.55-8.53 (m, 1H), 8.41 (s, 1H), 8.30 (d, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.70-7.68 (m, 1H), 7.32-7.29 (m, 1H), 7.05 (d, 1H), 6.45 (t, 1H), 6.41 (d, 1H), 4.85-4.81 (m, 1H), 4.29-4.27 (m, 1H), 4.10-4.07 (m, 1H), 3.80 (s, 3H), 2.17-2.12 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z = 481.1 (M + H)+

[0784] Example 20. (S)-11,6-Dimethyl-45-(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0785] Step 1. 6'-Chloro-4'-fluoro-3-(2,2,2-trifluoroethoxy)-2,3'-bipyridine

[0786] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-(2,2,2-trifluoroethoxy)pyridine (234.94 mg, 0.971 mmol), 1 M K2CO3soln. (2.91 mL, 2.913 mmol) and Pd(dppf)Cl2(118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 6'-chloro-4'-fluoro-3-(2,2,2-trifluoroethoxy)-2,3'-bipyridine (152.00 mg, 0.496 mmol, 51.06% yield).1H-NMR (CDCl3, 400MHz) δ 8.57 (d, 1H), 8.46 (d, 1H), 7.43-7.34 (m, 2H), 7.19 (d, 1H), 4.44-4.38 (m, 2H); MS (ESI) m / z = 242.1 (M + H)+

[0787] Step 2. (S)-3-((6'-Chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0788] The mixture of 6'-chloro-4'-fluoro-3-(2,2,2-trifluoroethoxy)-2,3'-bipyridine (135.10 mg, 0.441 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (39.27 mg, 0.441 mmol), and DIPEA (0.12 mL, 0.881 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (S)-3-((6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (164.00 mg, 0.436 mmol, 99.06% yield). MS (ESI) m / z = 376.0 (M + H)+

[0789] Step 3. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-amine

[0790] The mixture of (S)-3-((6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (154.23 mg, 0.410 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.47 mg, 0.410 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.437 mmol) in　toluene (1 mL) was stirred at 130oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-amine (113.00 mg, 0.206 mmol, 50.15% yield). MS (ESI) m / z = 549.1 (M + H)+

[0791] Step 4. (S)-11,6-Dimethyl-45-(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0792] The mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-4'-amine (84.04 mg, 0.153 mmol) prepared in step 3, cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3(28.04 mg, 0.031 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield (S)-11,6-dimethyl-45-(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (29.30 mg, 0.057 mmol, 37.35% yield).1H-NMR (CDCl3, 400MHz) δ 8.40-8.37 (m, 3H), 8.27 (d, 1H), 8.12 (s, 1H), 7.40-7.38 (m, 1H), 7.33 (d, 1H), 7.26-7.24 (m, 1H), 6.39 (d, 1H), 4.85-4.79 (m, 1H), 4.36-4.24 (m, 3H), 4.10-4.05 (m, 1H), 3.79 (s, 3H), 2.21-2.07 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z = 513.1 (M + H)+

[0793] Example 21. (S)-45-(5-Fluoro-3-methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0794] Step 1. 6'-Chloro-4',5-difluoro-3-methoxy-2,3'-bipyridine

[0795] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-5-fluoro-3-methoxypyridine (200.01mg, 0.971 mmol), 1 M K2CO3soln. (2.91 mL, 2.913 mmol) and Pd(dppf)Cl2(118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 6'-chloro-4',5-difluoro-3-methoxy-2,3'-bipyridine (105.00 mg, 0.409 mmol, 42.14% yield).1H-NMR (CDCl3, 400MHz) δ 8.51 (d, 1H), 8.23 (s, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 3.87 (s, 3H); MS (ESI) m / z = 257.1 (M + H)+

[0796] Step 2. (S)-3-((6'-Chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0797] The mixture of 6'-chloro-4',5-difluoro-3-methoxy-2,3'-bipyridine (113.07 mg, 0.441 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (39.27 mg, 0.441 mmol), and DIPEA (0.12 mL, 0.881 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (S)-3-((6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (133.00 mg, 0.408 mmol, 92.66% yield). MS (ESI) m / z = 326.0 (M + H)+

[0798] Step 3. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-amine

[0799] The mixture of (S)-3-((6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (133.71 mg, 0.410 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (78.47 mg, 0.410 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.437 mmol) in　toluene (1 mL) was stirred at 130oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-amine (129.00 mg, 0.259 mmol, 62.99% yield). MS (ESI) m / z = 499.1 (M + H)+

[0800] Step 4. (S)-45-(5-Fluoro-3-methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0801] The mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-5-fluoro-3-methoxy-[2,3'-bipyridin]-4'-amine (76.38 mg, 0.153 mmol) prepared in step 3, cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3(28.04 mg, 0.031 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield (S)-45-(5-fluoro-3-methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (5.40 mg, 0.012 mmol, 7.63% yield).1H-NMR (CDCl3, 400MHz) δ 8.40 (s, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.16 (d, 1H), 8.13 (s, 1H), 7.14-7.11 (m, 1H), 7.05 (d, 1H), 6.40 (d, 1H), 4.87-4.82 (m, 1H), 4.30-4.24 (m, 1H), 4.11-4.05 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.15-2.11 (m, 2H), 1.37 (d, 3H); MS (ESI) m / z = 463.1 (M + H)+

[0802] Example 22. (S)-45-(3-(2,2-Difluoroethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0803] Step 1. 6'-Chloro-3-(2,2-difluoroethoxy)-4'-fluoro-2,3'-bipyridine

[0804] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromo-3-(2,2-difluoroethoxy)pyridine (231.10 mg, 0.971 mmol), 1 M K2CO3soln. (2.91 mL, 2.913 mmol) and Pd(dppf)Cl2(118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 6'-chloro-3-(2,2-difluoroethoxy)-4'-fluoro-2,3'-bipyridine (138.00 mg, 0.478 mmol, 49.24% yield). MS (ESI) m / z = 289.1 (M + H)+

[0805] Step 2. (S)-3-((6'-Chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0806] The mixture of 6'-chloro-3-(2,2-difluoroethoxy)-4'-fluoro-2,3'-bipyridine (150.00 mg, 0.520 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (50.95 mg, 0.572 mmol), and DIPEA (0.15 mL, 1.039 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (S)-3-((6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (130.00 mg, 0.363 mmol, 69.92% yield). MS (ESI) m / z = 358.0 (M + H)+

[0807] Step 3. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-amine

[0808] The mixture of (S)-3-((6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (133.00 mg, 0.372 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (71.07 mg, 0.372 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.36 mL, 1.301 mmol) in　toluene (1 mL) was stirred at 130oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-amine (49.00 mg, 0.092 mmol, 24.83% yield). MS (ESI) m / z = 531.1 (M + H)+

[0809] Step 4. (S)-45-(3-(2,2-Difluoroethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0810] The mixture of (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-(2,2-difluoroethoxy)-[2,3'-bipyridin]-4'-amine (81.28 mg, 0.153 mmol) prepared in step 3, cesium carbonate (149.64 mg, 0.459 mmol), XPhos (29.19 mg, 0.061 mmol), and Pd2(dba)3(28.04 mg, 0.031 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield (S)-45-(3-(2,2-difluoroethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (9.10 mg, 0.018 mmol, 12.02% yield).1H-NMR (CDCl3, 400MHz) δ 8.39 (s, 1H), 8.36-8.34 (m, 2H), 8.29 (d, 1H), 8.14 (s, 1H), 7.40-7.23 (m, 2H), 6.38 (d, 1H), 6.22-5.94 (m, 1H), 4.86-4.80 (m, 1H), 4.28-4.16 (m, 3H), 4.11-4.07 (m, 1H), 3.80 (s, 3H), 2.19-2.11 (m, 2H), 1.38 (d, 3H); MS (ESI) m / z = 495.1 (M + H)+

[0811] Example 23. (S)-11,6-Dimethyl-45-(pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0812] Step 1. 2-(6-Chloro-4-fluoropyridin-3-yl)pyrazine

[0813] The mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250.00 mg, 0.971 mmol), 2-bromopyrazine (154.35 mg, 0.971 mmol), 1 M K2CO3soln. (2.91 mL, 2.913 mmol) and Pd(dppf)Cl2(118.93 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was stirred at 90oC for 2 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 2-(6-chloro-4-fluoropyridin-3-yl)pyrazine (54.00 mg, 0.258 mmol, 26.53% yield). MS (ESI) m / z = 210.1 (M + H)+

[0814] Step 2. (S)-3-((2-Chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol

[0815] The mixture of 2-(6-chloro-4-fluoropyridin-3-yl)pyrazine (54.00 mg, 0.258 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (27.56 mg, 0.309 mmol), and DIPEA (0.07 mL, 0.515 mmol) in DMA (3 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield (S)-3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (50.00 mg, 0.179 mmol, 69.63% yield). MS (ESI) m / z = 279.0 (M + H)+

[0816] Step 3. (S)-2-(5-(3-((2-Chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0817] The mixture of (S)-3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (100.00 mg, 0.359 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (68.59 mg, 0.359 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.34 mL, 1.256 mmol) in　toluene (1 mL) was stirred at 130oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield (S)-2-(5-(3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.00 mg, 0.111 mmol, 30.84% yield).1H-NMR (CDCl3, 400MHz) δ 9.02 (s, 1H), 8.85 (d, 1H), 8.48-8.46 (m, 2H), 8.38-8.37 (m, 1H), 8.09 (d, 1H), 7.98 (s, 1H), 6.72 (s, 1H), 6.15 (d, 1H), 4.94 (s, 2H), 4.56-4.42 (m, 2H), 3.99-3.96 (m, 1H), 2.17-2.12 (m, 2H), 1.39 (d, 3H); MS (ESI) m / z = 452.1 (M + H)+

[0818] Step 4. (S)-11,6-Dimethyl-45-(pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0819] The mixture of (S)-2-(5-(3-((2-chloro-5-(pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.00 mg, 0.111 mmol) prepared in step 3, cesium carbonate (108.15 mg, 0.332 mmol), XPhos (21.10 mg, 0.044 mmol), and Pd2(dba)3(20.26 mg, 0.022 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield (S)-11,6-dimethyl-45-(pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (2.00 mg, 0.005 mmol, 4.35% yield).1H-NMR (DMSO-d6, 400MHz) δ 9.29 (s, 1H), 8.97 (d, 1H), 8.67 (s, 1H), 8.63-8.62 (m, 1H), 8.51 (d, 1H), 8.31-8.29 (m, 1H), 7.93 (s, 1H), 6.81 (d, 1H), 4.57-4.52 (m, 1H), 4.37-4.33 (m, 1H), 4.11-4.08 (m, 1H), 3.80 (s, 3H), 2.20-2.18 (m, 1H), 2.06-2.03 (m, 1H), 1.42 (d, 3H); MS (ESI) m / z = 416.1 (M + H)+

