EP4658662A1 - Macrocyclic aminopyridine compounds as egfr inhibitors - Google Patents

Macrocyclic aminopyridine compounds as egfr inhibitors

Info

Publication number
EP4658662A1
EP4658662A1 EP24760549.6A EP24760549A EP4658662A1 EP 4658662 A1 EP4658662 A1 EP 4658662A1 EP 24760549 A EP24760549 A EP 24760549A EP 4658662 A1 EP4658662 A1 EP 4658662A1
Authority
EP
European Patent Office
Prior art keywords
pyrazol
ethynyl
pyrazolacyclononaphane
diaza
oxa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24760549.6A
Other languages
German (de)
French (fr)
Inventor
Byoungmoon LEE
Sol Park
Su Bin Choi
Young Ae Yoon
Misong KIM
Yejin Jo
Hyunjoo Lee
Kwan Hoon Hyun
Jae Young Sim
Marian C. Bryan
Scott Kuduk
James Campbell ROBERTSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yuhan Corp
Janssen Biotech Inc
Original Assignee
Yuhan Corp
Janssen Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yuhan Corp, Janssen Biotech Inc filed Critical Yuhan Corp
Publication of EP4658662A1 publication Critical patent/EP4658662A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • 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.
  • EGFR epidermal growth factor receptor
  • NSCLC non-small cell lung cancer
  • 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).
  • EGFR activating mutations such as in-frame deletions in exon 19 deletion (Del19) or a missense mutation in exon 21 (L858R).
  • TKI first and second-generation EGFR tyrosine kinase inhibitors
  • IRESSA TM gefitinib
  • TARCEVA TM erlotinib
  • GIOTRIF TM afatinib
  • 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).
  • 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.
  • 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.
  • 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).
  • the present invention relates to novel macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moiety of Formula (I) shown below, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, halogen, C 1-6 alkyl, or halo-C 1-6 alkyl
  • R 2 and R 3 are, independently each other, hydrogen or C 1-6 alkyl optionally substituted with one or more halogens,
  • B is C 2-3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene
  • A is C 6-10 aryl or 5-10 membered heteroaryl
  • R 4 is selected from the group consisting of
  • -CO-4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
  • n 0, 1, 2 or 3;
  • L is a linear or branched C 3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene,
  • R 5 is hydrogen or halogen
  • Y is CH or N.
  • 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.
  • 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.
  • halo includes fluoro, chloro, bromo and iodo.
  • alkyl refers to an aliphatic hydrocarbon radical, and includes both linear and branched hydrocarbon radicals.
  • C 1-6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
  • the alkyl refers to C 1-6 alkyl, preferably C 1-4 alkyl, more preferably C 1-3 alkyl.
  • alkenyl refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon double bond, and includes both linear and branched hydrocarbon radicals.
  • alkenyl is vinyl, allyl, but-1-enyl or but-2-enyl.
  • alkynyl refers to an aliphatic hydrocarbon radical comprising at least one carbon-carbon triple bond, and includes both linear and branched hydrocarbon radicals.
  • alkynyl is ethynyl, propargyl, but-1-ynyl or but-2-ynyl.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atom, and the alkyl group is defined as above.
  • halo refers to F, Cl, Br, or I, and the term is compatibly used with the term “halogen”.
  • the haloalkyl refers tofluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.
  • 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.
  • hydroxy or "hydroxyl” alone or in combination with other terms means -OH.
  • cycloalkyl refers to a cyclic alkyl which may be substituted or unsubstituted, and for example, the C 3-20 cycloalkyl represents a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms.
  • the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • the cycloalkyl may be C 3-8 cycloalkyl, or C 3-6 cycloalkyl.
  • 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).
  • 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.
  • the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl.
  • 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,
  • heterocycloalkyl refers to 4-12 membered heterocycloalkyl, preferably 4-10 membered heterocycloalkyl, more preferably 4-7 heterocycloalkyl.
  • 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.
  • heteroaryl examples 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.
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furopyridinyl and similar groups thereof, but are not limited thereto.
  • the heteroaryl is 4-12 membered heteroaryl, preferably 4-10 membered heteroaryl, more preferably 4-7 heteroaryl.
  • 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.
  • the compounds or pharmaceutically acceptable salts thereof of the present invention exhibit excellent inhibition activity against the EGFR triple/double mutant s as well as excellent kinase selectivity.
  • the compounds or pharmaceutically acceptable salts thereof of the present invention show excellent bioavailability according to the oral administration, along with improved pharmacokinetic characteristics.
  • 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.
  • the present invention provides compositions and methods for modulating the activity of the epidermal growth factor receptor (EGFR) mutants.
  • the present invention provides compounds which act as inhibitors of EGFR mutants.
  • a compound of Formula (I) shown below a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof:
  • R 1 is hydrogen, halogen, C 1-6 alkyl, or halo-C 1-6 alkyl
  • R 2 and R 3 are, independently each other, hydrogen or C 1-6 alkyl optionally substituted with one or more halogens,
  • B is C 2-3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene
  • A is C 6-10 aryl or 5-10 membered heteroaryl
  • -CO-4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
  • n 0, 1, 2 or 3;
  • L is a linear or branched C 3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene,
  • R 5 is hydrogen or halogen
  • Y is CH or N.
  • R 1 may be hydrogen, halogen, or methyl.
  • R 2 may be hydrogen or methyl.
  • R 2 may be methyl.
  • A may be phenyl, pyrazolyl, triazolyl, pyrazinyl, or pyridinyl.
  • L may be n -propylene, 1-methylpropylene, 3-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene.
  • 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.
  • suitable organic or inorganic acid examples 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.
  • 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.
  • suitable organic or inorganic base include, without limitations, alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N + (C 1-4 alkyl) 4 salts.
  • 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, ox
  • the compounds of the present invention may be synthesized by methods known in the art or by methods illustrated in Examples 1-77 below.
  • 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 amount of a compound of Formula (I) or a pharmaceutically acceptable salt, diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof
  • a compound of Formula (I) or a pharmaceutically acceptable salt diastereomers, enantiomers, racemates, tautomers, prodrugs, hydrates, or solvates thereof
  • the protein kinase-mediated disease is a cancer or immune disease.
  • cancer refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize.
  • 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).
  • the cancer is non-small cell lung cancer (NSCLC).
  • the method disclosed herein relates to treatment of cancer, wherein the cancer results from at least one mutation of EGFR.
  • 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.
  • the kinase inhibitor is a mutated EGFR inhibitor.
  • 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.
  • the at least one mutant is at least one single mutant selected from Table 1 shown below.
  • 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.
  • a 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.
  • 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.
  • 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.
  • 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.
  • treating 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.
  • treatment also refers to the act of treating as “treating” is defined immediately above.
  • treating also includes adjuvant treatment of a mammal.
  • the term "subject” or “patient” encompasses mammals and nonmammals.
  • 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.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition is for treating a protein kinase-mediated disease.
  • the pharmaceutical composition is for selectively inhibiting at least one mutant of EGFR as compared to wild type EGFR.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a base of the suppository witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerogelatin, etc. may be used.
  • 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.
  • 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
  • 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:
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and L are the same as defined in the above;
  • B is C 2-3 alkynylene; and
  • X is halogen.
  • the compound of formula (Ia) or its pharmaceutically acceptable salt may be prepared using a process which comprises: reacting a compound of formula (II) with NH 2 -L(R 5 )-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (III) to obtain a compound of formula (VI), reacting the compound of formula (VI) with a compound of formula (VII) to obtain a compound of formula (VIII), and cyclizing the compound of formula (VIII) to obtain a compound of formula (Ia).
  • the compounds of formula (II), (III), and NH 2 -L(R 5 )-OH are commercially available.
  • the reaction of the compound of formula (II) and NH 2 -L(R 5 )-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 40-120 o C.
  • the compound of formula (IV) is coupled with a compound of formula (III) to obtain a compound of formula (VI) by Sonogashira reaction.
  • the reaction of the compound of formula (IV) and (III) may be performed in the presence of a base such as TEA, diethylamine, etc. and a palladium complex and a copper(I) halide such as PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , copper(I) iodide, etc. as catalysts.
  • the reaction may be carried out in an organic solvent, e.g., TEA or DMF, etc. at room temperature or under heating, e.g. at a temperature of 40-100 o C.
  • the compound of formula (VI) may be obtained by reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (V) and reacting a compound of formula (V) with NH 2 -L(R 5 )-OH.
  • the compound of formula (II) is coupled with a compound of formula (III) to obtain a compound of formula (V) by Sonogashira reaction.
  • the reaction of the compound of formula (II) and (III) may be performed in the presence of a base such as TEA, diethylamine, etc. and a palladium complex and a copper(I) halide such as PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , copper(I) iodide, etc. as catalysts.
  • the reaction may be carried out in an organic solvent, e.g., TEA or DMF, etc. at room temperature or under heating, e.g. at a temperature of 40-100 o C.
  • the reaction of the compound of formula (V) and NH 2 -L(R 5 )-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 40-140 o C.
  • a base such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, TEA, DIPEA, etc.
  • an organic solvent such as anhydrous THF, DMF, DMA, etc. and at room temperature or under heating, e.g., at a temperature of 40-140 o C.
  • the compound of formula (VI) is coupled with a compound of formula (VII) to obtain a compound of formula (VIII) by Mitsunobu reaction.
  • the reaction of the compound of formula (VI) and (VII) 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 90-130 o C.
  • the compound of formula (VIII) is cyclized by Buchwald-Hartwig reaction to obtain the compound of formula (Ia).
  • the cyclization reaction of the compound of formula (VIII) 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 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4, Pd(dppf)Cl 2 , BrettPhos Pd G1 methyl t -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 90-130 o C.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and L are the same as defined in the above.
  • the hydrogenolysis of the compound of formula (Ia) 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.
  • palladium on carbon catalyst such as Pd/C, Pd(OH) 2 /C, etc. under hydrogen atmosphere.
  • an anhydrous organic solvent e.g., THF, DCM, or MeOH at room temperature or under heating.
  • the compound of formula (VII) may be obtained in accordance with the following Scheme 3:
  • R 1, R 2 and R 3 are the same as defined in the above; X is halogen; and M is B(OH) 2 or BPin.
  • the compound of formula (VII) may be prepared using a process which comprises: reacting a compound of formula (IX) with (X) to obtain a compound of formula (XI), and carrying out hydrogenolysis of a compound of formula (XI) to obtain a compound of formula (VII).
  • the compounds of formula (IX) is commercially available.
  • the reaction of the compound of formula (IX) and (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)Cl 2, Pd(PPh 3 ) 4, etc.
  • a base such as sodium carbonate, potassium carbonate, etc.
  • a ligand-coupled palladium catalyst such as Pd(dppf)Cl 2, Pd(PPh 3 ) 4, etc.
  • M is B(OH) 2 or BPin
  • 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 40-100 o C.
  • the hydrogenolysis of the compound of formula (XI) may be performed 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.
  • palladium on carbon catalyst such as Pd/C, Pd(OH) 2 /C, etc. under hydrogen atmosphere.
  • the reaction may be carried out in an anhydrous organic solvent, e.g., THF, DCM, or MeOH at room temperature or under heating.
  • R 2 and R 3 are the same as defined in the above; X is halogen; and M is B(OH) 2 or BPin.
  • the compound of formula (X) may be prepared using a process which comprises: reacting a compound of formula (XII) with Bn-X to obtain a compound of formula (XIII), halogenating a compound of formula (XIII) to obtain a compound of formula (XIV) and borylating a compound of formula (XIV) to obtain a compound of formula (X).
  • the compounds of formula (XII) and Bn-X are commercially available.
  • the reaction of the compound of formula (XII) 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 40-120 o C.
  • the halogenation of the compound of formula (XIII) 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 0-10 o C.
  • halogenating agents such as NIS, NBS, halogen acid, elemental halogens, etc.
  • an anhydrous organic solvent e.g., MeCN, DCM, or DCE at a temperature of 0-10 o C.
  • the borylation of the compound of formula (XIV) may be performed in the presence of boron reagent such as B 2 Pin 2 , B 2 Cat 2 , i PrOBPin, etc. and organometallic reagents such as i PrMgCl ⁇ 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 -10-30 o C.
  • boron reagent such as B 2 Pin 2 , B 2 Cat 2 , i PrOBPin, etc.
  • organometallic reagents such as i PrMgCl ⁇ LiCl complex etc.
  • 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.