[0820] Example 24. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-7-(trifluoromethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0821] Step 1. 2-(((2-Chloro-5-iodopyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol

[0822] The mixture of 2-chloro-4-fluoro-5-iodopyridine (500.00 mg, 1.942 mmol), 2-(aminomethyl)-3,3,3-trifluoropropan-1-ol (277.96 mg, 1.942 mmol), and DIPEA (0.68 mL, 3.885 mmol) in DMA (7 mL) was stirred at 80oC for overnight. After the reaction mixture was cooled, diluted in EA, washed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-15%) to yield 2-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (640.00 mg, 1.682 mmol, 86.59% yield). MS (ESI) m / z = 381.1 (M + H)+

[0823] Step 2. 2-(((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol

[0824] The mixture of 2-(((2-Chloro-5-iodopyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (639.80 mg, 1.681 mmol) prepared in step 1, 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (533.43 mg, 2.186 mmol), 1 M K2CO3soln. (5.04 mL, 5.04 mmol) and Pd(dppf)Cl2(68.65 mg, 0.084 mmol) in 1,4-dioxane (5 mL) was stirred at 70oC for 4 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (Hexane / EA = 0-30%) to yield 2-(((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (284.00 mg, 0.766 mmol, 45.56% yield).1H-NMR (CD3OD, 400MHz) δ 8.42 (s, 1H), 8.17 (s, 1H), 7.56 (t, 1H), 7.04 (d, 1H), 6.89 (s, 1H), 3.95-3.80 (m, 2H), 3.77-3.68 (m, 2H), 2.79-2.69 (m, 1H); MS (ESI) m / z = 371.1 (M + H)+

[0825] Step 3. 2-(5-(2-(((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0826] The mixture of 2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropan-1-ol (243.93 mg, 0.658 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (125.80 mg, 0.658 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (0.63 mL, 2.303 mmol) in　toluene (2 mL) was stirred at 130oC for 3 hours. After completion of the reaction, volatiles were removed and the crude was purified by column chromatography (MeOH / DCM = 0-10%) to yield 2-(5-(2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (22.00 mg, 0.040 mmol, 6.15% yield).1H-NMR (CD3OD, 400MHz) δ 8.41 (s, 1H), 8.12 (s, 1H), 7.91-7.87 (m, 2H), 7.39 (t, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 6.22 (d, 1H), 8.09 (d, 1H), 4.81-4.67 (m, 2H), 3.97-3.86 (m, 2H); MS (ESI) m / z = 544.1 (M + H)+

[0827] Step 4. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-7-(trifluoromethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0828] The mixture of 2-(5-(2-(((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)methyl)-3,3,3-trifluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (22.00 mg, 0.040 mmol) prepared in step 3, cesium carbonate (39.54 mg, 0.121 mmol), XPhos (7.71 mg, 0.016 mmol), and Pd2(dba)3(7.41 mg, 0.008 mmol) in 1,4-dioxane (2 mL) was stirred at 130oC for 3 hours. The reaction mixture was cooled, filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-20%) to yield 45-(1-(difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-7-(trifluoromethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (8.50 mg, 0.017 mmol, 41.41% yield).1H-NMR (CD3OD, 400MHz) δ 8.33 (s, 1H), 8.24-8.20 (m, 2H), 8.09-8.05 (m, 2H), 7.57 (t, 1H), 6.92 (d, 1H), 6.65 (d, 1H), 4.55-4.51 (m, 1H), 4.14-4.10 (m, 1H), 3.84-3.81 (m, 1H), 3.77 (s, 3H), 3.08-3.06 (m, 1H), 1.30-1.24 (m, 1H); MS (ESI) m / z = 508.1 (M + H)+

[0829] Example 25. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane

[0830] Step 1. 2-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol

[0831] To the solution of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine (150 mg, 0.606 mmol) prepared in Reference Example 1 in DMA (3 mL) was added 2-aminoethan-1-ol (47.53 uL, 0.788 mmol) and DIPEA (169.34 uL, 1.212 mmol). The reaction mixture was heated at 70oC for 2 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with EA. The combined organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (EA / n-Hex = 30-100%) to give 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol (156 mg, 0.54 mmol, 89.2% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.84 (t, 1H), 7.18 (s, 1H), 6.77 (s, 1H), 4.91 (t, 1H), 3.62 (q, 1H), 3.35 (t, 2H)

[0832] Step 2. 2-(5-(2-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0833] To the solution of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol (58.29 mg, 0.202 mmol) prepared in step 1 in toluene (1 mL) was added 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (38.6 mg, 0.202 mmol) prepared in Reference Example 23 and (tributylphosphoranylidene)acetonitrile (138.13 uL, 0.505 mmol). The reaction mixture was heated at 120oC for 3 hours. The reaction mixture was concentrated and purified by column chromatography (MeOH / EA = 0-15%) to give 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (20 mg, 0.043 mmol, 21.49% yield) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 2H), 8.17 (d, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.05 (t, 1H), 6.84 (s, 1H), 6.66 (s, 1H), 6.19 (d, 1H), 4.76 (s, 2H), 4.71 (t, 2H), 3.69 (t, 2H), 3.67 (s, 3H)

[0834] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane

[0835] To the solution of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (18 mg, 0.039 mmol) prepared in step 2 in 1,4-dioxane (1 mL) was added Pd2(dba)3(7.14mg, 0.008 mmol), XPhos (7.43mg, 0.016mmol) and Cs2CO3(38.09 mg, 0.117 mmol). The reaction mixture was heated at 100oC for 2 hours. The reaction mixture was added to water and extracted with DCM. The combined organic layer was washed with water, dried over MgSO4, concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / EA = 0-10%) to yield 45-(1-(difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane (5 mg, 0.012 mmol, 30.16% yield) as a white solid.1H-NMR (DMSO-d6, 400 MHz) δ 10.01 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.29 (d, 1H), 7.84 (t, 1H), 7.84 (s, 1H), 7.13 (s, 1H), 6.74 (d, 1H), 4.49 (t, 1H), 3.90 (t, 1H), 3.75 (s, 3H); MS (ESI) m / z = 426.1 (M + H)+

[0836] Example 26. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0837] Step 1. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol

[0838] The title compound as a white solid (158 mg) was prepared in the same fashion as step 1 in Example 25, except that 3-aminopropan-1-ol (92.67 uL, 1.212 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.21 (t, 1H), 6.83 (s, 1H), 6.63 (s, 1H), 3.86 (t, 2H), 3.42 (q, 2H), 1.99 (quin, 2H)

[0839] Step 2. 2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0840] The title compound as a white solid (32.5 mg) was prepared in the same fashion as step 2 in Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propan-1-ol (64.06 mg, 1.212 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (DMSO-d6, 400 MHz) δ 8.51 (s, 1H), 8.37 (s, 1H), 8.37 (t, 1H), 7.97 (d, 1H), 7.78 (t, 1H), 7.76 (s, 1H), 7.19 (s, 1H), 6.80 (s, 1H), 6.66 (s, 2H), 6.16 (d, 1H), 4.46 (t, 2H), 3.61 (s, 3H), 3.53 (q, 2H), 2.12 (t, 2H)

[0841] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0842] The title compound as a white solid (5.4 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (29 mg, 0.061 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400 MHz) δ 9.89 (s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 8.27 (s, 2H), 8.22 (t, 1H), 7.93 (s, 1H), 7.88 (t, 1H), 7.13 (s, 1H), 6.78 (d, 1H), 4.40 (s, 1H), 3.74 (s, 3H), 3.65 (s, 2H), 2.17 (s, 2H); MS (ESI) m / z = 440.1 (M + H)+

[0843] Example 27. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0844] Step 1. 4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol

[0845] The title compound as a white solid (111 mg) was prepared in the same fashion as step 1 in Example 25, except that 4-aminobutan-1-ol (0.07 mL, 0.808 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.23 (t, 1H), 6.83 (s, 1H), 6.59 (s, 1H), 3.75 (s, 2H), 3.30 (q, 2H), 1.88-1.81 (m, 2H), 1.76-1.71 (m, 2H), 1.26 (s, 1H)

[0846] Step 2. 2-(5-(4-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0847] The title compound as a pale brown solid (73 mg) was prepared in the same fashion as step 2 in Example 25, except that 4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (110 mg, 0.347 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (DMSO-d6, 400 MHz) δ 8.52 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.86 (t, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 6.78 (s, 1H), 6.66 (s, 2H), 6.17 (d, 1H), 4.40 (t, 2H), 3.61 (s, 3H), 3.43-3.37 (m, 3H), 0.89 (t, 3H)

[0848] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane

[0849] The title compound as an off white solid (3.8 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(4-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70 mg, 0.143 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.34 (d, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 8.05 (t, 1H), 7.86 (s, 1H), 7.49 (brs, 1H), 7.27 (t, 1H), 6.82 (s, 1H), 6.40 (d, 1H), 4.29 (s, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 1.99-1.95 (m, 4H); MS (ESI) m / z = 454.2 (M + H)+

[0850] Example 28. (S)-11,6-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0851] Step 1. (S)-3-((2-Chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol

[0852] The title compound as a white solid (41.5 mg) was prepared in the same fashion as step 1 in Example 25, except that 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine (52 mg, 0.185 mmol) prepared in Reference Example 26 and (S)-3-aminobutan-1-ol (21.39 mg, 0.24 mmol) were used instead of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine and 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.26 (d, 1H), 8.05 (d, 1H) 6.68 (s, 1H), 5.66 (t, 1H), 5.03 (t, 2H), 4.78 (t, 2H), 3.86-3.81 (m, 3H), 1.85 (q, 2H), 1.30 (s, 3H)

[0853] Step 2. (S)-2-(5-(3-((2-Chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0854] The title compound as a white solid (33 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (40 mg, 0.114 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.25 (s, 1H), 8.12-8.09 (m, 3H), 7.99 (s, 1H), 6.69 (s, 1H), 6.17 (d, 1H), 5.57 (q, 1H), 5.01 (t, 2H), 4.78-4.73 (m, 4H), 4.52-4.43 (m, 2H), 4.41-3.93 (m, 1H), 3.70 (s, 3H), 2.15-2.11 (m, 2H), 1.39 (d, 3H)

[0855] Step 3. (S)-11,6-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0856] The title compound as a white solid (7.4 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-2-(5-(3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (32 mg, 0.061 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400 MHz) δ 9.86 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.27-8.26 (m, 2H), 8.11 (d, 1H) 7.91 (s, 1H), 6.77 (d, 1H), 5.66-5.62 (m, 1H), 4.93 (t, 2H), 4.63 (s, 2H), 4.53 (t, 1H), 4.32 (brs, 1H), 4.04 (brs, 1H), 3.90 (s, 3H), 2.13 (brs, 1H), 2.01 (brs, 1H), 1.37 (s, 3H); MS (ESI) m / z = 488.2 (M + H)+