  • Step 3 ( S )-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)-5-fluoropyrimidin-4-amine
  • Step 4 ( S )-2 5 -Fluoro-1 1 ,6-dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-2-(5-(3-((2-Chloro-5-((1-(tetrahydro-2 H -pyran-4-yl)-1 H -pyrazol-4-yl)ethynyl) pyridine-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 4 ( S )-1 1 ,6-Dimethyl-4 5 -((1-(tetrahydro-2 H -pyran-4-yl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-2-(5-((4-((2-Chloro-5-((1-(tetrahydro-2 H -pyran-4-yl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • Step 4 ( S )-1 1 ,8-Dimethyl-4 5 -((1-(tetrahydro-2 H -pyran-4-yl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • the title compound as a brown viscous oil (77.30 mg) was prepared in the same fashion as step 3 in Example 2 except that ( S )-3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-1-ol (205.0 mg, 0.68 mmol) prepared in step 1 was used instead of ( S )-3-((2-chloro-5-((1-(tetrahydro-2 H -pyran-4-yl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol.
  • Step 3 ( S )-1 1 ,6-Dimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-1 1 ,8-Dimethyl-4 5 -(pyridin-3-ylethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl -1 H -pyrazol-4-yl)pyrimidin-4-amine
  • the title compound as a pink foamy solid (72.80 mg) was prepared in the same fashion as step 2 in Example 4 except that 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1 H -pyrazol-5-ol (40.34 mg, 0.20 mmol) prepared in Reference Example 8 was used instead of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol.
  • Example 7 1 1 ,7,7-Trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • reaction mixture was heated at 120 o C for 3 hours.
  • Step 4. 1 ,7,7-Trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • reaction mixture was stirred at 95 o C for 2 hours.
  • the reaction mixture was added to water and extracted with DCM.
  • Example 8 1 ,6,6-Trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutan-1-ol
  • the title compound as a brown solid (62 mg) was prepared in the same fashion as step 3 in Example 7, except that 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutan-1-ol (63.97 mg, 0.165 mmol) prepared in step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol.
  • Step 3 1 ,6,6-Trimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • the title compound as a white solid (20 mg) was prepared in the same fashion as step 4 in Example 7, except that 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine (60 mg, 0.107 mmol) prepared in step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine.
  • Step 1 ( R )-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • Step 2 ( R )-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 3 ( R )-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • Step 2 -2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • the title compound as a pale brown solid (53 mg) was prepared in the same fashion as step 3 in Example 7, except that ( S )-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (80.84 mg, 0.215 mmol) prepared in step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol.
  • Step 3 ( S )-7-Fluoro-1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 -6-Methyl-1 1 -(2,2,2-trifluoroethyl)-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-1 1 ,1 3 ,6-Trimethyl-4 5 -((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 4 ( S )-1 1 ,6-Dimethyl-4 5 -((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 4 ( S )-1 1 ,6-Dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-4 5 -((1-(Difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,1 3 ,6-trimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • the title compound as a solid (123 mg, 0.347 mmol, 56.61% yield) was prepared in the same fashion as step 1 in Example 15 except that 1-(2,2-difluoroethyl)-4-ethynyl-1 H -pyrazole (95.62 mg, 0.612 mmol) was used instead of 1-(difluoromethyl)-4-ethynyl-1 H -pyrazole.
  • Step 3 ( S )-4 5 -((1-(2,2-Difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,1 3 ,6-trimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • the title compound as a solid (137.00 mg, 0.407 mmol, 66.42% yield) was prepared in the same fashion as step 1 in Example 15 except that 4-ethynyl-1-(2-fluoroethyl)-1 H -pyrazole (95.62 mg, 0.612 mmol) was used instead of 1-(difluoromethyl)-4-ethynyl-1 H -pyrazole.
  • Step 3 ( S )-4 5 -((1-(2-Fluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,1 3 ,6-trimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-4 5 -((1-Isopropyl-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-1 1 ,6-Dimethyl-4 5 -((1-methyl-1 H -pyrazol-3-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-1 1 ,6-Dimethyl-4 5 -((1-methyl-3-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • the title compound as a solid (138.00 mg, 0.400 mmol, 65.34% yield) was prepared in the same fashion as step 1 in Example 18 except that 3-cyclopropyl-4-ethynyl-1-methyl-1 H -pyrazole (89.53 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1 H -pyrazole.
  • Step 3 ( S )-4 5 -((5-Cyclopropyl-1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-3-((2-Chloro-5-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • the title compound as a white solid (41 mg) was prepared in the same fashion as step 2 in Example 22 except that ( S )-3-((2-chloro-5-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (75.88 mg, 0.209 mmol) prepared in step 1 was used instead of ( S )-3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol.
  • Step 3 ( S )-7-Fluoro-1 1 -methyl-4 5 -((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( R )-3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • the title compound as a white solid (72 mg) was prepared in the same fashion as step 2 in Example 22 except that ( R )-3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (77.51 mg, 0.251 mmol) prepared in step 1 was used instead of ( S )-3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol.
  • Step 3 ( R )-7-Fluoro-1 1 -methyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-1 1 ,8-Dimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • the title compound as a white solid was prepared in the same fashion as step 2 in Example 22 except that ( R )-4-((2-chloro-5-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (75.06 mg, 0.209 mmol) prepared in step 1 was used instead of ( S )-3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol.
  • Step 3 ( S )-1 1 ,8-Dimethyl-4 5 -((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( R )-4-((2-Chloro-5-((1-(2,2-difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • Step 3 ( S )-4 5 -((1-(2,2-Difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,8-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Example 28 ( S )-1 1 ,8-Dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( R )-4-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • Step 2 -2-(5-((4-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 3 ( S )-1 1 ,8-Dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Example 29 1'-Methyl-5'-((1-methyl-1 H -pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Step 1 (1-(((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methanol
  • the title compound as a white solid (47 mg) was prepared in the same fashion as step 2 in Example 22 except that 3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (79.53 mg, 0.251 mmol) prepared in step 1 was used instead of ( S )-3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol.
  • Step 3 1'-Methyl-5'-((1-methyl-1 H -pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • the title compound as an off-white solid (3 mg) was prepared in the same fashion as step 3 in Example 22 except that 2-(5-((1-(((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine (45.75 mg, 0.093 mmol) prepared in step 2 was used instead of ( S )-2-(5-(3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine.
  • Example 30 1 1 ,7,7-Trimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol
  • the title compound as a white solid (46 mg) was prepared in the same fashion as step 2 in Example 22 except that 3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (80.04 mg, 0.251 mmol) prepared in step 1 was used instead of ( S )-3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol.
  • Step 3 1 ,7,7-Trimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • the title compound as an off-white solid (10.2 mg) was prepared in the same fashion as step 3 in Example 22 except that 2-(5-(3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine (45.94 mg, 0.093 mmol) prepared in step 2 was used instead of ( S )-2-(5-(3-((2-chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine.
  • Step 3 ( S )-1 1 ,6-Dimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( R )-1 1 ,6-Dimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( R )-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • Step 2 ( R )-2-(5-(3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 3 ( R )-4 5 -((1-(2,2-Difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • Step 3 ( S )-4 5 -((1-(2,2-Difluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Example 35 (6 S )-4 5 -((1-(2,2-Difluorocyclopropyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 (6 S )-4 5 -((1-(2,2-Difluorocyclopropyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Example 36 1 1 -Methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 2. 1 1 -Methyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( S )-4 5 -((1-(Difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( R )-4 5 -((1-(Difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( R )-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • Step 2 ( R )-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 3 ( R )-1 1 ,6-Dimethyl-4 5 -((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 3 ( R )-1 1 ,6-Dimethyl-4 5 -((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Example 41 (6 R )-4 5 -((1-(2,2-Difluorocyclopropyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 (3 R )-3-((2-Chloro-5-((1-(2,2-difluorocyclopropyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • Step 3 (6 R )-4 5 -((1-(2,2-Difluorocyclopropyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( R )-3-((2-Chloro-5-((1-(2-fluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • Step 3 ( R )-4 5 -((1-(2-Fluoroethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 ,6-dimethyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 -6-Methyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 -(2,2,2-trifluoroethyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 -1 1 -Ethyl-6-methyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 ( S )-4 5 -((1-(Difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-6-methyl-1 1 -(2,2,2-trifluoroethyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 ( S )-4 5 -((1-(Difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 -ethyl-6-methyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 ( S )-4 5 -((1-(Difluoromethyl)-1 H -pyrazol-4-yl)ethynyl)-1 1 -isopropyl-6-methyl-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)-5-methylpyrimidin-4-amine
  • Step 2 ( S )-1 1 ,2 5 ,6-Trimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1 H -pyrazol-4-yl)-6-methylpyrimidin-4-amine
  • Step 2 ( S )-1 1 ,2 6 ,6-Trimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1 ( S )-2-(5-(3-((2-Chloro-5-((1-methyl-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1 H -pyrazol-4-yl)pyrimidin-4-amine
  • Step 2 ( S )-1 1 ,1 3 ,6-Trimethyl-4 5 -((1-methyl-1 H -pyrazol-4-yl)ethynyl)-1 1 H -9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Example 51 1'-Methyl-5'-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Step 1 (3-(((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol
  • Step 3 1'-Methyl-5'-((1-(2,2,2-trifluoroethyl)-1 H -pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Example 52 1'-Methyl-5'-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Step 1 (3-(((2-Chloro-5-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol
  • Step 3 1'-Methyl-5'-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]

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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
  • 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.
    •
  • 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).
  • 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • References
  • Arulananda S, John T, Dobrovic A. et al. Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non-Small Cell Lung Cancer. Journal of Thoracic Oncology Vol. 12 No. 11: 1728-1732, 2017.
  • Chen JS, Riess JW. Advances in targeting acquired resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors. Justin A. Chen, Jonathan W. Riess. J Thorac Dis 2020; 12(5):2859-2876.
  • Engelhardt H, et al. Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors. Cite This: J. Med. Chem. 2019, 62, 10272-10293.
  • Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr. Oncol. 2010; 17: S18-30.
  • Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharm Sin B 2015; 5:390-401.
  • Kashima K, et al. CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation. Mol Cancer Ther; 19(11) November 2020.
  • Leonetti A, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. British Journal of Cancer (2019) 121:725-737.
  • Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-57.
  • Mehlman C, Cadranel J, Rousseau-Bussac G, Lacave R, Pujals A, Girard N, et al. Resistance mechanisms to osimertinib in EGFR-mutated advanced non-smallcell lung cancer: A multicentric retrospective French study. Lung Cancer 2019; 137:149-56.
  • Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018; 4:1527-34.
  • Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J. Clin. Oncol. 2018; 36:841-9.
  • Rangachari D, To C, Shpilsky JE, VanderLaan PA, Kobayashi SS, MushajiangM, et al. EGFR-mutated lung cancers resistant to osimertinib through EGFR C797S respond to first-generation reversible EGFR inhibitors but eventually acquire EGFR T790M/C797S in preclinical models and clinical samples. J. Thorac. Oncol. 2019; 14:1995-2002.
  • Schalm S, et al. BLU-945, a highly potent and selective 4th-generation EGFR TKI for the treatment of EGFR+/T790M/C797S resistant NSCLC. 2020, ESMO.
  • Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 2013; 31:3327-34.
  • Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97:339-46.
  • Shu Y, WuX, Tong X, WangX, Chang Z, MaoY, et al. Circulating tumor DNA mutation profiling by targeted next generation sequencing provides guidance for personalized treatments in multiple cancer types. Sci Rep 2017; 7:583.
  • Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H. et al. Osimertinib in untreated EGFR -mutated advanced non-small cell lung cancer. N. Engl. J. Med 378, 113-125 (2018).
  • Starrett JH,Guernet AA, CuomoME, Poels KE, van Alderwerelt van Rosenburgh IK, Nagelberg A, et al. Drug sensitivity and allele-specificity of first-line osimertinib resistance EGFR mutations. Cancer Res 2020; 80:2017-30.
  • Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer 2015; 88:74-9.
  • Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 2015; 21:560-2.
  • Wee, P.; Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017, 9, 52.
  • Yewale C, Baradia D, Vhora I, et al. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials 2013; 34:8690-707.
  • Yang Z, Yang N, et al. Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Clin Cancer Res; 2018
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  • Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12:735-42.
  • Zhou Z, Zhao Y, Shen S, Gu L,Niu X, Xu Y, et al. Durable clinical response of lung adenocarcinoma harboring EGFR 19Del/T790M/in trans-C797S to combination therapy of first- and third-generation EGFR tyrosine kinase inhibitors. J. Thorac. Oncol. 2019; 14:e157-e9.
    •
  • SUMMARY OF INVENTION
  • The present invention relates to novel macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moiety of Formula (I) shown below, or a pharmaceutically acceptable salt thereof:
  • wherein
  • R1 is hydrogen, halogen, C1-6 alkyl, or halo-C1-6 alkyl,
  • R2 and R3 are, independently each other, hydrogen or C1-6 alkyl optionally substituted with one or more halogens,
  • B is C2-3 alkylene, C2-3 alkenylene or C2-3 alkynylene,
  • A is C6-10 aryl or 5-10 membered heteroaryl,
  • R4 is selected from the group consisting of
  • hydrogen,
  • halogen,
  • -CN,
  • -S(O)2-C1-6 alkyl,
  • 4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
  • -CO-4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
  • C1-6 alkoxy optionally substituted by one or more halogens;
  • C1-6 alkyl optionally substituted by one or more halogens; and
  • C3-6 cycloalkyl optionally substituted by one or more halogens,
  • n is 0, 1, 2 or 3;
  • L is a linear or branched C3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene,
  • R5 is hydrogen or halogen, and
  • Y is CH or N.
  • 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.
  • 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.
    •
  • DETAILED DESCRIPTION OF THE INVENTION
  • Hereinafter, the present invention will be described in more detail.
  • 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.
  • 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.
  • As used herein, the term "halo", "halogen", "halide(s)" includes fluoro, chloro, bromo and iodo.
  • As used herein, the "alkyl" refers to an aliphatic hydrocarbon radical, and includes both linear and branched hydrocarbon radicals. For example, C1-6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. Unless otherwise defined, the alkyl refers to C1-6 alkyl, preferably C1-4 alkyl, more preferably C1-3 alkyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • As used herein, the term "hydroxy"or "hydroxyl" alone or in combination with other terms means -OH.
  • As used herein,the term "cycloalkyl" refers to a cyclic alkyl which may be substituted or unsubstituted, and for example, the C3-20 cycloalkyl 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 C3-8 cycloalkyl, or C3-6 cycloalkyl.
  • 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).
  • 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 membered heterocycloalkyl, more preferably 4-7 heterocycloalkyl.
  • 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 membered heteroaryl, more preferably 4-7 heteroaryl.
  • 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 the EGFR triple/double mutants as 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.
  • 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.
  • 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.
  • 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:
  • wherein
  • R1 is hydrogen, halogen, C1-6 alkyl, or halo-C1-6 alkyl,
  • R2 and R3 are, independently each other, hydrogen or C1-6 alkyl optionally substituted with one or more halogens,
  • B is C2-3 alkylene, C2-3 alkenylene or C2-3 alkynylene,
  • A is C6-10 aryl or 5-10 membered heteroaryl,
  • R4 is selected from the group consisting of
  • hydrogen,
  • halogen,
  • -CN,
  • -S(O)2-C1-6 alkyl,
  • 4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
  • -CO-4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
  • C1-6 alkoxy optionally substituted by one or more halogens;
  • C1-6 alkyl optionally substituted by one or more halogens; and
  • C3-6 cycloalkyl optionally substituted by one or more halogens,
  • n is 0, 1, 2 or 3;
  • L is a linear or branched C3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene,
  • R5 is hydrogen or halogen, and
  • Y is CH or N.
  • In certain embodiment, R1 may be hydrogen, halogen, or methyl.
  • In certain embodiment, R2 may be hydrogen or methyl. Preferably, R2 may be methyl.
  • In certain embodiment, B may be -CH2CH2-, -CH=CH-, or -C≡C-.
  • In certain embodiment, A may be phenyl, pyrazolyl, triazolyl, pyrazinyl, or pyridinyl.
  • In certain embodiment, L may be n-propylene, 1-methylpropylene, 3-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene.
  • Representative compounds of Formula (I) are listed below:
  • (1) (S)-25-Fluoro-11,6-dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (2) (S)-11,6-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (3) (S)-11,8-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (4) (S)-11,6-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (5) (S)-11,8-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (6) (S)-11,13,6-Trimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (7) 11,7,7-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (8) 11,6,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (9) (R)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (10) (S)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (11) (S)-6-Methyl-11-(2,2,2-trifluoroethyl)-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (12) (S)-11,13,6-Trimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (13) (S)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (14) (S)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (15) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (16) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (17) (S)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (18) (S)-45-((1-Isopropyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (19) (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (20) (S)-11,6-Dimethyl-45-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (21) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (22) (S)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (23) (S)-7-Fluoro-11-methyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (24) (R)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (25) (S)-11,8-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (26) (S)-11,8-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (27) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,8-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (28) (S)-11,8-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (29) 1'-Methyl-5'-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];
  • (30) 11,7,7-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (31) (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (32) (R)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (33) (R)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (34) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (35) (6S)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (36) 11-Methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (37) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (38) (R)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (39) (R)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (40) (R)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (41) (6R)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (42) (R)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (43) (S)-6-Methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (44) (S)-11-Ethyl-6-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (45) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-6-methyl-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (46) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-ethyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (47) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-isopropyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (48) (S)-11,25,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (49) (S)-11,26,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (50) (S)-11,13,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (51) 1'-Methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];
  • (52) 1'-Methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];
  • (53) (S)-11,6-Dimethyl-45-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (54) (S)-11,6-Dimethyl-45-((5-methylpyrazin-2-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (55) (S,E)-11,6-Dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (56) (S)-11,6-Dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (57) (S)-11,13,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (58) (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane;
  • (59) (S)-(4-Hydroxypiperidin-1-yl)(4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)phenyl)methanone;
  • (60) (S)-11,13,8-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (61) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (62) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (63) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (64) (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (65) (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (66) (S)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
  • (67) (S)-11,13,8-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (68) (S)-11,13,6-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (69) (S)-11,13,6-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (70) (S)-11,13,8-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (71) (S)-1-Methyl-4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
  • (72) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (73) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (74) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (75) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (76) (R)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile; and
  • (77) (R)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.
  • Further representative compounds of Formula (I) are listed below:
  • (6) (S)-11,13,6-Trimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (16) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (17) (S)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (50) (S)-11,13,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (59) (S)-(4-Hydroxypiperidin-1-yl)(4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)phenyl)methanone.
  • (60) (S)-11,13,8-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (61) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (62) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (63) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (66) (S)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
  • (67) (S)-11,13,8-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (68) (S)-11,13,6-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (70) (S)-11,13,8-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (71) (S)-1-Methyl-4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
  • (72) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (73) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (74) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (75) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (76) (R)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile; and
  • (77) (R)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane.
  • Further preferable representative compounds of Formula (I) are listed below:
  • (50) (S)-11,13,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (61) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (63) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (66) (S)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
  • (67) (S)-11,13,8-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (72) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (73) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
  • (75) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • The compounds of the present inventionmay be synthesized by methods known in the art or by methods illustrated in Examples 1-77 below.
  • PHARMACEUTICAL COMPOSITIONS, METHODS AND USE
  • 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 amount of 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.
  • 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).
  • In one embodiment, the method disclosed herein relates to treatment of cancer, wherein the cancer results from at least one mutation of EGFR.
  • 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.
  • 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.
  • In one embodiment, the at least one mutant is at least one single mutant selected from Table 1 shown below.
  • Number (#) Mutation type
    1 EGFR Del19 (Del E746-A750)
    2 EGFR L858R
    3 EGFR Del19/T790M
    4 EGFR Del19/C797S
    5 EGFR Del19/C797X (X=G, N)
    6 EGFR Del19/L792X (X=F, H, P, R, V, Y)
    7 EGFR Del19/L718X (X=Q, V)
    8 EGFR L858R/T790M
    9 EGFR L858R/C797S
    10 EGFR L858R/C797X (X=G, N)
    11 EGFR L858R/L792X (X=F, H, P, R, V, Y)
    12 EGFR L858R/L718X (X=Q, V)
    13 EGFR Del19/T790M/C797S
    14 EGFR Del19/T790M/C797X (X=G, N)
    15 EGFR Del19/T790M/L792X (X=F, H, P, R, V, Y)
    16 EGFR Del19/T790M/L718X (X=Q, V)
    17 EGFR L858R/T790M/C797S
    18 EGFR L858R/T790M/C797X (X=G, N)
    19 EGFR L858R/T790M/L792X (X=F, H, P, R, V, Y)
    20 EGFR L858R/T790M/L718X (X=Q, V)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • GENERAL REACTION SCHEME AND SUMMARY OF THE SYNTHESIS ROUTE
  • 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:
  • Scheme 1.
  • In the Scheme 1, R1, R2, R3, R4, R5, A and L are the same as defined in the above; B is C2-3 alkynylene; and X is halogen.
  • Specifically, the compound of formula (Ia) or its pharmaceutically acceptable salt may be prepared using a process which comprises: reacting a compound of formula (II) with NH2-L(R5)-OH to obtain a compound of formula (IV), reacting the compound of formula (IV) with a compound of formula (III) to obtain a compound of formula (VI), reacting the compound of formula (VI) with a compound of formula (VII) to obtain a compound of formula (VIII), and cyclizing the compound of formula (VIII) to obtain a compound of formula (Ia).
  • In the processes of Scheme 1, the compounds of formula (II), (III), and NH2-L(R5)-OH are commercially available. The reaction of the compound of formula (II) and NH2-L(R5)-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.
  • The compound of formula (IV) is coupled with a compound of formula (III) to obtain a compound of formula (VI) by Sonogashira reaction. The reaction of the compound of formula (IV) and (III) may be performed in the presence of a base such as TEA, diethylamine, etc. and a palladium complex and a copper(I) halide such as PdCl2(PPh3)2, Pd(PPh3)4, copper(I) iodide, etc. as catalysts. Further, the reaction may be carried out in an organic solvent, e.g., TEA or DMF, etc. at room temperature or under heating, e.g. at a temperature of 40-100oC.
  • Alternately, the compound of formula (VI) may be obtained by reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (V) and reacting a compound of formula (V) with NH2-L(R5)-OH.
  • The compound of formula (II) is coupled with a compound of formula (III) to obtain a compound of formula (V) by Sonogashira reaction. The reaction of the compound of formula (II) and (III) may be performed in the presence of a base such as TEA, diethylamine, etc. and a palladium complex and a copper(I) halide such as PdCl2(PPh3)2, Pd(PPh3)4, copper(I) iodide, etc. as catalysts. Further, the reaction may be carried out in an organic solvent, e.g., TEA or DMF, etc. at room temperature or under heating, e.g. at a temperature of 40-100oC.
  • The reaction of the compound of formula (V) and NH2-L(R5)-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.
  • The compound of formula (VI) is coupled with a compound of formula (VII) to obtain a compound of formula (VIII) by Mitsunobu reaction. The reaction of the compound of formula (VI) and (VII) 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.
  • The compound of formula (VIII) is cyclized by Buchwald-Hartwig reaction to obtain the compound of formula (Ia). The cyclization reaction of the compound of formula (VIII) 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 methyl t-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.
  • Alternately, the compound of formula (Ib) may be obtained in accordance with the following Scheme 2:
  • Scheme 2.
  • In the Scheme 2, R1, R2, R3, R4, R5, A and L are the same as defined in the above.
  • The hydrogenolysis of the compound of formula (Ia) 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.
  • In an embodiment, the compound of formula (VII) may be obtained in accordance with the following Scheme 3:
  • Scheme 3.
  • In the Scheme 3, R1, R2 and R3 are the same as defined in the above; X is halogen; and M is B(OH)2 or BPin.
  • Specifically, the compound of formula (VII) may be prepared using a process which comprises: reacting a compound of formula (IX) with (X) to obtain a compound of formula (XI), and carrying out hydrogenolysis of a compound of formula (XI) to obtain a compound of formula (VII).
  • In the processes of Scheme 3, the compounds of formula (IX) is commercially available. The reaction of the compound of formula (IX) and (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, in case that M is B(OH)2 or BPin, 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.
  • The hydrogenolysis of the compound of formula (XI) may be performed 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.
  • In another embodiment, the compound of formula (X) may be prepared in accordance with the following Scheme 4:
  • Scheme 4.
  • In the Scheme 4, R2 and R3 are the same as defined in the above; X is halogen; and M is B(OH)2 or BPin.
  • Specifically, the compound of formula (X) may be prepared using a process which comprises: reacting a compound of formula (XII) with Bn-X to obtain a compound of formula (XIII), halogenating a compound of formula (XIII) to obtain a compound of formula (XIV) and borylating a compound of formula (XIV) to obtain a compound of formula (X).
  • In the processes of Scheme 4, the compounds of formula (XII) and Bn-X are commercially available. The reaction of the compound of formula (XII) 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.
  • The halogenation of the compound of formula (XIII) 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 0-10 oC.
  • The borylation of the compound of formula (XIV) may be performed in the presence of boron reagent such as B2Pin2, B2Cat2, iPrOBPin, etc. and organometallic reagents such as iPrMgCl·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 -10-30 oC.