[0857] Example 29. (6S)-11,6-Dimethyl-45-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0858] Step 1. 2-Bromo-5-((tetrahydrofuran-3-yl)oxy)pyrazine

[0859] The title compound as a white solid (100 mg) was prepared in the same fashion as step 1 in Reference Example 26, except that tetrahydrofuran-3-ol (64.08 uL, 0.42 mmol) was used instead of 3-hydroxyoxetane.1H-NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 8.03 (s, 1H), 5.49 (s, 1H), 4.05-3.98 (m, 2H), 3.94-3.89 (m, 2H), 2.32-2.26 (m, 1H), 2.18-2.13 (m, 1H)

[0860] Step 2. 2-(6-Chloro-4-fluoropyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazine

[0861] The title compound as a white solid (82 mg) was prepared in the same fashion as step 2 in Reference Example 26, except that 2-bromo-5-((tetrahydrofuran-3-yl)oxy)pyrazine (91.22 mg, 0.372 mmol) prepared in step 1 was used instead of 2-bromo-5-(oxetan-3-yloxy)pyrazine.1H-NMR (CDCl3, 400 MHz) δ 9.00 (d, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 7.23 (d, 1H), 5.61 (s, 1H), 4.10-3.92 (m, 4H), 2.38-2.29 (m, 1H), 2.22-2.18 (m, 1H)

[0862] Step 3. (3S)-3-((2-Chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol

[0863] The title compound as a white solid (60 mg) was prepared in the same fashion as step 1 in Example 25, except that 2-(6-chloro-4-fluoropyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazine (54.92 mg, 0.185 mmol) prepared in step 2 and (S)-3-aminobutan-1-ol (21.39 mg, 0.24 mmol) were used instead of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine and 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.03 (d, 1H), 6.68 (s, 1H), 5.59 (s, 1H), 4.08-3.91 (m, 4H), 3.85-3.80 (m, 3H), 2.35-2.30 (m, 1H), 2.20-2.17 (m, 1H), 1.85 (q, 2H), 1.30 (d, 3H)

[0864] Step 4. 2-(5-((3S)-3-((2-Chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0865] The title compound as a white solid (36 mg) was prepared in the same fashion as step 2 in Example 25, except that (3S)-3-((2-chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-1-ol (41.6 mg, 0.114 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.26 (s, 1H), 8.12-8.06 (m, 2H), 8.02 (s, 1H), 7.98 (s, 1H), 6.69 (s, 1H), 6.16 (d, 1H), 5.53 (s, 1H), 4.75-4.73 (m, 2H), 4.50-4.43 (m, 2H), 4.06-3.94 (m, 5H), 3.70 (s, 3H), 2.32-2.28 (m, 1H), 2.18-2.11 (m, 3H), 1.38 (d, 3H)

[0866] Step 5. (6S)-11,6-Dimethyl-45-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0867] The title compound as a white solid (7.7 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-((3S)-3-((2-chloro-5-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (32.86 mg, 0.061 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400 MHz) δ 9.86 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.26 (s, 2H), 8.08 (d, 1H), 7.91 (s, 1H), 6.77 (d, 1H), 5.55 (s, 1H), 4.53 (t, 1H), 4.32-4.30 (m, 1H), 4.04-3.94 (m, 1H), 3.93-3.77 (m, 3H), 3.66 (s, 3H), 2.67-2.28 (m, 1H), 2.26-2.15 (m, 4H), 1.40 (s, 3H); MS (ESI) m / z = 502.2 (M + H)+

[0868] Example 30. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-11-(2,2,2-trifluoroethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0869] Step 1. (S)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

[0870] The title compound as a white solid (34 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (61.1 mg, 0.193 mmol) prepared in Reference Example 21 and 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (50 mg, 0.193 mmol) prepared in Reference Example 34 were used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol.1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.14 (d, 1H), 8.09 (s, 1H), 7.93 (d, 1H), 7.87 (s, 1H), 7.13 (s, 1H), 6.83 (t, 1H), 6.66 (s, 1H), 6.20 (d, 1H), 4.76 (s, 2H), 4.65-4.54 (m, 4H), 3.96-3.93 (m, 2H), 2.19 -2.16 (m, 2H), 1.41 (d, 3H)

[0871] Step 2. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-11-(2,2,2-trifluoroethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0872] The title compound as an off white solid (9.6 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (26 mg, 0.047 mmol) prepared in step 1 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400 MHz) δ 9.95 (s, 1H), 8.47 (s, 1H) 8.32-8.30 (m, 2H), 8.23 (s, 1H), 8.11 (s, 1H), 8.07 (d, 1H), 7.88 (t, 1H), 7.14 (s, 1H), 6.83 (d, 1H), 5.09-4.98 (m, 2H), 4.80 (t, 1H), 4.26-4.24 (m, 1H), 4.11 (brs, 1H), 2.14 (brs, 2H), 1.43 (d, 3H); MS (ESI) m / z = 522.1 (M + H)+

[0873] Example 31. (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0874] Step 1. (R)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol

[0875] The title compound as a white solid (78.6 mg) was prepared in the same fashion as step 1 in Example 25, except that (R)-3-amino-2-fluoropropan-1-ol (79.03 uL, 0.565 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.89 (d, 1H), 7.23 (t, 1H), 6.84 (d, 1H), 6.65 (s, 1H), 4.94-4.77 (m, 1H), 3.97-3.86 (m, 2H), 3.67-3.64 (m, 1H), 3.62-3.59 (m, 1H)

[0876] Step 2. (R)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0877] The title compound as a pale brown solid (53.4 mg) was prepared in the same fashion as step 2 in Example 25, except that (R)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (71 mg, 0.221 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.27 (t, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.89 (d, 1H), 7.15 (t, 1H), 6.85 (d, 1H), 6.67 (s, 1H), 6.20 (d, 1H), 5.31-5.06 (m, 1H), 4.78 (s, 2H), 4.75-4.65 (m, 2H), 3.81-3.73 (m, 5H)

[0878] Step 3. (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0879] The title compound as a white solid (11 mg) was prepared in the same fashion as step 3 in Example 25, except that (R)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50 mg, 0.101 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.36-8.34 (m, 2H), 8.28-8.26 (m, 2H), 8.17 (s, 1H), 7.89 (d, 1H), 7.51 (s, 1H), 7.28 (t, 1H), 6.82 (d, 1H), 6.40 (d, 1H), 5.04-4.91 (m, 1H), 4.84-4.71 (m, 1H), 4.58-4.50 (m, 1H), 4.30-4.24 (m, 1H), 3.85 (s, 3H), 3.73-3.63 (m, 1H); MS (ESI) m / z = 458.0 (M + H)+

[0880] Example 32. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0881] Step 1. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol

[0882] The title compound as a white solid (127 mg) was prepared in the same fashion as step 1 in Example 25, except that 3-amino-2,2-dimethylpropan-1-ol (83.33 mg, 0.808 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.18 (t, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 3.52 (s, 2H), 3.17 (d, 1H), 1.67 (s, 1H), 1.05 (s, 6H)

[0883] Step 2. 2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0884] The title compound as a pale brown solid (44 mg) was prepared in the same fashion as step 2 in Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (55 mg, 0.166 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31 (s, 1H), 8.13 (d, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 6.94 (t, 1H), 6.82 (s, 1H), 6.67 (s, 1H), 6.17 (d, 1H), 4.86 (s, 2H), 4.16 (s, 2H), 3.66 (s, 3H), 3.38 (d, 2H), 1.23 (s, 6H)

[0885] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0886] The title compound as a white solid (4 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (38 mg, 0.075 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.34-8.30 (m, 3H), 8.17 (s, 1H), 8.11 (t, 1H), 7.86 (d, 1H), 7.50 (s, 1H), 7.24 (t, 1H), 6.83 (d, 1H), 6.38 (d, 1H), 4.86 (brs, 1H), 4.30 (brs, 1H), 3.86 (s, 3H), 3.55 (brs, 1H), 2.98 (brs, 1H), 1.42 (brs, 3H), 0.99 (brs, 3H); MS (ESI) m / z = 467.9 (M + H)+

[0887] Example 33. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0888] Step 1. (S)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol

[0889] The title compound as a white solid (78.6 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-amino-2-fluoropropan-1-ol (31.58 mg, 0.339 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.22 (s, 1H), 7.89 (d, 1H), 7.22 (t, 1H), 6.85 (d, 1H), 6.66 (s, 1H), 4.92-4.78 (m, 1H), 3.98-3.86 (m, 2H), 3.67-3.59 (m, 2H), 1.97 (brs, 1H)

[0890] Step 2. (S)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0891] The title compound as a pale brown solid (50 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (48.48 mg, 0.151 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.26 (t, 1H), 8.16 (d, 1H), 8.02 (s, 1H), 7.88 (d, 1H), 7.14 (t, 1H), 6.84 (d, 1H), 6.66 (s, 1H), 6.19 (d, 1H), 5.19-5.03 (m, 1H), 4.77 (s, 2H), 4.74-4.64 (m, 2H), 3.78-3.72 (m, 5H)

[0892] Step 3. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0893] The title compound as a white solid (12 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47 mg, 0.095 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400 MHz) δ 9.99 (s, 1H), 8.48 (s, 1H), 8.36-8.29 (m, 3H), 8.15 (s, 1H), 7.98 (s, 1H), 7.89 (t, 1H), 7.15 (d, 1H), 6.81 (d, 1H), 4.97-4.84 (m, 1H), 4.79-4.67 (m, 1H), 4.41 (t, 1H), 4.27-4.20 (m, 1H), 3.76 (s, 3H), 3.66-3.64 (m, 1H); MS (ESI) m / z = 458.2 (M + H)+

[0894] Example 34. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-isopropyl-6-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0895] Step 1. (S)-2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0896] The title compound as a white solid (48 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butan-1-ol (61.1 mg, 0.193 mmol) prepared in Reference Example 21 and 4-(4-aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol (42.73 mg, 0.195 mmol) prepared in Reference Example 35 were used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol.1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.19 (d, 1H), 8.03 (s, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.13 (t, 1H), 6.84 (d, 1H), 6.72 (s, 1H), 6.19 (d, 1H), 4.74 (s, 2H), 4.60-4.49 (m, 2H), 4.38-4.37 (m, 1H), 4.15-4.05 (m, 1H), 2.20-2.16 (m, 2H), 1.42 (d, 6H), 1.32 (d, 3H)

[0897] Step 2. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-isopropyl-6-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0898] The title compound as a white solid (15 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.087 mmol) prepared in step 1 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.35-8.33 (m, 2H), 8.21 (s, 1H), 7.92 (d, 1H), 7.88 (d, 1H), 7.44 (s, 1H), 7.23 (t, 1H), 6.84 (d, 1H), 6.38 (d, 1H), 4.96 (t, 1H), 4.52 (quin, 1H), 4.40-4.38 (m, 1H), 4.02-3.98 (m, 1H), 2.27-2.20 (m, 2H), 1.60 (d, 3H), 1.51 (d, 6H); MS (ESI) m / z = 481.9 (M + H)+

[0899] Example 35. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0900] Step 1. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutan-1-ol

[0901] The title compound as a white solid (65.3 mg) was prepared in the same fashion as step 1 in Example 25, except that 3-amino-3-methyl-butan-1-ol (50 mg, 0.485 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.89 (d, 1H), 7.21 (t, 1H), 6.83 (d, 1H), 6.81 (s, 1H), 3.83 (q, 2H), 2.11 (t, 2H), 1.52 (s, 6H)

[0902] Step 2. 2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0903] The title compound as a pale brown solid (53.2 mg) was prepared in the same fashion as step 2 in Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutan-1-ol (60 mg, 0.181 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.20 (s, 1H), 8.13 (d, 1H), 7.98 (s, 1H), 7.86 (d, 1H), 7.14 (t, 1H), 6.81-6.80 (m, 2H), 6.16 (d, 1H), 4.71 (s, 2H), 4.49 (t, 2H), 3.68 (s, 3H), 2.40 (t, 2H), 1.56 (s, 6H)

[0904] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0905] The title compound as a white solid (12.5 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50 mg, 0.099 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.35-8.33 (m, 2H), 8.24 (s, 1H), 8.14 (s, 1H), 7.87 (d, 1H), 7.42 (s, 1H), 7.20 (t, 1H), 6.83 (d, 1H), 6.39 (d, 1H), 4.66 (t, 2H), 3.82 (s, 3H), 2.43 (t, 2H), 1.64 (s, 6H); MS (ESI) m / z = 467.9 (M + H)+

[0906] Example 36. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0907] Step 1. 3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropan-1-ol

[0908] The title compound as a white solid (106.8 mg) was prepared in the same fashion as step 1 in Example 25, except that 3-amino-2,2-difluoropropan-1-ol (53.84 mg, 0.485 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.33 (s, 1H), 7.91 (d, 1H), 7.23 (t, 1H), 6.86 (d, 1H), 6.77 (s, 1H), 3.95-3.81 (m, 4H), 2.36 (s, 1H)

[0909] Step 2. 2-(5-(3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0910] The title compound as a pale brown solid (53 mg) was prepared in the same fashion as step 2 in Example 25, except that 3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropan-1-ol (100 mg, 0.295 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.39 (t, 1H), 8.10 (d, 1H), 8.04 (s, 1H), 7.90 (d, 1H), 7.10 (t, 1H), 6.87 (d, 1H), 6.80 (s, 1H), 6.18 (d, 1H), 4.81-4.74 (m, 4H), 4.01 (t, 2H), 3.78 (s, 3H)

[0911] Step 3. 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0912] The title compound as a white solid (13 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-difluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.5 mg, 0.101 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (DMSO-d6, 400 MHz) δ 10.07 (s, 1H), 8.54 (s, 1H), 8.38-8.35 (m, 2H), 8.31 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.90 (t, 1H), 7.18 (d, 1H), 6.83 (d, 1H), 4.61 (brs, 2H), 4.16 (brs, 2H), 3.78 (s, 3H); MS (ESI) m / z = 475.9 (M + H)+

[0913] Example 37. 11,7,7-Trimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0914] Step 1. 2-Chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine

[0915] The title compound as an off white solid (586 mg) was prepared in the same fashion as Reference Example 1, except that (1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)boronic acid (587.57 mg, 3.03 mmol) was used instead of 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 9.00 (d, 1H), 7.61 (d, 1H), 7.18 (d, 1H), 6.79 (dd, 1H), 4.80 (q, 2H)

[0916] Step 2. 3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol

[0917] The title compound as a white solid (165 mg) was prepared in the same fashion as step 1 in Example 25, except that 3-amino-2,2-dimethyl-1-propanol (126.36 mg, 1.225 mmol) and 2-chloro-4-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridine (137 mg, 0.49 mmol) prepared in step 1 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.20 (s, 1H), 7.58 (d, 1H), 6.75 (d, 1H), 6.66 (s, 1H), 3.52 (s, 2H), 3.17 (d, 2H), 1.07 (s, 6H)

[0918] Step 3. 2-(5-(3-((2-Chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0919] The title compound as a pale brown solid (137 mg) was prepared in the same fashion as step 2 in Example 25, except that 3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (160 mg, 0.441 mmol) prepared in step 2 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.32 (t, 1H), 8.14 (d, 1H), 7.99 (s, 1H), 7.52 (d, 1H), 6.73 (d, 1H), 6.66 (s, 1H), 6.17 (d, 1H), 4.72 (s, 2H), 4.52 (q, 2H), 4.20 (s, 2H), 3.65 (s, 3H), 3.38 (d, 2H), 1.24 (s, 6H)

[0920] Step 4. 11,7,7-Trimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0921] The title compound as a white solid (12 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(3-((2-chloro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (130 mg, 0.243 mmol) prepared in step 3 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.34-8.28 (m, 4H), 8.18 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.73 (d, 1H), 6.37 (d, 1H), 4.86 (brs, 1H), 4.73 (s, 2H), 4.27 (brs, 1H), 3.87 (s, 3H), 3.56 (brs, 1H), 2.96 (brs, 1H), 1.44 (brs, 3H), 0.98 (brs, 3H); MS (ESI) m / z = 499.9 (M + H)+

[0922] Example 38. 11,7,7-Trimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0923] Step 1. 3-((2-Chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol

[0924] The title compound as a white solid (95.8 mg) was prepared in the same fashion as step 1 in Example 25, except that 3-amino-2,2-dimethyl-1-propanol (41.2 mg, 0.399 mmol) and 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine (75 mg, 0.266 mmol) prepared in Reference Example 26 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 8.47 (d, 1H), 8.31 (s, 1H), 8.27 (d, 1H), 6.66 (s, 1H), 5.71-5.65 (m, 1H), 5.05 (t, 2H), 4.81-4.77 (m, 2H), 3.50 (s, 2H), 3.13 (d, 2H), 1.04 (s, 6H)

[0925] Step 2. 2-(5-(3-((2-Chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0926] The title compound as a pale brown solid (45 mg) was prepared in the same fashion as step 2 in Example 25, except 3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (79.04 mg, 0.217 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.40 (t, 1H), 8.33 (d, 1H), 8.24 (s, 1H), 8.07 (d, 1H), 8.00 (s, 1H), 7.91 (d, 1H), 6.69 (s, 1H), 6.14 (d, 1H), 5.60-5.53 (m, 1H), 5.00 (t, 1H), 4.76-4.73 (m, 2H), 4.71 (s, 2H), 4.12 (s, 2H), 3.70 (s, 3H), 3.36 (d, 2H)

[0927] Step 3. 11,7,7-Trimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0928] The title compound as a white solid (5.5 mg) was prepared in the same fashion as step 3 in Example 25, except that 2-(5-(3-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (43 mg, 0.08 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.55 (t, 1H), 8.48 (d, 1H), 8.35 (d, 2H), 8.29 (s, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.45 (s, 1H), 6.39 (d, 1H), 5.71-5.65 (m, 1H), 5.06 (t, 2H), 4.88 (brs, 1H), 4.82-4.79 (m, 2H), 4.27 (brs, 1H), 3.87 (s, 3H), 3.56 (brs, 1H), 2.95 (brs, 1H), 1.41 (s, 3H), 1.00 (s, 3H); MS (ESI) m / z = 502.2 (M + H)+

[0929] Example 39. (S)-11,8-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0930] Step 1. (S)-4-((2-Chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-ol

[0931] The title compound as a white solid (77.6 mg) was prepared in the same fashion as step 1 in Example 25, except that (2R)-4-aminobutan-2-ol (35.6 mg, 0.399 mmol) and 2-(6-chloro-4-fluoropyridin-3-yl)-5-(oxetan-3-yloxy)pyrazine (75 mg, 0.266 mmol) prepared in Reference Example 26 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.44 (d, 1H), 8.30 (s, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 6.64 (s, 1H), 5.69-5.65 (m, 1H), 5.06-5.03 (m, 2H), 4.80-4.77 (m, 2H), 4.01 (s, 1H), 3.40-3.35 (m, 2H), 1.89-1.77 (m, 2H), 1.31 (d, 3H)

[0932] Step 2. (S)-2-(5-((4-((2-Chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0933] The title compound as a pale brown solid (75 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-4-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-ol (79.04 mg, 0.217 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H), 8.20 (s, 1H), 8.14 (t, 1H), 8.08 (d, 1H), 8.03 (s, 1H), 7.89 (d, 1H), 6.67 (s, 1H), 6.16 (d, 1H), 5.78-5.55 (m, 1H), 5.09-5.06 (m, 1H), 5.01 (t, 2H), 4.78-4.73 (m, 4H), 3.71 (s, 3H), 3.63-3.52 (m, 2H), 2.24-2.20 (m, 1H), 2.00-1.96 (m, 1H), 1.26 (d, 3H)

[0934] Step 3. (S)-11,8-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0935] The title compound as an off white solid (3 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-2-(5-((4-((2-chloro-5-(5-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg, 0.139 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.53 (t, 1H), 8.47 (d, 1H), 8.42 (s, 1H), 8.36 (d, 1H), 8.26 (s, 2H), 8.25 (s, 1H), 7.33 (brs, 1H), 6.38 (d, 1H), 5.71-5.65 (m, 1H), 5.54-5.52 (m, 1H), 5.06 (t, 2H), 4.81 (t, 2H), 4.10-4.02 (m, 1H), 3.78 (s, 3H), 3.60-3.49 (m, 1H), 2.31-2.27 (m, 1H), 1.96-1.91 (m, 1H), 1.13 (d, 3H); MS (ESI) m / z = 487.9 (M + H)+

[0936] Example 40. (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0937] Step 1. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-amine

[0938] The title compound as a pale brown solid (96 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (61.4 mg, 0.321 mmol) prepared in Reference Example 28 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.17 (s, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.99 (s, 1H), 7.48 (dd, 1H), 6.72 (s, 1H), 6.17 (d, 1H), 4.74 (s, 2H), 4.48-4.43 (m, 2H), 3.99-3.94 (m, 1H), 3.70 (s, 3H), 3.48 (s, 2H), 2.49 (brs, 8H), 2.31 (s, 3H), 2.24-2.16 (m, 1H), 2.11-2.03 (m, 1H), 1.39 (d, 3H)