  • EXAMPLES
  • 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.
  • 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 each Example 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:
  • Table 2
  • List of abbreviations
  • Reference Example 1. (S)-3-((2-Chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol The suspension of 2-chloro-4-fluoro-5-iodopyridine (350 mg, 1.36 mmol), (2S)-3-amino-2-fluoro-propan-1-ol (126.58 mg, 1.36 mmol), and DIPEA (0.59 mL, 3.399 mmol) in DMA (6.06 mL) was stirred at 90 oC for 3 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 (EA/n-Hex = 0-50%) to yield (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol (375 mg, 1.135 mmol, 83.45% yield) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 6.51 (s, 1H), 5.21 (brs, 1H), 4.90-4.73 (m, 1H), 4.02-3.83 (m, 2H), 3.62 (t, 1H), 3.58 (t, 1H), 2.37 (t, 1H)
  • Reference Example 2. (R)-3-((2-Chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol
  • The title compound as an off-white solid (402 mg) was prepared in the same fashion as Reference Example 1 except that (2R)-3-amino-2-fluoro-propan-1-ol (93.1 mg, 1.36 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 6.50 (s, 1H), 5.22 (brs, 1H), 4.89-4.73 (m, 1H), 4.01-3.84 (m, 2H), 3.64-3.56 (m, 2H), 2.62 (brs, 1H)
  • Reference Example 3. (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol
  • The title compound as an off-white solid (406 mg) was prepared in the same fashion as Reference Example 1 except that (R)-4-aminobutan-2-ol (89.14 mg, 1.36 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 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)
  • Reference Example 4. (1-(((2-Chloro-5-iodopyridin-4-yl)amino)methyl)cyclopropyl)methanol
  • The title compound as an off-white solid (402 mg) was prepared in the same fashion as Reference Example 1 except that (1-(aminomethyl)cyclopropyl)methanol (101.15 mg, 1.632 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 6.36 (s, 1H), 5.68 (brs, 1H), 3.64 (s, 2H), 3.20 (d, 2H), 2.46 (brs, 1H), 0.67-0.60 (m, 4H)
  • Reference Example 5. 3-((2-Chloro-5-iodopyridin-4-yl)amino)-2,2-dimethylpropan-1-ol
  • The title compound as an off-white solid (402 mg) was prepared in the same fashion as Reference Example 1 except that 3-amino-2,2-dimethylpropan-1-ol (103.16 mg, 1.632 mmol) was used instead of (2S)-3-amino-2-fluoro-propan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 6.45 (s, 1H), 5.72 (brs, 1H), 3.56 (d, 2H), 3.12 (d, 2H), 2.04 (t, 1H), 1.05 (s, 6H)
  • Reference Example 6. (S)-3-((2-Chloro-5-iodopyridin-4-yl)amino)butan-1-ol
  • 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 90 oC for 3 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 (EA/n-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); MS (ESI) m/z = 327.1 (M + H)+
  • Reference Example 7. 4-(4-Aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol
  • Step 1. 5-(Benzyloxy)-1-methyl-1H-pyrazole
  • To a solution of 1-methyl-1H-pyrazol-5-ol (50.0 g, 0.51 mol) in DMF (500 mL) 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)+
  • Step 2. 5-(Benzyloxy)-4-iodo-1-methyl-1H-pyrazole
  • To a solution of 5-(benzyloxy)-1-methyl-1H-pyrazole (44.4 g, 236 mmol) prepared in step 1 in MeCN (675 mL) was added N-iodosuccinimide (53.1 g, 236 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3 solution 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-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)+
  • Step 3. 5-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
  • To a stirred solution 5-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole (41.5 g, 132 mmol) prepared in step 2 in THF (420 mL), was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 112 mL, 145 mmol) at -10-0 ℃ 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)+
  • Step 4. 2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of 2-bromopyrimidin-4-amine (16.0 g, 91.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28.9 g, 91.9 mmol) prepared in step 3 in 1,4-dioxane (460 mL) were added 3 M K2CO3 soln. (91.9 mL, 276 mmol) and Pd(dppf)Cl2 dichloromethane 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)+
  • Step 5. 4-(4-Aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol
  • To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (12.3 g, 43.7 mmol) prepared in step 4 in methanol (120 mL) was added Pd(OH)2 on carbon (20% Pd, 120 mg) and stirred under H2 atmosphere 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)+
  • Reference Example 8. 4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol
  • Step 1. 5-(Benzyloxy)-1,3-dimethyl-1H-pyrazole
  • To a solution of 1,3-dimethyl-1H-pyrazol-5-ol (13.0 g, 116 mmol) in THF (500 mL) 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)+
  • Step 2. 5-(Benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole
  • To a solution of 5-(benzyloxy)-1,3-dimethyl-1H-pyrazole (9.20 g, 45.5 mmol) prepared in step 1 in MeCN (100 mL) was added N-iodosuccinimide (10.2 g, 45.5 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3 solution 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)+
  • Step 3. 5-(Benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
  • To a stirred solution 5-(benzyloxy)-4-iodo-1,3-dimethyl-1H-pyrazole (7.40 g, 22.6 mmol) prepared in step 2 in THF (75 mL), was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 26 mL, 33.8 mmol) at -10-0 ℃ 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)+
  • Step 4. 2-(5-(Benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of 2-bromopyrimidin-4-amine (530 mg, 3.05 mmol) and 5-(benzyloxy)-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 3.05 mmol) prepared in step 3 in 1,4-dioxane (15 mL) were added 3 M K2CO3 soln. (3.05 mL, 9.14 mmol) and Pd(dppf)Cl2 dichloromethane 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)+
  • Step 5. 4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (1.26 g, 4.27 mmol) prepared in step 4 in methanol (15 mL) was added Pd(OH)2 on carbon (20% Pd, 126 mg) and stirred under H2 atmosphere 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)+
  • Reference Example 9. 4-(4-Amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • Step 1. 2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine
  • To a solution of 2-chloro-5-fluoropyrimidin-4-amine (2.11 g, 14.3 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.50 g, 14.3 mmol) prepared in step 3 in Reference Example 7 in dioxane (70.0 mL) was added a 3 M K2CO3 soln. (14.3 mL, 42.9 mmol) and Pd(dppf)Cl2, complex with dichloromethane (1.16 g, 1.43 mmol). The mixture was degassed by argon and then stirred at 90 ℃ for overnight. Upon completion, the mixture was diluted with water and extracted several times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA/DCM = 0-80%) to yield 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (960.0 mg, 22% yield) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 8.06 (d, 1H), 7.85 (s, 1H), 7.35 (s, 5H), 5.41 (s, 2H), 3.38 (s, 3H); MS (ESI) m/z = 300.1 (M + H)+
  • Step 2. 4-(4-Amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (270.0 mg, 0.90 mmol) in methanol (1.0 mL) and THF (3.5 mL) was added acetic acid (1 drop), Pd(OH)2 on carbon (108.0 mg, 40% wt) under H2 atmosphere. The reaction mixture was stirred at 55 oC for 3 hours, filtered through celite pad and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM = 10-30%) to yield 4-(4-amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (186.0 mg, 0.89 mmol, 98.6% yield). 1H-NMR (DMSO-d 6, 400 MHz) δ 8.15-8.14 (m, 3H), 7.49 (s, 1H), 3.16 (s, 3H); MS (ESI) m/z = 210.0 (M + H)+
  • Reference Example 10. 2-Chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (3.50 g, 13.600 mmol), 4-ethynyl-1-methylpyrazole (1.59 g, 14.956 mmol), PdCl2(PPh3)2 (477 mg, 0.680 mmol), and CuI (518 mg, 2.719 mmol) was charged nitrogen gas for 10 minutes. After DMF (40 mL) and TEA (3.79 mL, 27.192 mmol) were added, the reaction mixture was stirred at 50 oC for 1 hour. 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 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine (2.00 g) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.49 (d, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.13 (d, 1H), 3.93 (s, 3H); MS (ESI) m/z = 236.0 (M + H)+
  • Reference Example 11. 2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.0 g, 3.88 mmol), 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (606 mg, 3.88 mmol), PdCl2(PPh3)2 (136 mg, 0.19 mmol), and CuI (148 mg, 0.78 mmol) was charged nitrogen gas for 10 minutes. After DMF (20 mL) and TEA (1.08 mL, 7.77 mmol) were added, the reaction mixture was stirred at 50 oC for 1 hour. 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 2-chloro-5-((1-(2,2-difluoroethyl-1H-pyrazol-4-yl)ethynyl)4-fluoropyridine (0.9 g) as an off-white solid. MS (ESI) m/z = 285.9 (M + H)+
  • Reference Example 12. 2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • Step 1. 3-((2-Chloro-5-iodopyridin-4-yl)amino)propan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (0.50 g, 1.942 mmol) and 3-amino-1-propanol (145 mg, 1.942 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.68 mL, 3.885 mmol) were added, the reaction mixture was stirred at 80 oC overnight. The reaction mixture was cooled, diluted in EA, waed by water, dried over MgSO4, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex = 0-40%) to yield 3-((2-chloro-5-iodopyridin-4-yl)amino)propan-1-ol (595 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 2H), 6.43 (s, 1H), 5.39 (s, 1H), 3.89-3.85 (q, 2H), 3.39-3.34 (q, 2H), 1.98-1.92 (m, 2H); MS (ESI) m/z = 312.9 (M + H)+
  • Step 2. 2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 3-((2-chloro-5-iodopyridin-4-yl)amino)propan-1-ol (570 mg, 1.824 mmol) prepared in step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (348.69 mg, 1.824 mmol) prepared in Reference Example 7 and (tributylphosphoranylidene)acetonitrile (1.75 mL, 6.383 mmol) in toluene (2 mL) was stirred at 100 oC 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-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (427 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.26-8.25 (d, 2H), 8.17-8.15 (d, 1H), 8.01 (s, 1H), 6.45 (s, 1H), 6.25-6.24 (d, 1H), 5.69 (s, 1H), 5.42 (s, 1H), 4.42-4.39 (t, 2H), 3.73 (s, 3H), 3.56-3.54 (d, 2H), 1.75-1.68 (m, 1H), 1.53-1.39 (m, 1H); MS (ESI) m/z = 486.0 (M + H)+
  • Reference Example 13. 2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.902 g, 7.389 mmol), 1-(difluoromethyl)-4-ethynyl-1H-pyrazole (1.00 g, 7.037 mmol), PdCl2(PPh3)2 (246 mg, 0.352 mmol), and CuI (268 mg, 1.407 mmol) was charged nitrogen gas for 10 minutes. After DMF (50 mL) and TEA (1.96 mL, 14.074 mmol) were added, the reaction mixture was stirred at 50 oC 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 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (1.39 g) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.51-8.49 (d, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.35-7.05 (m, 2H); MS (ESI) m/z = 272.0 (M + H)+
  • Reference Example 14. (R)-3-((2-Chloro-5-iodopyridin-4-yl)amino)butan-1-ol
  • 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) were added, the reaction mixture was stirred at 80 oC 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, 400 MHz) δ 8.20 (s, 1H), 6.44 (s, 1H), 5.13-5.11 (d, 1H), 3.85-3.80 (q, 2H), 1.91-1.88 (q, 1H), 1.82-1.78 (t, 1H), 1.29-1.25 (d, 3H); MS (ESI) m/z = 327.0 (M + H)+
  • Reference Example 15. 4-(4-Aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol
  • Step 1. 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-5-ol
  • To a solution of (2,2,2-trifluoroethyl)hydrazine hydrochloride (20.0 g, 133 mmol) in ethanol (200 mL) 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.
  • Step 2. 5-(Benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazole
  • To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (30.0 g, 180.6 mmol) prepared in step 1 in DMF (300 mL) 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)+
  • Step 3. 5-(Benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole
  • To a solution of 5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g, 31.2 mmol) prepared in step 2 in MeCN (80 mL) was added N-iodosuccinimide (7.02 g, 31.2 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3 solution 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) δ 7.46-7.40 (m, 6H), 5.33 (s, 2H), 4.36 (q, 2H); MS (ESI) m/z = 383.0 (M + H)+
  • Step 4. 5-(Benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole
  • To a stirred solution 5-(benzyloxy)-4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (8.0 g, 20.9 mmol) prepared in step 3 in THF (90 mL), was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 17.7 mL, 23.1 mmol) at -10-0 ℃ 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)+
  • Step 5. 2-(5-(Benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of 2-bromopyrimidin-4-amine (2.3 g, 13.2 mmol) and 5-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.6 g, 12.0 mmol) prepared in step 4 in 1,4-dioxane (60 mL) were added 3 M K2CO3 soln. (12.0 mL, 36.1 mmol) and Pd(dppf)Cl2 dichloromethane 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, J = 6.0 Hz, 1H), 7.98 (s, 1H), 7.38-7.35 (m, 5H), 6.36 (d, 1H), 5.49 (s, 2H), 4.53 (q, 2H); MS (ESI) m/z = 350.2 (M + H)+
  • Step 6. 4-(4-Aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (450 mg, 1.29 mmol) prepared in step 5 in methanol (5 mL) was added Pd(OH)2 on carbon (20% Pd, 45 mg) and stirred under H2 atmosphere 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)+
  • Reference Example 16. 4-(4-Aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol
  • Step 1. 5-(Benzyloxy)-1-ethyl-1H-pyrazole
  • To a solution of 1-ethyl-1H-pyrazol-5-ol (2.0 g, 17.8 mmol) in DMF (20 mL) were added K2CO3 (3.7 g, 26.8 mmol) and benzyl bromide (2.54 mL, 21.4 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-ethyl-1H-pyrazole (2.28 g) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.40-7.34 (m, 5H), 7.31 (d, 1H), 5.54 (d, 1H), 5.07 (s, 2H), 4.02 (q, 2H), 1.36 (t, 3H); MS (ESI) m/z = 203.1 (M + H)+
  • Step 2. 5-(Benzyloxy)-1-ethyl-4-iodo-1H-pyrazole
  • To a solution of 5-(benzyloxy)-1-ethyl-1H-pyrazole (2.28 g, 11.3 mmol) prepared in step 1 in MeCN (23 mL) was added N-iodosuccinimide (2.54 g, 11.3 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3 solution 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)-1-ethyl-4-iodo-1H-pyrazole (2.51 g) as a pale yellow liquid. 1H NMR (CDCl3, 400 MHz) δ 7.39-7.37 (m, 6H), 5.24 (s, 2H), 3.82 (q, 2H), 1.19 (t, 3H); MS (ESI) m/z = 329.0 (M + H)+
  • Step 3. 5-(Benzyloxy)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
  • To a stirred solution 5-(benzyloxy)-1-ethyl-4-iodo-1H-pyrazole (2.51 g, 7.65 mmol) prepared in step 2 in THF (25 mL), was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 6.47 mL, 8.41 mmol) at -10-0 ℃ 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 (1.87 mL, 9.18 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-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.16 g) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.63 (s, 1H), 7.40-7.35 (m, 5H), 5.39 (s, 2H), 3.92 (q, 2H), 1.32 (s, 12 H), 1.25 (t, 3H); MS (ESI) m/z = 328.8 (M + H)+
  • Step 4. 2-(5-(Benzyloxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of 2-bromopyrimidin-4-amine (1.14 g, 6.55 mmol) and 5-(benzyloxy)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.15 g, 6.55 mmol) prepared in step 3 in 1,4-dioxane (33 mL) were added 3 M K2CO3 soln. (6.55 mL, 19.6 mmol) and Pd(dppf)Cl2 dichloromethane complex (535 mg, 0.66 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-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (550 mg) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 8.08 (d, 1H), 7.90 (s, 1H), 7.35-7.34 (m, 5H), 6.34 (d, 1H), 5.41 (s, 2H), 3.80 (q, 2H), 1.13 (t, 3H); MS (ESI) m/z = 296.2 (M + H)+
  • Step 5. 4-(4-Aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (550 mg, 1.86 mmol) prepared in step 4 in methanol (10 mL) was added Pd(OH)2 on carbon (20% Pd, 55 mg) and stirred under H2 atmosphere 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-ethyl-1H-pyrazol-5-ol (350 mg) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.86 (d, 1H), 7.70 (s, 1H), 6.20 (d, 1H), 3.86 (q, 2H), 1.29 (t, 3H); MS (ESI) m/z = 206.1 (M + H)+
  • Reference Example 17. 4-(4-Aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol
  • Step 1. 5-(Benzyloxy)-1-isopropyl-1H-pyrazole
  • To a solution of 1-isopropyl-1H-pyrazol-5-ol (2.0 g, 15.8 mmol) in DMF (20 mL) 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)+
  • Step 2. 5-(Benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole
  • To a solution of 5-(benzyloxy)-1-isopropyl-1H-pyrazole (2.07 g, 9.57 mmol) prepared in step 1 in MeCN (20 mL) was added N-iodosuccinimide (2.15 g, 9.57 mmol) at 0 ℃. The reaction mixture was continued to stir at 0 ℃ for 1 hour. After completion, the reaction was quenched by addition of saturated Na2S2O3 solution 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)+
  • Step 3. 5-(Benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
  • To a stirred solution 5-(benzyloxy)-4-iodo-1-isopropyl-1H-pyrazole (2.30 g, 6.72 mmol) in THF (23 mL), was slowly added a solution of iPrMgCl LiCl complex in THF (1.3 M, 5.69 mL, 7.39 mmol) at -10-0 ℃ 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)+
  • Step 4. 2-(5-(Benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of 2-bromopyrimidin-4-amine (1.0 g, 5.75 mmol) and 5-(benzyloxy)-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.97 g, 5.75 mmol) in 1,4-dioxane (30 mL) were added 3 M K2CO3 soln. (5.75 mL, 17.2 mmol) and Pd(dppf)Cl2 dichloromethane 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)+
  • Step 5. 4-(4-Aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (570 mg, 1.84 mmol) in methanol (10 mL) was added Pd(OH)2 on carbon (20% Pd, 57 mg) and stirred under H2 atmosphere 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)+
  • Reference Example 18. 4-(4-Amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • Step 1. 2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine
  • To a solution of 2-chloro-5-methylpyrimidin-4-amine (4.0 g, 27.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.75 g, 27.9 mmol) prepared in step 3 in Reference Example 7 in 1,4-dioxane (140 mL) were added 3 M K2CO3 soln. (27.9 mL, 83.6 mmol) and Pd(dppf)Cl2 dichloromethane complex (2.28 g, 2.79 mmol). The mixture was degassed by argon and then heated to 90 ℃ for 8 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)-5-methylpyrimidin-4-amine (1.34 g) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.96 (s, 1H), 7.85 (s, 1H), 7.33 (s, 5H), 5.39 (s, 2H), 3.39 (s, 3H), 2.09 (s, 3H); MS (ESI) m/z = 296.1 (M + H)+
  • Step 2. 4-(4-Amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine (2.12 g, 7.18 mmol) in methanol (50 mL) was added Pd(OH)2 on carbon (20% Pd, 212 mg) and stirred under H2 atmosphere at 25 ℃ for 6-7 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-amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (1.42 g) as a gray solid. 1H NMR (CD3OD, 400 MHz) δ 7.75 (s, 1H), 7.68 (s, 1H), 3.45 (s, 3H), 2.06 (s, 3H); MS (ESI) m/z = 206.1 (M + H)+
  • Reference Example 19. 4-(4-Amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • Step 1. 2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine
  • To a solution of 2-chloro-6-methylpyrimidin-4-amine (3.0 g, 20.9 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.56 g, 20.9 mmol) prepared in step 3 in Reference Example 7 in 1,4-dioxane (105 mL) were added 3 M K2CO3 soln. (20.9 mL) and Pd(dppf)Cl2 dichloromethane complex (1.71 g, 2.09 mmol). The mixture was degassed by argon and then heated to 90 ℃ for 8 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)-6-methylpyrimidin-4-amine (1.11 g) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.88 (s, 1H), 7.34-7.33 (m, 5H), 6.21 (s, 1H), 5.40 (s, 2H), 3.43 (s, 3H), 2.31 (s, 3H); MS (ESI) m/z = 296.5 (M + H)+
  • Step 2. 4-(4-Amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine (1.34 g, 4.54 mmol) in methanol (30 mL) was added Pd(OH)2 on carbon (20% Pd, 134 mg) and stirred under H2 atmosphere at 25 ℃ for 6-7 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-amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (870 mg) as a gray solid. 1H NMR (CD3OD, 400 MHz) δ 7.68 (s, 1H), 6.06 (s, 1H), 3.46 (s, 3H), 2.36 (s, 3H); MS (ESI) m/z = 206.0 (M + H)+
  • Reference Example 20. (3-(((2-Chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.50 g, 5.827 mmol) and 3-aminomethyloxetan-3-ylmethanol (682 mg, 5.827 mmol) was charged nitrogen gas for 10 minutes. After DMF (30 mL) and DIPEA (2.03 mL, 11.654 mmol) were added, the reaction mixture was stirred at 80 oC 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 (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (1.774 g) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 6.50 (s, 1H), 5.85-5.83 (t, 1H), 4.58-4.56 (d, 2H), 4.51-4.50 (d, 1H), 4.16-4.09 (m, 2H), 3.61-3.60 (d, 2H)
  • Reference Example 21. 4-(4-Aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • Step 1. 2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-amine
  • To a solution of 2-bromopyridin-4-amine (16.0 g, 92.5 mmol) and 5-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.1 g, 92.5 mmol) prepared in step 3 in Reference Example 7 in 1,4-dioxane (460 mL) were added 3 M K2CO3 soln. (92.5 mL, 277 mmol) and Pd(dppf)Cl2 dichloromethane complex (7.55 g, 9.25 mmol). The mixture was degassed by argon and then heated to 90 ℃ for 8 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)pyridin-4-amine (6.90 g) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.98 (d, 1H), 7.69 (s, 1H), 7.35-7.34 (m, 5H), 6.87 (d, 1H), 6.47 (dd, 1H), 5.07 (s, 2H), 3.43 (s, 3H); MS (ESI) m/z = 281.2 (M + H)+
  • Step 2. 4-(4-Aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol
  • To a solution of 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-amine (6.90 g, 24.6 mmol) in methanol (70 mL) was added Pd(OH)2 on carbon (20% Pd, 690 mg) and stirred under H2 atmosphere at 25 ℃ for 6-7 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-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol (4.31 g) as a brown solid. 1H NMR (CD3OD, 400 MHz) δ 7.74 (d, 1H), 7.59 (s, 1H), 6.63 (s, 1H), 6.37 (d, 1H), 3.46 (s, 3H); MS (ESI) m/z = 190.9 (M + H)+
  • Reference Example 22. (4-((6-Chloro-4-fluoropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone
  • The title compound as a solid (1121 mg) was prepared in the same fashion as Reference Example 10 except that (4-ethynylphenyl)-(4-hydroxy-1-piperidinyl)methanone (1000 mg, 4.36 mmol) was used instead of 4-ethynyl-1-methylpyrazole. MS (ESI) m/z = 359.1 (M + H)+
  • Example 1. (S)-25-Fluoro-11,6-dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 2-Chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (3.0 g, 11.65 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)pyrazole (2.03 g, 11.65 mmol), PdCl2(PPh3)2 (408.98 mg, 0.58 mmol), and CuI (444.10 mg, 2.33 mmol) was charged N2 for 10 minutes, and then DMF (60.0 mL) and TEA (3.25 mL, 23.31 mmol) were added. The reaction mixture was stirred at 50 oC for 4 hours. The reaction mixture was cooled to r.t. and work-up was performed by using EA and water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA/n-Hex = 0-50%) to yield 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (649.80 mg, 2.14 mmol, 18.4% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H), 7.78 (s, 2H), 7.16 (d, 1H), 4.74 (q, 2H); MS (ESI) m/z = 303.9 (M + H)+