[0939] Step 2. (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0940] The title compound a white solid (21 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-5-((4-methylpiperazin-1-yl)methyl)-[2,3'-bipyridin]-4'-amine (83 mg, 0.143 mmol) prepared in step 1 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.43-8.42 (m, 2H), 8.38 (s, 1H), 8.35-8.33 (m, 2H), 8.31 (s, 1H), 8.16 (s, 1H), 7.60 (d, 1H), 6.42 (d, 1H), 4.84 (t, 1H), 4.33-4.31 (m, 1H), 4.13-4.11 (m, 1H), 3.83 (s, 3H), 3.60 (s, 2H), 2.56-2.51 (m, 8H), 2.34 (s, 3H), 2.26-2.15 (m, 1H), 2.04-2.03 (m, 1H), 1.44 (d, 3H); MS (ESI) m / z = 545.2 (M + H)+

[0941] Example 41. (S)-11,6-Dimethyl-45-(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0942] Step 1. 2-Bromo-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridine

[0943] To the solution of 2-bromo-4-fluoro-pyridine (150 mg, 0.852 mmol) in DMA (2 mL) was added 3-(2,2,2-trifluoroethyl)azetidine hydrochloride (179.58 mg, 1.023 mmol) and DIPEA (0.36 mL, 2.557 mmol). The reaction mixture was heated at 90oC for 4 hours. The reaction mixture was cooled to room temperature and added to water and extracted with EA. The combined organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography (EA / n-Hex = 0-40%) to give 2-bromo-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridine (225 mg, 0.761 mmol, 89.46% yield) as colorless oil.1H-NMR (CDCl3, 400 MHz) δ 7.97 (d, 1H), 6.42 (d, 1H), 6.20 (dd, 1H), 4.19 (t, 2H), 3.74 (t, 2H), 3.19-3.12 (m, 1H), 2.57-2.47 (m, 2H)

[0944] Step 2. 6'-Chloro-4'-fluoro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-2,3'-bipyridine

[0945] The title compound as a pale yellow solid (149.8 mg) was prepared in the same fashion as Reference Example 1, except that 2-bromo-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridine (220 mg, 0.746 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (230.36 mg, 0.895 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.97 (d, 1H), 8.37 (d, 1H), 7.18 (d, 1H), 6.66 (t, 1H), 6.31 (dd, 1H), 4.24 (t, 2H), 3.79 (t, 2H), 3.21-3.15 (m, 1H), 2.59-2.51 (m, 2H)

[0946] Step 3. (S)-3-((6'-Chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0947] The title compound as a white solid (80.3 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminobutan-1-ol (79.84 mg, 0.862 mmol) and 6'-chloro-4'-fluoro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-2,3'-bipyridine (149 mg, 0.431 mmol) prepared in step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.92 (d, 1H), 8.25 (s, 1H), 8.20 (d, 1H), 6.63 (s, 1H), 6.53 (d, 1H), 6.24 (dd, 1H), 4.24 (t, 2H), 3.84-3.75 (m, 5H), 3.19-3.16 (m, 2H), 2.59-2.49 (m, 2H), 1.90-1.84 (m, 2H), 1.29 (d, 3H)

[0948] Step 4. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3'-bipyridin]-4'-amine

[0949] The title compound as a white bubble (61 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (78 mg, 0.188 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 9.21 (d, 1H), 8.26 (s, 1H), 8.15 (d, 1H), 8.11 (d, 1H), 7.98 (s, 1H), 6.63 (s, 1H), 6.49 (d, 1H), 6.18 (dd, 2H), 4.86 (s, 2H), 4.56-4.51 (m, 1H), 4.43-4.38 (m, 1H), 4.20 (t, 2H), 3.94-3.88 (m, 1H), 3.76-3.72 (m, 2H), 3.20-3.10 (m, 1H), 2.66 (s, 3H), 2.55-2.50 (m, 2H), 2.13-2.12 (m, 2H), 1.37 (d, 3H)

[0950] Step 5. (S)-11,6-Dimethyl-45-(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0951] The title compound a white solid (5.1 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)-[2,3'-bipyridin]-4'-amine (33 mg, 0.056 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 9.29 (d, 1H), 8.34-8.33 (m, 2H), 8.25-8.24 (m, 2H), 8.15 (s, 1H), 7.63 (brs, 1H), 6.58 (d, 1H), 6.40 (d, 1H), 6.23 (dd, 1H), 4.83 (t, 1H), 4.29-4.23 (m, 2H), 4.12-4.09 (m, 1H), 3.83 (s, 3H), 3.81-3.77 (m, 2H), 3.21-3.14 (m, 1H), 2.57-2.52 (m, 2H), 2.24-2.16 (m, 3H), 1.45 (d, 3H); MS (ESI) m / z = 552.3 (M + H)+

[0952] Example 42. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0953] Step 1. (S)-3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol

[0954] The title compound as a white solid (167 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminopentan-1-ol hydrochloride (169.17 uL,1.212 mmol) was used instead of 2-aminoethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.90-7.86 (m, 2H), 7.20 (t, 1H), 6.79 (d, 1H), 6.69 (s, 1H), 3.82 (t, 2H), 3.74-3.73 (m, 1H), 2.07 (brs, 1H), 1.98-1.94 (m, 1H), 1.82-1.63 (m, 5H)

[0955] Step 2. (S)-2-(5-((3-((2-Chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0956] The title compound as a white solid (48 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentan-1-ol (163 mg, 0.493 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.15 (d, 1H), 8.10 (s, 1H), 8.01-7.99 (m, 2H), 7.88 (d, 1H), 7.13 (t, 1H), 6.84 (d, 1H), 6.70 (s, 1H), 6.19 (d, 1H), 4.86 (s, 2H), 4.54-4.50 (m, 1H), 4.45-4.43 (m, 1H), 3.85-3.80 (m, 1H), 3.70 (s, 3H), 2.23-2.20 (m, 1H), 2.08-2.04 (m, 1H), 1.96-1.88 (m, 2H), 1.86-1.69 (m, 2H), 1.48-1.42 (m, 1H), 1.04 (t, 3H)

[0957] Step 3. (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0958] The title compound a white solid (11.7 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-2-(5-((3-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)pentyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.089 mmol) prepared in step 2 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.35-8.33 (m, 2H), 8.17 (s, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.49 (brs, 1H), 7.21 (t, 1H), 6.85 (d, 1H), 6.40 (d, 1H), 4.93-4.87 (m, 1H), 4.16-4.11 (m, 1H), 4.10-4.07 (m, 1H), 3.83 (s, 3H), 2.30-2.24 (m, 2H), 2.16-2.13 (m, 1H), 1.88-1.85 (m, 1H), 1.21 (t, 3H); MS (ESI) m / z = 468.2 (M + H)+

[0959] Example 43. (S)-N-(3,3-Difluorocyclobutyl)-2-(11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-amine

[0960] Step 1. 2-Bromo-N-(3,3-difluorocyclobutyl)pyridin-4-amine

[0961] The title compound as a colorless oil (170.2 mg) was prepared in the same fashion as step 1 in Example 41, except that 3,3-difluorocyclobutanamine hydrochloride (183.54 mg, 1.278 mmol) was used instead of 3-(2,2,2-trifluoroethyl)azetidine hydrochloride.1H-NMR (CDCl3, 400 MHz) δ 7.98 (d, 1H), 6.58 (d, 1H), 6.39 (dd, 1H), 4.71 (brs, 1H), 3.92-3.86 (m, 1H), 3.17-3.08 (m, 2H), 2.57-2.50 (m, 2H)

[0962] Step 2. 6'-Chloro-N-(3,3-difluorocyclobutyl)-4'-fluoro-[2,3'-bipyridin]-4-amine

[0963] The title compound as a pale yellow solid (173 mg) was prepared in the same fashion as Reference Example 1, except that 2-bromo-N-(3,3-difluorocyclobutyl)pyridin-4-amine (220.24 mg, 0.837 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (258.69 mg, 1.005 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.97 (d, 1H), 8.37 (d, 1H), 7.17 (d, 1H), 6.83 (s, 1H), 6.43 (dd, 1H), 4.50 (d, 1H), 3.97-3.95 (m, 1H), 3.16-3.07 (m, 2H), 2.56-2.49 (m, 2H)

[0964] Step 3. (S)-3-((6'-Chloro-4-((3,3-difluorocyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0965] The title compound as a white solid (132.6 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminobutan-1-ol (98.32 mg, 1.103 mmol) and 6'-chloro-N-(3,3-difluorocyclobutyl)-4'-fluoro-[2,3'-bipyridin]-4-amine (173 mg, 0.551 mmol) prepared in step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.23-8.22 (m, 2H), 6.76 (s, 1H), 6.64 (s, 1H), 6.40 (dd, 1H), 4.86 (brs, 1H), 4.02-3.98 (m, 1H), 3.99-3.77 (m, 3H), 3.20-3.04 (m, 2H), 2.62-2.50 (m, 2H), 1.94-1.80 (m, 2H), 1.30 (d, 3H)

[0966] Step 4. (S)-N4'-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N4-(3,3-difluorocyclobutyl)-[2,3'-bipyridine]-4,4'-diamine

[0967] The title compound as a pale brown solid (69 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-4-((3,3-difluorocyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (116.34 mg, 0.304 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 9.16 (d, 1H), 8.25 (s, 1H), 8.17-8.13 (m, 2H), 8.00 (s, 1H), 6.70 (d, 1H), 6.65 (s, 1H), 6.33 (dd, 1H), 6.18 (d, 1H), 4.80 (s, 2H), 4.78-4.76 (m, 1H), 4.57-4.52 (m, 1H), 4.46-4.40 (m, 1H), 3.94-3.92 (m, 2H), 3.68 (s, 3H), 3.13-3.11 (m, 2H), 2.56-2.51 (m, 2H), 2.15-2.11 (m, 2H), 1.38 (d, 3H)

[0968] Step 5. (S)-N-(3,3-Difluorocyclobutyl)-2-(11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-amine

[0969] The title compound as a beige solid (18.1 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-N4'-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N4-(3,3-difluorocyclobutyl)-[2,3'-bipyridine]-4,4'-diamine (56 mg, 0.101 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 9.27 (d, 1H), 8.35-8.33 (m, 2H), 8.26-8.23 (m, 2H), 8.16 (s, 1H), 7.68 (s, 1H), 6.75 (d, 1H), 6.42-6.37 (m, 2H), 4.87-4.80 (m, 1H), 4.48-4.47 (m, 1H), 4.30-4.28 (m, 1H), 4.16-4.10 (m, 1H), 4.09-3.99 (m, 1H), 3.83 (s, 3H), 3.19-3.12 (m, 2H), 2.56-2.51 (m, 2H), 2.24-2.17 (m, 2H), 1.46 (d, 3H); MS (ESI) m / z = 520.3 (M + H)+