  • Step 2. (S)-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • To a solution of 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (99.60 mg, 0.33 mmol) prepared in step 1 in DMA (2.0 mL) was added (S)-3-aminobutan-1-ol (29.24 mg, 0.33 mmol) and DIPEA (0.09 mL, 0.66 mmol). The reaction mixture was stirred at 80 oC for 12 hours. The reaction mixture was cooled to r.t., added to water and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM = 0-10%) to yield (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100.0 mg, 027 mmol, 81.8% yield). 1H-NMR (CD3OD, 400 MHz) δ 8.06 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 6.70 (s, 1H), 4.98 (q, 1H), 3.86 (sex, 1H), 3.78-3.68 (m, 2H), 1.92-1.82 (m, 2H), 1.29 (d, 3H); MS (ESI) m/z = 372.9 (M + H)+
  • Step 3. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine
  • To a solution of (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (60.0 mg, 0.16 mmol) prepared in step 2 in toluene (1.16 mL) was added (tributylphosphoranylidene)acetonitrile (121.58 mg, 0.40 mmol) and 4-(4-amino-5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (33.76 mg, 0.16 mmol) prepared in Reference Example 9. The reaction mixture was stirred at 100 oC 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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (80.0 mg, 0.14 mmol, 87.9% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 6.51 (s, 1H), 5.84 (d, 1H), 5.42 (s, 2H), 4.61 (q, 2H), 4.50-4.48 (m, 1H), 4.39-4.35 (m, 1H), 3.91 (quin, 1H), 3.60 (s, 3H), 2.20-2.02 (m, 2H), 1.36 (d, 3H)
  • Step 4. (S)-25-Fluoro-11,6-dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • To a solution of (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-4-amine (80.0 mg, 0.14 mmol) prepared in step 3 in 1,4-dioxane (2.84 mL) was added Cs2CO3 (138.66 mg, 0.43 mmol), Pd2(dba)3 (25.98 mg, 0.03 mmol) and XPhos (27.05 mg, 0.06 mmol). The reaction mixture was stirred at 130 oC for 2 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 residue was then purified by silica gel column chromatography (EA/n-Hex = 0-100%) & (MeOH/DCM = 0-30%) to yield (S)-25-fluoro-11,6-dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (29.0 mg, 0.06 mmol, 38.8% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.25 (s, 1H), 8.07(s, 1H), 8.05 (s, 1H), 7.75 (s, 2H), 5.11 (d, 1H), 4.78-4.67 (m, 3H), 4.28 (t, 1H), 4.10-4.07 (m, 1H), 3.80 (s, 3H), 2.19 (d, 2H), 1.50 (d, 3H); MS (ESI) m/z = 528.0 (M + H)+
  • Example 2. (S)-11,6-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-iodopyridin-4-yl)amino)butan-1-ol
  • To a solution of 2-chloro-4-fluoro-5-iodopyridine (3.0 g, 11.65 mmol) in DMA (23.31 mL) was added (S)-3-aminobutan-1-ol (1.35 g, 15.15 mmol) and DIPEA (4.95 mL, 29.13 mmol). The reaction mixture was stirred at 90 oC for 4 hours. After being cooled to r.t., the reaction mixture was quenched with water, then extracted with EA. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA/n-Hex = 0-50%) to yield (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (3.32 g, 10.17 mmol, 87.3% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 6.49 (s, 1H), 5.12 (d, 1H), 3.92-3.80 (m, 3H), 1.97-1.81 (m, 3H), 1.34 (d, 3H); MS (ESI) m/z = 326.8 (M + H)+
  • Step 2. (S)-3-((2-Chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • To a solution of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (300.0 mg, 0.92 mmol) prepared in step 1 in DMF (3.67 mL) was added 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole (161.89 mg, 0.92 mmol), PdCl2(PPh3)2 (64.48 mg, 0.09 mmol), CuI (34.99 mg, 0.18 mmol) and TEA (0.32 mL, 2.3 mmol). The reaction mixture was stirred at 70 oC for 3 hours. After being cooled to r.t., the reaction mixture was quenched with water, then extracted with EA. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EA/n-Hex = 0-70%) to yield (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (257.0 mg, 0.69 mmol, 74.6% yield) as yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.69 (s, 1H), 7.68 (s, 1H), 6.56 (s, 1H), 5.53 (d, 1H), 4.37 (sep, 1H), 4.15 (dd, 2H), 3.90-3.82 (m, 3H), 3.57 (td, 2H), 2.14-2.07 (m, 4H), 1.92-1.84 (m, 2H), 1.54 (t, 1H), 1.33 (d, 3H); MS (ESI) m/z = 374.9 (M + H)+
  • Step 3. (S)-2-(5-(3-((2-Chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl) pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100.0 mg, 0.27 mmol) prepared in step 2 in toluene (1.07 mL) was added 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (51.0 mg, 0.27 mmol) prepared in Reference Example 7 and (tributylphosphoranylidene)acetonitrile (181.68 uL, 0.67 mmol). The reaction mixture was stirred at 110 oC for 6 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (MeOH/DCM = 0-10%) to yield (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (44.30 mg, 0.08 mmol, 30.3% yield) as brown solid. 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 6.58 (s, 1H), 6.20 (d, 1H), 5.90 (d, 1H), 4.76 (s, 2H), 4.57-4.48 (m, 2H), 4.25 (sep, 1H), 4.14 (dd, 1H), 3.97 (quin, 1H), 3.69 (s, 3H),3.54 (td, 3H), 2.24-2.07 (m, 6H), 1.44 (d, 3H); MS (ESI) m/z = 547.9 (M + H)+
  • Step 4. (S)-11,6-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • To a solution of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (44.30 mg, 0.08 mmol) in 1,4-dioxane (1.0 mL) was added Pd2(dba)3 (11.10 mg, 0.01 mmol), XPhos (11.56 mg, 0.02 mmol) and Cs2CO3 (79.01 mg, 0.24 mmol). The reaction mixture was stirred at r.t. for 30 min, and then heated to 95 oC for 2 hours. The reaction mixture was filtered through celite pad, washed with DCM, and then the organic solution was concentrated in-vacuo. The crude residue was purified by silica gel column chromatography (MeOH/DCM = 0-10%) to yield (S)-11,6-dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (2.0 mg, 0.004 mmol, 4.8% yield) as yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.35 (d, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 6.43 (d, 1H), 5.00 (d, 1H), 4.80 (td, 1H), 4.40 (sep, 1H), 4.36-4.26 (m, 1H), 4.17-4.12 (m, 3H), 3.82 (s, 3H), 3.56 (td, 2H), 2.19-2.04 (m, 6H), 1.49 (d, 3H); MS (ESI) m/z = 511.9 (M + H)+
  • Example 3. (S)-11,8-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-iodopyridin-4-yl)amino)butan-2-ol
  • The title compound as a white solid (3.67 g) was prepared in the same fashion as step 1 in Example 2 except that (R)-4-aminobutan-2-ol (1.35 g, 15.15 mmol) was used instead of (S)-3-aminobutan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 6.44 (s, 1H), 5.55 (s, 1H), 4.07 (sex, 1H), 3.43-3.30 (m, 2H), 1.92-1.78 (m, 2H), 1.78 (s, 1H), 1.33 (d, 3H); MS (ESI) m/z = 326.8 (M + H)+
  • Step 2. (R)-4-((2-Chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a brown-yellow solid (292.10 mg) was prepared in the same fashion as step 2 in Example 2 except that (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (300.0 mg, 0.92 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 6.50 (s, 1H), 5.90 (t, 1H), 4.36 (sep, 1H), 4.16 (dd, 2H), 4.12-4.05 (m, 1H), 3.56 (td, 2H), 3.43-3.33 (m, 2H), 2.13-2.07 (m, 4H), 1.88-1.79 (m, 2H), 1.67 (d, 1H), 1.32 (d, 3H); MS (ESI) m/z = 374.9 (M + H)+
  • Step 3. (S)-2-(5-((4-((2-Chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a pale brown solid (44.30 mg) was prepared in the same fashion as step 3 in Example 2 except that (R)-4-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (100.0 mg, 0.27 mmol) prepared in step 2 was used instead of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.37 (s, 1H), 7.09 (s, 1H), 6.75 (t, 1H), 6.55(s, 1H), 6.16 (d, 1H), 5.03 (t, 1H), 4.79 (s, 2H), 4.24 (sep, 1H), 4.12 (dd, 2H), 3.69-3.52 (m, 7H), 2.17-2.03 (m, 6H), 1.16 (d, 3H); MS (ESI) m/z = 547.9 (M + H)+
  • Step 4. (S)-11,8-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a yellow solid (20.60 mg) was prepared in the same fashion as step 4 in Example 2 except that (S)-2-(5-((4-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.20 mg, 0.19 mmol) prepared in step 3 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.35 (d, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 6.38 (d, 1H), 5.52-5.43 (m, 2H), 4.40 (sep, 1H), 4.17-4.05 (m, 3H), 3.77 (s, 3H), 3.58 (td, 3H), 2.29-1.94 (m, 6H), 1.11 (d, 3H); MS (ESI) m/z = 512.0 (M + H)+
  • Example 4. (S)-11,6-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-1-ol
  • The title compound as a brown viscous oil (212.70 mg) was prepared in the same fashion as step 2 in Example 2 except that 3-ethynylpyridine (110.52 mg, 1.07 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.83 (d, 1H), 7.34 (t, 1H), 6.58 (s, 1H), 5.81 (d, 1H), 3.96-3.93 (m, 1H), 3.89-3.84 (m, 2H), 1.99-1.82 (m, 2H), 1.74 (s, 1H), 1.35 (d, 3H); MS (ESI) m/z = 302.0 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a brown viscous oil (77.30 mg) was prepared in the same fashion as step 3 in Example 2 except that (S)-3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-1-ol (205.0 mg, 0.68 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.57 (d, 1H), 8.52 (dd, 1H), 8.16 (s, 1H), 8.13 (d, 1H), 7.94 (s, 1H), 7.52 (dt, 1H), 7.18 (dd, 1H), 6.62 (s, 1H), 6.16 (d, 1H), 5.93 (d, 1H), 4.74 (s, 2H), 4.56-4.46 (m, 2H), 4.09 (sep, 1H), 3.68 (s, 3H), 2.28-2.08 (m, 2H), 1.45 (d, 3H); MS (ESI) m/z = 474.9 (M + H)+
  • Step 3. (S)-11,6-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a yellow solid (22.80 mg) was prepared in the same fashion as step 4 in Example 2 except that (S)-2-(5-(3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (77.30 mg, 0.15 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.76 (d, 1H), 8.57 (dd, 1H), 8.41 (s, 1H), 8.34 (d, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 7.80 (dt, 1H), 7.47 (s, 1H), 7.32 (dd, 1H), 6.37 (d, 1H), 4.95 (d, 1H), 4.79 (td, 1H), 4.32-4.29 (m, 1H), 4.08-4.05 (m, 1H), 3.80 (s, 3H), 2.21-2.15 (m, 2H), 1.49 (d, 3H); MS (ESI) m/z = 438.9 (M + H)+
  • Example 5. (S)-11,8-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a pale brown solid (249.80 mg) was prepared in the same fashion as step 2 in Example 3 except that 3-ethynylpyridine (110.52 mg, 1.07 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.59 (d, 1H), 8.17 (s, 1H), 7.83 (d, 1H), 7.33 (dd, 1H), 6.52 (s, 1H), 6.16 (s, 1H), 4.12 (s, 1H), 3.48-3.32 (m, 2H), 1.94-1.80 (m, 2H), 1.74 (d, 1H), 1.34 (d, 3H); MS (ESI) m/z = 301.9 (M + H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a brown solid (80.20 mg) was prepared in the same fashion as step 3 in Example 2 except that (R)-4-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-ol (249.80 mg, 0.82 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.46 (dd, 1H), 8.36 (d, 1H), 8.10 (s, 1H), 8.07 (d, 1H), 7.86 (s, 1H), 7.24-7.23 (m, 1H), 7.11 (dd, 1H), 6.90-6.88 (m, 1H), 6.56 (s, 1H), 6.10 (d, 1H), 4.98 (quin, 1H), 4.74 (s, 1H), 3.69-3.56 (m, 6H), 2.20-2.15 (m, 1H), 1.90-1.87 (m, 1H), 1.20 (d, 3H); MS (ESI) m/z = 474.8 (M + H)+
  • Step 3. (S)-11,8-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a pale yellow solid (9.30 mg) was prepared in the same fashion as step 4 in Example 2 except that (S)-2-(5-((4-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (80.0 mg, 0.16 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.79 (d, 1H), 8.59 (dd, 1H), 8.46 (s, 1H), 8.36 (d, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.84 (dt, 1H), 7.34 (m, 2H), 6.37 (d, 1H), 5.52-5.43 (m, 2H), 4.13-4.09 (m, 1H), 3.78 (s, 3H), 3.59-3.55 (m, 1H), 2.32-2.24 (m, 1H), 2.00-1.94 (m, 1H), 1.13 (d, 3H); MS (ESI) m/z = 438.9 (M + H)+
  • Example 6. (S)-11,13,6-Trimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl -1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a pink foamy solid (72.80 mg) was prepared in the same fashion as step 2 in Example 4 except that 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (40.34 mg, 0.20 mmol) prepared in Reference Example 8 was used instead of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.57 (d, 1H), 8.52 (dd, 1H), 8.16 (s, 1H), 8.15 (d, 1H), 7.52 (dt, 1H), 7.16 (dd, 1H), 6.59 (s, 1H), 6.17 (d, 1H), 5.95 (d, 1H), 4.71 (s, 2H), 4.46-4.32 (m, 2H), 3.97 (sep, 1H), 3.63 (s, 3H), 2.45 (s, 3H), 2.20-2.04 (m, 2H), 1.41 (d, 3H); MS (ESI) m/z = 488.9 (M + H)+