[0970] Example 44. (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0971] Step 1. 4-((6-Bromo-5-fluoropyridin-3-yl)methyl)morpholine

[0972] The title compound as a white solid (254.7 mg) was prepared in the same fashion as step 1 in Reference Example 27, except that morpholine (102.49 mg, 1.176 mmol) was used instead of 1-methylpiperazine.1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 7.51 (dd, 1H), 3.73 (t, 4H), 3.52 (s, 2H), 2.47 (t, 4H)

[0973] Step 2. 4-((6'-Chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)morpholine

[0974] The title compound as a pale yellow solid (54 mg) was prepared in the same fashion as Reference Example 1, except that 4-((6-bromo-5-fluoropyridin-3-yl)methyl)morpholine (254 mg, 0.923 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (246.63 mg, 0.958 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.65 (d, 1H), 8.50 (s, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.11 (t, 4H), 3.60 (s, 2H), 2.51 (t, 4H)

[0975] Step 3. (S)-3-((6'-Chloro-3-fluoro-5-(morpholinomethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0976] The title compound as a white solid (125 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminobutan-1-ol (98.32 mg, 1.103 mmol) and 4-((6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-5-yl)methyl)morpholine (154 mg, 0.473 mmol) prepared in step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.41-8.39 (m, 2H), 7.98 (d, 1H), 7.64 (d, 1H), 6.71 (s, 1H), 3.86-3.76 (m, 7H) 3.60 (s, 2H), 2.53 (s, 4H), 1.89-1.79 (m, 3H), 1.30 (d, 3H)

[0977] Step 4. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-5-(morpholinomethyl)-[2,3'-bipyridin]-4'-amine

[0978] The title compound as a pale brown solid (130 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-5-(morpholinomethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (120 mg, 0.304 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.16 (s, 1H), 8.11 (d, 1H), 8.06 (d, 1H), 7.98 (s, 1H), 7.47 (d, 1H), 6.72 (s, 1H), 6.17 (d, 1H), 4.73 (s, 2H), 4.48-4.43 (m, 2H), 4.00-3.97 (m, 1H), 3.74-3.72 (m, 4H), 3.70 (s, 3H), 3.45 (s, 2H), 2.47-2.45 (m, 4H), 2.24-2.19 (m, 1H), 2.10-2.05 (m, 1H), 1.29 (d, 3H)

[0979] Step 5. (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0980] The title compound as a pale yellow solid (21.48 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-5-(morpholinomethyl)-[2,3'-bipyridin]-4'-amine (102 mg, 0.18 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.43-8.42 (m, 2H), 8.39 (s, 1H), 8.35 (d, 1H), 8.29 (d, 1H), 8.16 (s, 1H), 7.63-7.60 (m, 2H), 6.40 (d, 1H), 4.84-4.82 (m, 1H), 4.33-4.31 (m, 1H), 4.16-4.11 (m, 1H), 3.83 (s, 3H), 3.77 (t, 4H), 3.59 (s, 2H), 2.53 (t, 4H), 2.23-2.14 (m, 2H), 1.29 (d, 3H); MS (ESI) m / z = 532.3 (M + H)+

[0981] Example 45. (S)-45-(3-Fluoro-5-(piperidin-1-ylmethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0982] Step 1. 2-Bromo-3-fluoro-5-(piperidin-1-ylmethyl)pyridine

[0983] The title compound as a white solid (132.1 mg) was prepared in the same fashion as step 1 in Reference Example 27, except that piperidine (100.18 mg, 1.176 mmol) was used instead of 1-methylpiperazine.1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.50 (dd, 1H), 3.47 (s, 2H), 2.39 (s, 4H), 1.62-1.57 (m, 4H), 1.49-1.45 (m, 2H)

[0984] Step 2. 6'-Chloro-3,4'-difluoro-5-(piperidin-1-ylmethyl)-2,3'-bipyridine

[0985] The title compound as a pale yellow solid (87 mg) was prepared in the same fashion as Reference Example 1, except that 2-bromo-3-fluoro-5-(piperidin-1-ylmethyl)pyridine (132 mg, 0.483 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (149.33 mg, 0.58 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.65 (d, 1H), 8.47 (s, 1H), 7.60 (d, 1H), 7.22 (d, 1H), 3.56 (s, 2H), 2.43 (s, 4H), 1.64-1.58 (m, 4H), 1.50-1.27 (m, 2H)

[0986] Step 3. (S)-3-((6'-Chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0987] The title compound as a white solid (125 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminobutan-1-ol (28.58 mg, 0.321 mmol) and 6'-chloro-3,4'-difluoro-5-(piperidin-1-ylmethyl)-2,3'-bipyridine (86.5 mg, 0.267 mmol) prepared in step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.40-8.37 (m, 2H), 7.98 (d, 1H), 7.62 (d, 1H), 6.70 (s, 1H), 3.85-3.78 (m, 3H), 3.55 (d, 2H), 2.45 (s, 4H), 1.89-1.81 (m, 3H), 1.65 (s, 4H), 1.50-1.49 (m, 2H), 1.31 (d, 3H)

[0988] Step 4. (S)-N-(4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3'-bipyridin]-4'-amine

[0989] The title compound as a pale brown solid (77.5 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (58.1 mg, 0.304 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.18 (s, 1H), 8.13-8.08 (m, 2H), 7.99 (s, 1H), 7.50 (d, 1H), 6.72 (s, 1H), 6.17 (d, 1H), 4.73 (s, 2H), 4.48-4.44 (m, 2H), 3.99-3.94 (m, 1H), 3.71 (s, 3H), 3.44 (s, 2H), 2.40 (s, 4H), 2.23-2.16 (m, 1H), 2.11-2.04 (m, 1H), 1.47 (s, 4H), 1.39 (d, 3H), 1.36-1.27 (m, 2H)

[0990] Step 5. (S)-45-(3-Fluoro-5-(piperidin-1-ylmethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane

[0991] The title compound as a pale yellow solid (16 mg) was prepared in the same fashion as step 3 in Example 25, except that (S)-N-(4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-3-fluoro-5-(piperidin-1-ylmethyl)-[2,3'-bipyridin]-4'-amine (57 mg, 0.101 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.41-8.40 (d, 2H), 8.38 (s, 1H), 8.35 (d, 1H), 8.28 (d, 1H), 8.16 (s, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 6.40 (d, 1H), 4.84 (t, 1H), 4.32-4.31 (m, 1H), 4.13-4.11 (m, 1H), 3.83 (s, 3H), 3.55 (s, 2H), 2.45 (s, 4H), 2.21-2.05 (m, 2H), 1.66-1.61 (m, 4H), 1.50 (d, 3H), 1.15 (d, 3H); MS (ESI) m / z = 530.3 (M + H)+

[0992] Example 46. 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine

[0993] Step 1. 2-Bromo-N-((1r,3r)-3-methoxycyclobutyl)pyridin-4-amine

[0994] The title compound as a colorless oil (182.4 mg) was prepared in the same fashion as step 1 in Example 41, except that (1r,3r)-3-methoxycyclobutan-1-amine hydrochloride (183.54 mg, 1.278 mmol) was used instead of 3-(2,2,2-trifluoroethyl)azetidine hydrochloride.1H-NMR (CDCl3, 400 MHz) δ 7.94 (d, 1H), 6.54 (d, 1H), 6.33 (dd, 1H), 4.47 (s, 1H), 4.15-4.02 (m, 2H), 3.29 (s, 3H), 2.51-2.44 (m, 2H), 2.21-2.16 (m, 2H)

[0995] Step 2. 6'-Chloro-4'-fluoro-N-((1r,3r)-3-methoxycyclobutyl)-[2,3'-bipyridin]-4-amine

[0996] The title compound as a pale yellow solid (124 mg) was prepared in the same fashion as Reference Example 1, except that 2-bromo-N-((1r,3r)-3-methoxycyclobutyl)pyridin-4-amine (215.26 mg, 0.837 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (258.69 mg, 1.005 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.95 (d, 1H), 8.32 (d, 1H), 7.16 (d, 1H), 6.78 (s, 1H), 6.39 (dd, 1H), 4.46-4.44 (m, 1H), 4.13-4.07 (m, 2H), 3.28 (s, 3H), 2.51-2.45 (m, 2H), 2.23-2.16 (m, 2H)

[0997] Step 3. (S)-3-((6'-Chloro-4-(((1r,3S)-3-methoxycyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[0998] The title compound as a white solid (109.4 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminobutan-1-ol (65.38 mg, 0.733 mmol) and 6'-chloro-4'-fluoro-N-((1r,3r)-3-methoxycyclobutyl)-[2,3'-bipyridin]-4-amine (112.86 mg, 0.367 mmol) prepared in step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 8.21-8.17 (m, 2H), 6.72 (s, 1H), 6.63 (s, 1H), 6.37 (d, 1H), 4.17-4.10 (m, 2H), 3.84-3.77 (m, 3H), 3.30 (s, 3H), 2.53-2.47 (m, 2H), 2.26-2.18 (m, 2H), 1.95-1.84 (m, 2H), 1.30 (d, 3H)

[0999] Step 4.N4'-((S)-4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N4-((1r,3S)-3-methoxycyclobutyl)-[2,3'-bipyridine]-4,4'-diamine

[1000] The title compound as a pale brown solid (126.3 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-4-(((1r,3S)-3-methoxycyclobutyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (94.48 mg, 0.251 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 9.23 (d, 1H), 8.27 (s, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 6.67-6.64 (m, 2H), 6.32-6.30 (m, 1H), 6.18 (d, 1H), 4.75 (s, 2H), 4.54-4.44 (m, 3H), 4.14-4.10 (m, 2H), 3.68 (s, 3H), 3.30 (s, 3H), 2.52-2.47 (m, 2H), 2.22-2.11 (m, 4H), 1.38 (d, 3H)

[1001] Step 5. 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine

[1002] The title compound as a pale yellow solid (24.3 mg) was prepared in the same fashion as step 3 in Example 25, except thatN4'-((S)-4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N4-((1r,3S)-3-methoxycyclobutyl)-[2,3'-bipyridine]-4,4'-diamine (108 mg, 0.196 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 9.25 (d, 1H), 8.34-8.32 (d, 2H), 8.24 (s, 1H), 8.21 (d, 1H), 8.15 (s, 1H), 7.70 (brs, 1H), 6.71 (d, 1H), 6.39 (d, 1H), 6.34 (dd, 1H), 4.84 (t, 1H), 4.44-4.43 (m, 1H), 4.29-4.27 (m, 1H), 4.18-4.08 (m, 3H), 3.83 (s, 3H), 3.31 (s, 3H), 2.53-2.48 (m, 2H), 2.26-2.16 (m, 3H), 1.45 (d, 3H); MS (ESI) m / z = 514.3 (M + H)+