  • Step 2. (S)-11,13,6-Trimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a yellow solid (18.90 mg) was prepared in the same fashion as step 4 in Example 2 except that (S)-2-(5-(3-((2-chloro-5-(pyridin-3-ylethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70.10 mg, 0.14 mmol) prepared in step 1 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.59 (d, 1H), 8.38 (d, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.82 (d, 1H), 7.33 (dd, 1H), 6.38 (d, 1H), 4.96 (d, 1H), 4.80 (t, 1H), 4.31 (q, 1H), 4.03-4.00 (m, 1H), 3.76 (s, 3H), 2.60 (s, 3H), 2.18 (dt, 2H), 1.50 (d, 3H); MS (ESI) m/z = 453.0 (M + H)+
  • Example 7. 11,7,7-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 2-Chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (3.00 g, 11.65 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)pyrazole (2.03 g, 11.65 mmol), PdCl2(PPh3)2 (408.98 mg, 0.58 mmol), and CuI (444.10 mg, 2.33 mmol) was charged N2 for 10 minutes. And DMF (60.0 mL) and TEA (3.25 mL, 23.31 mmol) were added. The reaction mixture was stirred at 50 oC for 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with EA. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (Hex/n-Hex = 0-50%) to yield 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (650 mg, 2.141 mmol, 18.37% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H), 7.78 (s, 2H), 7.16 (d, 1H), 4.74 (q, 2H); MS (ESI) m/z = 303.9 (M + H)+
  • Step 2. 3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol
  • To a solution of 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (120 mg, 0.395 mmol) prepared in step 1 in DMA (1 mL) was added 3-amino-2,2-dimethyl-1-propanol (48.92 mg, 0.474 mmol) and DIPEA (138.09 uL, 0.988 mmol). The reaction mixture was stirred at 80 oC 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 MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (EA/n-Hex = 30-100%) to yield 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (89 mg, 0.23 mmol, 58.22% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.75 (d, 1H), 6.70 (s, 1H), 6.24 (s, 1H), 4.73 (q, 2H), 3.92-3.91 (m, 2H), 1.99 (t, 2H), 1.50 (s, 6H)
  • Step 3. 2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (83 mg, 0.215 mmol) prepared in step 2 in toluene (1 mL) was added 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (41.03 mg, 0.215 mmol) prepared in Reference Example 7 and (tributylphosphoranylidene)acetonitrile (140.58 uL, 0.536 mmol). The reaction mixture was heated at 120 oC for 3 hours. The reaction mixture was concentrated and purified by column chromatography (EA/n-Hex = 50-100% → MeOH/EA = 0-15%) and recrystallization (DCM/Hex) to yield 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70 mg, 0.125 mmol, 58.26% yield) as a pale brown solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 6.74 (s, 1H), 6.19 (d, 1H), 5.32 (s, 2H), 4.73-4.53 (m, 4H), 3.60 (s, 3H), 2.29 (t, 2H), 1.61 (s, 6H)
  • Step 4. 11,7,7-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • To a solution of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (65 mg, 0.116 mmol) prepared in step 3 in 1,4-dioxane (1 mL) was added Pd2(dba)3 (15.94 mg, 0.017 mmol), Xphos (16.6mg, 0.035 mmol) and Cs2CO3 (113.46 mg, 0.348 mmol). The reaction mixture was stirred at 95 oC for 2 hours. The reaction mixture was added to water and extracted with DCM. The crude residue was purified by column chromatography (MeOH/EA = 0-15%) and recrystallization (MeOH) to yield 11,7,7-trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (17 mg, 0.032 mmol, 27.98% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.35 (d, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 7.73 (s, 1H), 6.38 (d, 1H), 4.75 (q, 2H), 4.62 (t, 2H), 3.82 (s, 3H), 2.36 (t, 2H), 1.63 (s, 6H); MS (ESI) m/z = 523.9 (M + H)+
  • Example 8. 11,6,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutan-1-ol
  • The title compound as a white solid (75 mg) was prepared in the same fashion as step 2 in Example 7, except that 3-amino-3,3-dimethylpropanol (35 mg, 0.339 mmol) was used instead of 3-amino-2,2-dimethyl-1-propanol. 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.74 (s, 2H), 6.69 (s, 1H), 6.21 (s, 1H), 4.72 (q, 2H), 3.90 (q, 2H), 1.98 (t, 2H), 1.49 (s, 6H)
  • Step 2. 2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a brown solid (62 mg) was prepared in the same fashion as step 3 in Example 7, except that 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutan-1-ol (63.97 mg, 0.165 mmol) prepared in step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 6.74 (s, 1H), 6.20-6.18 (m, 2H), 4.73 (s, 2H), 4.62-4.53 (m, 4H), 3.60 (s, 3H), 2.29 (t, 2H), 2.03 (s, 2H), 1.60 (s, 6H)
  • Step 3. 11,6,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a white solid (20 mg) was prepared in the same fashion as step 4 in Example 7, except that 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-3-methylbutoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (60 mg, 0.107 mmol) prepared in step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (DMSO-d 6, 400 MHz) δ 9.95 (s, 1H), 8.43 (s, 1H), 8.29 (d, 1H), 8.24 (s 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 6.78 (d, 1H), 5.34 (s, 1H), 5.19 (q, 1H), 4.55 (t, 2H), 3.76 (s, 3H), 2.32 (t, 2H), 1.53 (s, 6H); MS (ESI) m/z = 523.9 (M + H)+
  • Example 9. (R)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • The title compound as a white solid (91 mg) was prepared in the same fashion as step 2 in Example 7, except that (2R)-3-amino-2-fluoro-propan-1-ol (27.6 mg, 0.296 mmol) was used instead of 3-amino-2,2-dimethyl-1-propanol. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.75 (s, 2H), 6.56 (s, 1H), 5.52 (t, 1H), 4.87-4.84 (m, 1H), 4.77-4.71 (m, 2H), 4.01-3.82 (m, 2H), 3.65-3.57 (m, 2H), 2.09 (s, 1H)
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a brown solid (51 mg) was prepared in the same fashion as step 3 in Example 7, except that (R)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (80.84 mg, 0.215 mmol) prepared in step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 2H), 8.15 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 6.07 (s, 1H), 6.18 (d, 1H), 5.92 (t, 1H), 5.11-4.96 (m, 1H), 4.89 (s, 2H), 4.73-4.62 (m, 4H), 3.86-3.73 (m, 5H)
  • Step 3. (R)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a white solid (7.6 mg) was prepared in the same fashion as step 4 in Example 7, except that (R)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (43 mg, 0.078 mmol) prepared in step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.77 (d, 2H), 7.42 (s, 1H), 6.39 (d, 1H), 5.47 (t, 1H), 4.98-4.85 (m, 1H), 4.83-4.70 (m, 3H), 4.53-4.45 (m, 1H), 4.31-4.25 (m, 1H), 3.86 (s, 3H), 3.71-3.61 (m, 1H); MS (ESI) m/z = 514.1 (M + H)+
  • Example 10. (S)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • The title compound as a white solid (81 mg) was prepared in the same fashion as step 2 in Example 7, except that (2S)-3-amino-2-fluoro-propan-1-ol (27.6 mg, 0.296 mmol) was used instead of 3-amino-2,2-dimethyl-1-propanol. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.75 (s, 2H), 6.56 (s, 1H), 5.52 (s, 1H), 4.87-4.83 (m, 1H), 4.77-4.70 (m, 2H), 4.01-3.82 (m, 2H), 3.65-3.57 (m, 2H), 2.05 (s, 1H)
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a pale brown solid (53 mg) was prepared in the same fashion as step 3 in Example 7, except that (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (80.84 mg, 0.215 mmol) prepared in step 1 was used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 6.61 (s, 1H), 6.18 (d, 2H), 5.92 (t, 1H), 5.10-4.97 (m, 1H), 4.90 (s, 2H), 4.73-4.60 (m, 4H), 3.87-3.71 (m, 5H)
  • Step 3. (S)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a white solid (9.8 mg) was prepared in the same fashion as step 4 in Example 7, except that (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (43 mg, 0.078 mmol) prepared in step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.77 (d, 2H), 7.40 (s, 1H), 6.39 (d, 1H), 5.47 (t, 1H), 4.97-4.85 (m, 1H), 4.83-4.70 (m, 4H), 4.53-4.45 (m, 1H), 4.31-4.25 (m, 1H), 3.86 (s, 3H), 3.69-3.65 (m, 1H); MS (ESI) m/z = 514.1 (M + H)+
  • Example 11. (S)-6-Methyl-11-(2,2,2-trifluoroethyl)-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a pale brown solid (62 mg) was prepared in the same fashion as step 3 in Example 7, except that (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (57.53 mg, 0.154 mmol) prepared in step 2 of Example 1 and 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (40 mg, 0.154 mmol) prepared in Reference Example 15 were used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H-NMR (CDCl3, 400 MHz) δ .8.14 (d, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 6.55 (s, 1H), 6.20 (d, 1H), 5.63 (d, 1H), 4.77 (s, 2H), 4.71-4.63 (m, 4H), 4.56-4.50 (m, 2H), 3.95-3.90 (m, 1H), 2.26-2.07 (m, 2H), 1.42 (d, 3H)
  • Step 2. (S)-6-Methyl-11-(2,2,2-trifluoroethyl)-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a white solid (19 mg) was prepared in the same fashion as step 4 in Example 7, except that (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (60 mg, 0.098 mmol) prepared in step 1 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.35 (d, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.74 (d, 2H), 7.44 (s, 1H), 6.40 (d, 1H), 5.18-5.15 (m, 1H), 5.13-5.12 (m, 1H), 4.97-4.70 (m, 3H), 4.59-4.53 (m, 1H), 4.36-4.31 (m, 1H), 4.03-3.99 (m, 1H), 2.27-2.20 (m, 1H), 2.12-2.06 (m, 1H), 1.45 (d, 3H); MS (ESI) m/z = 578.2 (M + H)+
  • Example 12. (S)-11,13,6-Trimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • To a solution of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol) prepared in Reference Example 6 in DMF (3mL) was added 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (122.57 mg, 0.766 mmol), PdCl2(PPh3)2 (53.73 mg, 0.077 mmol), CuI (29.16 mg, 0.153 mmol) and TEA (0.27 mL, 1.914 mmol). The reaction mixture was stirred at 60 oC for 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with EA. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (EA/n-Hex = 0-70%) to give (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (214 mg, 0.597 mmol, 77.92% yield) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 6.57 (s, 1H), 5.68 (d, 1H), 3.94-3.82 (m, 3H), 1.99-1.85 (m, 1H), 1.83-1.79 (m, 1H), 1.66 (brs, 1H), 1.33 (d, 3H)
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a pale brown solid (181 mg) was prepared in the same fashion as step 3 in Example 7, except that (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (194 mg, 0.541 mmol) prepared in step 1 and 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (110.98 mg, 0.541 mmol) prepared in Reference Example 8 were used instead of 3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 6.58 (s ,1H), 6.17 (d, 1H), 6.08 (d, 1H), 4.73 (s, 2H), 4.50-4.44 (m, 1H), 4.35-4.30 (m, 1H), 3.98-3.94 (m, 1H), 3.64 (s, 3H), 2.48 (s, 3H), 2.25-2.20 (m, 1H), 2.07-2.03 (m, 1H), 1.41 (d, 3H)
  • Step 3. (S)-11,13,6-Trimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a white solid (60.5 mg) was prepared in the same fashion as step 4 in Example 7, except that (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (157.04 mg, 0.288 mmol) prepared in step 2 was used instead of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 6.37 (d, 1H), 4.87 (d, 1H), 4.82-4.77 (m, 1H), 4.32-4.27 (m, 1H), 4.04-3.99 (m, 1H), 3.76 (s, 3H), 2.60 (s, 3H), 2.30-2.23 (m, 1H), 2.11-2.05 (m, 1H), 1.48 (d, 3H); MS (ESI) m/z = 510.2 (M + H)+