[1003] Example 47. 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1S,3S-3-methoxycyclopentyl)pyridin-4-amine

[1004] Step 1. 2-Bromo-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine

[1005] The title compound as a colorless oil (162.7 mg) was prepared in the same fashion as step 1 in Example 41, except that (1S,3S)-3-methoxycyclopentan-1-amine hydrochloride (175.93 mg, 1.278 mmol) was used instead of 3-(2,2,2-trifluoroethyl)azetidine hydrochloride.1H-NMR (CDCl3, 400 MHz) δ 7.92 (d, 1H), 6.62 (d, 1H), 6.38 (dd, 1H), 4.25 (s, 1H), 4.00-3.92 (m, 2H), 3.32 (s, 3H), 2.29-2.23 (m, 2H), 2.01-1.82 (m, 1H), 1.65-1.58 (m, 1H), 1.49-1.44 (m, 1H), 1.30-1.26 (m, 1H)

[1006] Step 2. 6'-Chloro-4'-fluoro-N-((1S,3S)-3-methoxycyclopentyl)-[2,3'-bipyridin]-4-amine

[1007] The title compound as a pale yellow solid (118 mg) was prepared in the same fashion as Reference Example 1, except that 2-bromo-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine (227 mg, 0.837 mmol) prepared in step 1 and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (258.69 mg, 1.005 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.94 (d, 1H), 8.30 (d, 1H), 7.16 (d, 1H), 6.84 (d, 1H), 6.47 (dd, 1H), 4.26-4.24 (m, 1H), 4.04-3.92 (m, 1H), 3.30 (s, 3H), 2.30-2.25 (m, 2H), 2.02-1.98 (m, 1H), 1.84-1.76 (m, 1H), 1.66-1.52 (m, 1H), 1.46 (m, 1H), 1.27-1.24 (m, 1H)

[1008] Step 3. (S)-3-((6'-Chloro-4-(((1S,3S)-3-methoxycyclopentyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol

[1009] The title compound as a white solid (100.8 mg) was prepared in the same fashion as step 1 in Example 25, except that (S)-3-aminobutan-1-ol (65.38 mg, 0.733 mmol) and 6'-chloro-4'-fluoro-N-((1S,3S)-3-methoxycyclopentyl)-[2,3'-bipyridin]-4-amine (118 mg, 0.367 mmol) prepared in step 2 were used instead of 2-aminoethan-1-ol and 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-4-fluoropyridine.1H-NMR (CDCl3, 400 MHz) δ 8.77 (brs, 1H), 8.21 (s, 1H), 8.16 (d, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 6.44 (dd, 1H), 4.16-4.06 (m, 2H), 3.97-3.96 (m, 1H), 3.84-3.77 (m, 3H), 3.32 (s, 3H), 2.32-2.27 (m, 2H), 2.05-1.89 (m, 1H), 1.86-1.66 (m, 5H), 1.30 (d, 3H)

[1010] Step 4.N4'-((S)-4-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N4-((1S,3S)-3-methoxycyclopentyl)-[2,3'-bipyridine]-4,4'-diamine

[1011] The title compound as a pale brown solid (107.2 mg) was prepared in the same fashion as step 2 in Example 25, except that (S)-3-((6'-chloro-4-(((1S,3S)-3-methoxycyclopentyl)amino)-[2,3'-bipyridin]-4'-yl)amino)butan-1-ol (98 mg, 0.251 mmol) prepared in step 3 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 9.23 (d, 1H), 8.27 (s, 1H), 8.18 (d, 1H), 8.09 (d, 1H), 8.00 (s, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 6.38 (dd, 1H), 6.18 (d, 1H), 4.74 (s, 2H), 4.56-4.52 (m, 1H), 4.45-4.41 (m, 1H), 4.27-4.25 (m, 1H), 4.07-3.97 (m, 1H), 3.98-3.90 (m, 2H), 3.68 (s, 3H), 3.33 (s, 3H), 2.30-2.26 (m, 2H), 2.15-2.09 (m, 2H), 2.07-1.98 (m, 1H), 1.86-1.82 (m, 1H), 1.38 (d, 3H)

[1012] Step 5. 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine

[1013] The title compound as a pale yellow solid (25.77 mg) was prepared in the same fashion as step 3 in Example 25, except thatN4'-((S)-4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-6'-chloro-N4-((1S,3S)-3-methoxycyclopentyl)-[2,3'-bipyridine]-4,4'-diamine (195 mg, 0.168 mmol) prepared in step 4 was used instead of 2-(5-(2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 9.24 (d, 1H), 8.34-8.32 (m, 2H), 8.24 (s, 1H), 8.19 (d, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 6.78 (d, 1H), 6.41-6.38 (m, 2H), 4.84 (t, 1H), 4.24-4.08 (m, 3H), 3.97-3.96 (m, 1H), 3.83 (s, 3H), 3.33 (s, 3H), 2.32-2.15 (m, 4H), 2.07-2.03 (m, 2H), 1.71-1.64 (m, 2H), 1.46-1.45 (m, 1H), 1.29 (d, 3H); MS (ESI) m / z = 528.3 (M + H)+

[1014] Example 48. (3-Fluoro-2-(11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)methanol

[1015] Step 1.tert-Butyl (3-hydroxy-2,2-dimethylpropyl)carbamate

[1016] To a solution of 3-amino-2,2-dimethylpropan-1-ol (347.18 mg, 3.365 mmol) in DCM (6 mL) was added TEA followed by di-tert-butyl dicarbonate. The reaction mixture was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with DCM. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to givetert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (690 mg, 3.394 mmol, quantitative) as a white solid.1H-NMR (CDCl3, 400 MHz) δ 4.85 (s, 1H), 3.69 (t, 1H), 3.21 (d, 2H), 2.98 (d, 2H), 1.47 (s, 9H), 0.87 (s, 6H)

[1017] Step 2. (6'-Chloro-3,4'-difluoro-[2,3'-bipyridin]-4-yl)methanol

[1018] The title compound as an off white solid (176 mg) was prepared in the same fashion as Reference Example 1, except that (2-bromo-3-fluoropyridin-4-yl)methanol (200 mg, 0.971 mmol) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (299.99 mg, 1.165 mmol) were used instead of 2-chloro-4-fluoro-5-iodopyridine and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (CDCl3, 400 MHz) δ 8.67 (d, 1H), 8.60 (d, 1H), 7.64 (t, 1H), 7.25 (d, 1H), 4.95 (d, 2H)

[1019] Step 3.tert-Butyl (3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)carbamate

[1020] The title compound as a pale brown solid (94.4 mg) was prepared in the same fashion as step 2 in Example 25, except thattert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (53.16 mg, 0.262 mmol) prepared in step 1 was used instead of 2-((2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-4-yl)amino)ethan-1-ol.1H-NMR (CDCl3, 400 MHz) δ 8.53 (d, 1H), 8.06 (s, 1H), 6.81 (s, 1H), 6.23 (d, 1H), 4.87 (s, 2H), 3.92 (s, 2H), 3.75 (s, 3H), 3.30 (d, 2H), 1.52 (s, 9H), 1.06 (s, 6H)

[1021] Step 4. 2-(5-(3-Amino-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine dihydrochloride

[1022] To a solution oftert-butyl (3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)carbamate (92.44mg, 0.246 mmol) prepared in step 3 in DCM (2mL) was added 4 M HCl soln. in dioxane (0.31 mL, 1.228 mmol) at room temperature. The reaction mixture was stirred for 2 hours. Upon completion of the reaction, the mixture was concentrated, washed with DCM / ether and filtered to give 2-(5-(3-amino-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine dihydrochloride (78 mg, 0.223 mmol, 90.95% yield) as a white solid.1H-NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 8.13-8.09 (m, 3H), 6.57 (d, 1H), 4.21 (s, 2H), 3.73 (s, 4H), 2.93 (d, 2H), 1.10 (s, 6H)

[1023] Step 5. (4'-((3-((4-(4-Aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4-yl)methanol

[1024] To a solution of (6'-chloro-3,4'-difluoro-[2,3'-bipyridin]-4-yl)methanol prepared in step 2 (55.89 mg, 0.218 mmol) and DIPEA (0.19 mL, 1.089 mmol) in DMA (2 mL) were added 2-(5-(3-amino-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine dihydrochloride (76.06 mg, 0.218 mmol) prepared in step 4. The reaction mixture was heated to 90oC for 18 hours .The reaction mixture was cooled to room temperature, quenched with water, and extracted with EA. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (EA / n-Hex = 40-100% → MeOH / EA = 0-20%) to give (4'-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6'-chloro-3-fluoro-[2,3'-bipyridin]-4-yl)methanol (57 mg, 0.111 mmol, 51.03% yield) as a white solid.1H-NMR (CD3OD, 400 MHz) δ 8.02 (d, 1H), 7.92 (d, 1H), 7.86-7.83 (m, 2H), 7.25 (t, 1H), 6.97 (s, 1H), 6.21 (d, 1H), 4.47 (s, 2H), 4.04 (s, 2H), 3.69 (s, 3H), 3.42 (s, 2H), 1.16 (s, 6H)

[1025] Step 6. (3-Fluoro-2-(11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)methanol

[1026] The title compound as a white solid (2.3 mg) was prepared in the same fashion as step 3 in Example 25, except that (4'...

Claims

1.A compound of formula (I) or a pharmaceutically acceptable salt thereof,whereinR1and R2are, independently each other, hydrogen or C1-6alkyl optionally substituted with one or more halogens,A is 5-10 membered heteroaryl,R3and R4are, independently each other,hydrogen;halogen;C1-6alkyl optionally substituted by one or more substituents selected from the group consisting of halogens, hydroxy, and 4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkyl,hydroxyl-C1-6alkyl, C1-6alkyl substituted by one or more halogens, C1-6alkoxy optionally substituted by one or more halogens, -CH2-S(O)2-C1-6alkyl, oxo, and C3-6cycloalkyl optionally substituted by one or more OH;C1-6alkoxy optionally substituted by one or more halogens;-S(O)2-C1-6alkyl;4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl optionally substituted by one or more halogens, and mono or di-(C1-6alkyl)amino;-O-4-8 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl and halo-C1-6alkyl; and-NHC3-6cycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen and C1-6alkoxy optionally substituted by one or more halogens,L is a linear or branched C2-6alkylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene,R5is hydrogen or C1-6alkyl,R6and R7are, independently each other, is hydrogen, halogen or halo-C1-6alkyl, andX1is CH or N.2.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen or methyl.3.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.4.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is C1-6alkyl optionally substituted with one or more halogens.5.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, pyrazinyl, thiazolyl, pyridinyl, or pyrimidinyl.6.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the 4-8 membered heterocyclyl is azetidinyl, oxetanyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[2.3]hexanyl, pyrrolidinyl, 2-thio-6-azaspiro[3.3]heptanyl, hexahydro-1H-thieno[3,4-c]pyrrolyl, or 2-azaspiro[3.3]heptanyl.7.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is ethylene,n-propylene, 1-methylpropylene, 1-ethylpropylene, 3-methylpropylene, 2-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene,n-butylene, 1-methylbutylene, 3-methylbutylene, cyclopentane-3-methylene, cyclopropane-1,1-dimethylene, cyclobutane-1,1-dimethylene, cyclopentane-1,1-dimethylene, cycloheptane-1,1-dimethylene, or oxetane-3,3-dimethylene.8.The compound of claim 1, which is selected from any one of the compounds as described below, or a pharmaceutically acceptable salt thereof:(1) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(2) (S)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(3) (R)-11,6-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(4) 11-Methyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(5) (R)-11,6-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(6) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(7) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,5-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(8) (S)-2-(6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)propan-2-ol;(9) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(10) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;(11) (61S,63R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazola-6(1,3)-cyclopentanacyclooctaphane;(12) (R)-45-(3-Fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(13) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(14) 45-(3-Methoxypyridin-2-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(15) (S)-45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(16) 45-(3-Methoxypyridin-2-yl)-11,6-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;(17) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;(18) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(19) (S)-45-(3-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(20) (S)-11,6-Dimethyl-45-(3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(21) (S)-45-(5-Fluoro-3-methoxypyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(22) (S)-45-(3-(2,2-Difluoroethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(23) (S)-11,6-Dimethyl-45-(pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(24) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-7-(trifluoromethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(25) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-8-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclooctaphane;(26) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(27) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-methyl-11H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane;(28) (S)-11,6-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(29) (6S)-11,6-Dimethyl-45-(5-((tetrahydrofuran-3-yl)oxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(30) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-methyl-11-(2,2,2-trifluoroethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(31) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(32) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(33) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(34) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11-isopropyl-6-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(35) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(36) 45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-7,7-difluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(37) 11,7,7-Trimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(38) 11,7,7-Trimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(39) (S)-11,8-Dimethyl-45-(5-(oxetan-3-yloxy)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(40) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(41) (S)-11,6-Dimethyl-45-(4-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(42) (S)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-ethyl-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(43) (S)-N-(3,3-Difluorocyclobutyl)-2-(11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-amine;(44) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(45) (S)-45-(3-Fluoro-5-(piperidin-1-ylmethyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(46) 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1r,3S)-3-methoxycyclobutyl)pyridin-4-amine;(47) 2-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-N-((1S,3S)-3-methoxycyclopentyl)pyridin-4-amine;(48) (3-Fluoro-2-(11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)methanol;(49) (S)-(1-((6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)-5-fluoropyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methanol;(50) (S)-45-(3-Fluoro-5-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(51) 45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(52) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(53) 45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(54) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(55) (S)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(56) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(57) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(58) (S)-45-(5-((3,3-Difluoroazetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(59) (S)-45-(5-((3,3-Difluoroazetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(60) (S)-45-(5-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(61) (S)-45-(5-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(62) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];(63) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];(64) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[cyclobutane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];(65) 5'-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-1'-methylspiro[cyclopentane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];(66) (R)-45-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(67) (S)-11,6-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(68) (S)-11,8-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(69) (S)-7-Fluoro-11-methyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(70) (R)-7-Fluoro-11-methyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(71) 11,7,7-Trimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(72) (R)-11,8-Dimethyl-45-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(73) (S)-11,8-Dimethyl-45-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(74) (S)-11,6-Dimethyl-45-(2-(trifluoromethyl)thiazol-4-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(75) (R)-11,6-Dimethyl-45-(2-(trifluoromethyl)thiazol-4-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(76) (S)-45-(1,4-Dimethyl-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(77) (S)-45-(1,4-Dimethyl-1H-pyrazol-3-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(78) (S)-45-(5-(Difluoromethoxy)pyrazin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(79) (S)-2-(6-(11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(80) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(81) (S)-45-(4-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(82) (S)-45-(4-(Difluoromethoxy)pyridin-2-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(83) (S)-45-(4-(Difluoromethoxy)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(84) 45-(4-(Difluoromethoxy)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(85) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(86) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,8-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(87) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(88) (R)-45-(5-(Difluoromethoxy)pyridin-2-yl)-7-fluoro-11-methyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(89) 45-(5-(Difluoromethoxy)pyridin-2-yl)-11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(90) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(91) 45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,7,7-tetramethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(92) (S)-45-(4-(Difluoromethoxy)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(93) (S)-11,6-Dimethyl-45-(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(94) (S)-45-(3-Methoxy-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(95) 2-(6-((S)-11,6-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;(96) 2-(6-((S)-11,8-Dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;(97) 1,1,1-Trifluoro-2-(6-(11,7,7-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(98) 1,1,1-Trifluoro-2-(6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(99) (S)-45-(4-(3-(2,2-Difluoroethyl)azetidin-1-yl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(100) (S)-45-(4-(3-(2,2-Difluoropropyl)azetidin-1-yl)pyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(101) (S)-11,6-Dimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(102) (S)-11,13,6-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(103) (S)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(104) 11,13,7,7-Tetramethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(105) (R)-11,13,8-Trimethyl-45-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(106) (S)-45-(5-((3-(2,2-Difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(107) (S)-45-(5-((3-(2,2-Difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(108) (S)-45-(5-((3-(Difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(109) (S)-45-(5-((3-(2,2-Difluoroethyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(110) (S)-45-(5-((3-(2,2-Difluoropropyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(111) (S)-45-(5-((3-(Difluoromethoxy)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(112) (S)-46-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-11,6-dimethyl-11H-9-oxa-3,5-diaza-2(2,4),4(3,5)-dipyrimidina-1(4,5)-pyrazolacyclononaphane;(113) (S)-2-(5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(114) (S)-2-(5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(115) (S)-45-(3-Fluoro-5-(methylsulfonyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(116) (S)-45-(3-Fluoro-5-(methylsulfonyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(117) 1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol;(118) 1-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4,4-dimethylpyrrolidin-3-ol;(119) (S)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;(120) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(121) (S)-45-(3-Fluoro-5-((3-(2-fluoropropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(122) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(123) (S)-45-(3-Fluoro-5-(morpholinomethyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(124) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-3-fluoropyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(125) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(126) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(127) (S)-11,13,6-Trimethyl-45-(5-(morpholinomethyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(128) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(129) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(130) (S)-45-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(131) (S)-45-(5-((4,4-Difluoropiperidin-1-yl)methyl)pyrazin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(132) (S)-45-(5-(Difluoromethoxy)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(133) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(134) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(135) (S)-2-(5-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;(136) (S)-45-(3-Fluoro-5-(((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(137) (S)-45-(3-Fluoro-5-(((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(138) (S)-45-(3-Fluoro-5-(((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(139) (S)-2-(5-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrazin-2-yl)propan-2-ol;(140) (S)-6-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;(141) (S)-6-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;(142) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(143) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrazin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(144) 5-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide;(145) 5-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide;(146) (S)-45-(3-Fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(147) (S)-45-(3-Fluoro-5-((3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(148) (S)-45-(3-Fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(149) (S)-45-(3-Fluoro-5-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(150) (S)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyrimidin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(151) (S)-11,13,6-Trimethyl-45-(5-(methylsulfonyl)pyrimidin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(152) (R)-2-(5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(153) (R)-11,13,8-Trimethyl-45-(5-(methylsulfonyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(154) (R)-45-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(155) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;(156) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;(157) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)azetidin-3-yl)propan-2-ol;(158) (S)-2-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;(159) (S)-1-(1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;(160) (S)-2-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-ol;(161) (S)-2-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)propan-2-ol;(162) (S)-1-(1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-yl)cyclopropan-1-ol;(163) (S)-2-(2-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)propan-2-ol;(164) (S)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-4-yl)propan-2-ol;(165) (S)-2-(6-(11,13,6-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-2-yl)propan-2-ol;(166) (S)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-2-yl)propan-2-ol;(167) (R)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;(168) (R)-1-((5-Fluoro-6-((S)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)pyrrolidin-3-ol;(169) (S)-1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-ol;(170) (S)-1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-4-ol;(171) (S)-1-((5-Fluoro-6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol;(172) (S)-1-((5-Fluoro-6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)-4-methylpiperidin-4-ol;(173) (R)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-3-ol;(174) (S)-1-((5-Fluoro-6-((S)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)methyl)piperidin-3-ol;(175) (S)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(176) (R)-2-(6-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)propan-2-ol;(177) (S)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(178) (S)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(179) (R)-45-(5-(2-Fluoropropan-2-yl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(180) (S)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;(181) (R)-2-(2-(11,13,8-Trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyrimidin-5-yl)propan-2-ol;(182) (S)-45-(5-(2-Fluoropropan-2-yl)pyrimidin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(183) (S)-45-(5-(2-Fluoropropan-2-yl)pyrimidin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(184) (S)-N,N-Dimethyl-1-(6-(11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;(185) (S)-N,N-Dimethyl-1-(6-(11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)pyridin-3-yl)piperidin-4-amine;(186) (S)-45-(5-(Difluoromethyl)pyridin-2-yl)-11,13,6-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(187) (S)-45-(5-(Difluoromethyl)pyridin-2-yl)-11,13,8-trimethyl-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(188) (S)-11,13,6-Trimethyl-45-(5-(trifluoromethyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(189) (S)-11,13,8-Trimethyl-45-(5-(trifluoromethyl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;(190) (S)-11,13,6-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane; and(191) (S)-11,13,8-Trimethyl-45-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.9.A method of treating protein kinase-mediated disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amountof a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.10.The method of claim 9, wherein the protein kinase-mediated disease is cancer or immune disease.11.The method of claim 10, wherein the cancer is bladder cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, endometrium 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 hematological tumors.12.The method of claim 10, wherein the cancer is lung cancer.13.The method of claim 10, wherein the cancer is non-small cell lung cancer.14.A method of selectively inhibiting at least one mutant of EGFR, in biological sample or in a patient, comprising contacting the biological sample with or administering to a patient a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.15.The method according to claim 14, wherein the at least one mutant is at least one single mutant selected from the group consisting of EGFR Del19 (Del E746-A750) and EGFR L858R.16.The method according to 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.The method according to 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 method according to claim 14, wherein the at least one mutant is at least one triple mutant 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 L858R / T790M / L718X (X=Q, V).19.The method according to 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 a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof as active ingredients.21.The composition of claim 20, the protein kinase-mediated disease is cancer or immune disease.22.The composition of claim 21, wherein the cancer is bladder cancer, colorectal cancer, brain cancer, breast cancer, ovarian cancer, endometrium 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 hematological tumors.23.A pharmaceutical composition for inhibiting at least one mutant of EGFR selectively as compared to wild type EGFR, comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof as active ingredients.

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