  • Example 13. (S)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step1. 2-Chloro-4-fluoro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.00 g, 3.885 mmol), 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (621.92 mg, 3.885 mmol), PdCl2(PPh3)2 (136.33 mg, 0.194 mmol), and CuI (148.03 mg, 0.777 mmol) was charged nitrogen gas for 10 minutes. After DMF (20 mL) and TEA (1.08 mL, 7.769 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield 2-chloro-4-fluoro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (890.00 mg, 3.073 mmol, 79.11% yield). 1H-NMR (CDCl3, 400MHz) δ 8.51 (d, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.17 (d,1H); MS (ESI) m/z = 290.1 (M + H)+
  • Step 2. (S)-3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (95.00 mg, 0.328 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (29.24 mg, 0.328 mmol), and DIPEA (0.09 mL, 0.656 mmol) in DMA (2 mL) was stirred at 80 oC 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-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (94.00 mg, 0.262 mmol, 79.88% yield). 1H-NMR (CD3OD, 400MHz) δ 8.51 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 6.72 (s, 1H), 3.95-3.87 (m ,1H), 3.83-3.69 (m, 2H), 1.95-1.78 (m, 2H), 1.29 (d, 3H); MS (ESI) m/z = 358.9 (M + H)+
  • Step 3. (S)-2-(5-(3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The mixture of (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (130.00 mg, 0.362 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (69.28 mg, 0.362 mmol) prepared in Reference Example 7 and (tributylphosphoranylidene)acetonitrile (0.35 mL, 1.268 mmol) in　toluene (1 mL) was stirred at 100 oC 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (140.00 mg, 0.263 mmol, 72.63% yield). 1H-NMR (CD3OD, 400MHz) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.80 (d, 2H), 6.76 ( s, 1H), 6.25 (d, 1H), 4.53-4.46 (m ,2H), 4.07-4.04 (m, 1H), 3.65 (s, 3H), 2.27-2.08 (m, 2H), 1.38 (d, 3H); MS (ESI) m/z = 532.0 (M + H)+
  • Step 4. (S)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The mixture of (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (20.00 mg, 0.038 mmol) prepared in step 3, Cs2CO3 (36.75 mg, 0.113 mmol), XPhos (7.17 mg, 0.015 mmol), and Pd2(dba)3 (6.89 mg, 0.008 mmol) in 1,4-dioxane (4 mL) was stirred at 130 oC 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 (S)-11,6-dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (3.60 mg, 0.007 mmol, 19.32% yield). 1H-NMR (CD3OD, 400MHz) δ 8.51 (s, 1H), 8.30 (s, 1H), 8.23 (d, 1H), 8.02-7.99 (m, 3H), 6.67 (d, 1H), 4.71-4.66 (m, 1H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 2.29-1.99 (m, 2H); MS (ESI) m/z = 496.1 (M + H)+
  • Example 14. (S)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 2-Chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (3.00 g, 11.654 mmol), 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.29 g, 11.654 mmol), PdCl2(PPh3)2 (408.98 mg, 0.583 mmol), and CuI (444.10 mg, 2.331 mmol) was charged nitrogen gas for 10 minutes. After DMF (60 mL) and TEA (3.25 mL, 23.307 mmol) were added, the reaction mixture was stirred at 50 oC for 4 hour. 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 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (650.00 mg, 2.141 mmol, 18.37% yield). 1H-NMR (CDCl3, 400MHz) δ 8.50 (d, 1H), 7.78 (s, 2H), 4.77-4.71 (m, 2H); MS (ESI) m/z = 303.9 (M + H)+
  • Step 2. (S)-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridine (99.60 mg, 0.328 mmol) prepared in step 1, (S)-3-aminobutan-1-ol (29 mg, 0.328 mmol), and DIPEA (0.09 mL, 0.656 mmol) in DMA (2 mL) was stirred at 80 oC 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-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100.00 mg, 0.268 mmol, 81.78% yield). 1H-NMR (CD3OD, 400MHz) δ 8.06 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 6.70 (s, 1H), 5.01-4.95 (m, 2H), 3.92-3.91 (m ,1H), 3.89-3.68 (m, 2H), 1.92-1.80 (m, 2H), 1.29 (d, 3H); MS (ESI) m/z = 372.9 (M + H)+
  • Step 3. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The mixture of (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (135.08 mg, 0.362 mmol) prepared in step 2, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (69.28 mg, 0.362 mmol) prepared in Reference Example 7 and (tributylphosphoranylidene)acetonitrile (0.35 mL, 1.268 mmol) in　toluene (1 mL) was stirred at 100 oC 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-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (143.00 mg, 0.262 mmol, 72.28% yield). 1H-NMR (CD3OD, 400MHz) δ 7.98-7.96 (m, 2H), 7.84-7.78 (m, 2H), 7.56 (s, 1H), 6.73 ( s, 1H), 6.26 (d, 1H), 4.94-4.87 (m ,2H), 4.54-4.46 (m, 2H), 4.05-4.01 (m, 1H), 3.64 (s, 3H), 2.25-2.10 (m, 2H), 1.37 (d, 3H); MS (ESI) m/z = 546.0 (M + H)+
  • Step 4. (S)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The mixture of (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (20.53 mg, 0.038 mmol) prepared in step 3, Cs2CO3 (36.75 mg, 0.113 mmol), XPhos (7.17 mg, 0.015 mmol), and Pd2(dba)3 (6.89 mg, 0.008 mmol) in 1,4-dioxane (4 mL) was stirred at 130 oC 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 (S)-11,6-dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (3.40 mg, 0.007 mmol, 17.75% yield). 1H-NMR (CD3OD, 400MHz) δ 8.29 (s, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 6.67 (d, 1H), 5.03-4.96 (m, 2H), 4.66-4.61 (m, 1H), 4.20-4.17 (m, 2H), 3.80 (s, 3H), 2.28-2.00 (m, 2H), 1.46 (d, 3H); MS (ESI) m/z = 510.0 (M + H)+
  • Example 15. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (200.00 mg, 0.612 mmol) prepared in Reference Example 6, 1-(difluoromethyl)-4-ethynyl-1H-pyrazole (87.03 mg, 0.612 mmol), PdCl2(PPh3)2 (21.49 mg, 0.031 mmol), CuI (23.34 mg, 0.122 mmol) and TEA (0.17 ml, 1.225 mmol) in DMF (3 mL) was stirred at 50 oC 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 yield (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (134.00 mg, 0.393 mmol, 64.21% yield). 1H-NMR (CD3OD, 400MHz) δ 8.37 (s, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.52 (t, 1H), 6.72 (s, 1H), 3.94-3.89 (m, 1H), 3.84-3.70 (m, 2H), 1.94-1.81 (m, 2H), 1.30 (d, 3H); MS (ESI) m/z = 341.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The mixture of (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (134.00 mg, 0.393 mmol), 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (75.18 mg, 0.393 mmol) prepared in Reference Example 8 and (tributylphosphoranylidene)acetonitrile (0.38 mL, 1.376 mmol) in　toluene (2 mL) was stirred at 130 oC 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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (114.00 mg, 0.216 mmol, 54.91% yield). 1H-NMR (CD3OD, 400MHz) δ 8.19 (s, 1H), 8.02-7.99 (m, 2H), 7.76 (s, 1H), 7.46 (t, 1H), 6.73 ( s, 1H), 6.29-6.26 (m, 1H), 4.38-4.29 (m ,2H), 4.04-3.99 (m, 1H), 3.37 (s, 3H), 2.35 (s, 3H), 2.35-2.03 (m, 2H), 1.33 (d, 3H); MS (ESI) m/z = 528.1 (M + H)+
  • Step 3. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The mixture of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (114.00 mg, 0.216 mmol) prepared in step 2, Cs2CO3 (211.06 mg, 0.648 mmol), XPhos (41.18 mg, 0.086 mmol), and Pd2(dba)3 (39.55 mg, 0.043 mmol) in 1,4-dioxane (4 mL) was stirred at 100 oC 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-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (30 mg, 0.061 mmol, 28.27% yield). 1H-NMR (CD3OD, 400MHz) δ 8.35 (s, 1H), 8.29 (d, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H),7.52 (t, 1H), 6.60 (d, 1H), 4.69-4.63 (m, 1H), 4.17-4.13 (m, 1H), 4.06-4.03 (m, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 2.30-2.25 (m, 1H), 2.06-2.01 (m, 1H), 1.79-1.74 (m, 1H), 1.42 (d, 3H); MS (ESI) m/z = 492.2 (M + H)+
  • Example 16. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The title compound as a solid (123 mg, 0.347 mmol, 56.61% yield) was prepared in the same fashion as step 1 in Example 15 except that 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (95.62 mg, 0.612 mmol) was used instead of 1-(difluoromethyl)-4-ethynyl-1H-pyrazole. 1H-NMR (CD3OD, 400MHz) δ 8.00 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 6.71 (s, 1H), 6.36-6.08 (m, 1H), 4.64-4.56 (m, 2H), 3.93-3.88 (m, 1H), 3.83-3.69 (m, 2H), 1.91-1.82 (m, 2H), 1.30 (d, 3H); MS (ESI) m/z = 355.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a solid (101.00 mg, 0.186 mmol, 47.39% yield) was prepared in the same fashion as step 2 in Example 15 except that (S)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (139.51 mg, 0.393 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 8.01 (d, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 6.72 (s, 1H), 6.32-6.04 (m, 2H), 4.58-4.50 (m, 2H), 4.38-4.30 (m, 2H), 4.02-3.98 (m, 1H), 3.60 (s, 3H), 2.36 (s, 3H), 2.16-2.06 (m, 2H), 1.33 (d, 2H); MS (ESI) m/z = 542.2 (M + H)+
  • Step 3. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a solid (28.00 mg, 0.055 mmol, 25.65% yield) was prepared in the same fashion as step 3 in Example 15 except that (S)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (117.03 mg, 0.216 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.32 (d, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 6.65 (d, 1H), 6.36-6.09 (m, 1H), 4.65-4.57 (m, 2H), 4.21-4.09 (m, 2H), 3.73 (s, 3H), 2.50 (s, 3H), 1.45 (d, 3H); MS (ESI) m/z = 506.2 (M + H)+
  • Example 17. (S)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The title compound as a solid (137.00 mg, 0.407 mmol, 66.42% yield) was prepared in the same fashion as step 1 in Example 15 except that 4-ethynyl-1-(2-fluoroethyl)-1H-pyrazole (95.62 mg, 0.612 mmol) was used instead of 1-(difluoromethyl)-4-ethynyl-1H-pyrazole. 1H-NMR (CD3OD, 400MHz) δ 7.99-7.97 (m, 2H), 7.75 (s, 1H), 6.70 (s, 1H), 4.84-4.81 (m, 1H), 4.72-4.70 (m, 1H), 4.52-4.43 (m, 2H), 3.92-3.69 (m, 3H), 1.90-1.83 (m, 2H), 1.30 (d, 3H); MS (ESI) m/z = 337.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a solid (95.00 mg, 0.181 mmol, 46.10% yield) was prepared in the same fashion as step 2 in Example 15 except that (S)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (132.44 mg, 0.393 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 8.01 (d, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 6.71 (s, 1H), 6.27 (d, 1H), 4.80-4.78 (m, 1H), 4.69-4.66 (m, 2H), 4.46-4.43 (m, 1H), 4.39-4.30 (m, 4H), 3,60 (s, 3H), 2.36 (s, 3H), 2.16-2.07 (m, 2H), 1.33 (d, 2H); MS (ESI) m/z = 524.1 (M + H)+
  • Step 3. (S)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a solid (14.00 mg, 0.029 mmol, 13.30% yield) was prepared in the same fashion as step 3 in Example 15 except that (S)-2-(5-(3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (113.14mg, 0.216 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.32 (d, 1H), 8.19 (s, 1H), 7.96 (s, 2H), 7.74 (s, 1H), 6.64 (d, 1H), 4.87-4.82 (m, 1H), 4.74-4.69 (m, 1H), 4.53-4.44 (m, 2H), 4.20-4.08 (m, 2H), 3.73 (s, 3H), 2.50 (s, 3H), 2.35-2.29 (m, 1H), 2.09-2.03 (m, 2H), 1.44 (d, 3H); MS (ESI) m/z = 488.3 (M + H)+
  • Example 18. (S)-45-((1-Isopropyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (200.00 mg, 0.612 mmol) prepared in Reference Example 6, 4-ethynyl-1-isopropyl-1H-pyrazole (82.18 mg, 0.612 mmol), PdCl2(PPh3)2 (21.49 mg, 0.031 mmol), CuI (23.34 mg, 0.122 mmol) and TEA (0.17 ml, 1.225 mmol) in DMF (3 mL) was stirred at 50 oC 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 yield (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (140.00 mg, 0.420 mmol, 68.68% yield). 1H-NMR (CD3OD, 400MHz) δ 7.99-7.97 (m, 2H), 7.71 (s, 1H), 6.70 (s, 1H), 4.59-4.52 (m, 1H), 3.93-3.88 (m, 1H), 3.83-3.70 (m, 2H), 1.93-1.81 (m, 1H), 1.51 (s, 6H), 1.30 (s, 3H); MS (ESI) m/z = 333.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The mixture of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (79.52 mg, 0.239 mmol) prepared in step 1, 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (45.68 mg, 0.239 mmol) prepared in Reference Example 7 and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.836 mmol) in　toluene (2 mL) was stirred at 130 oC 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-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (52.00 mg, 0.103 mmol, 43.01% yield). 1H-NMR (CD3OD, 400MHz) δ 7.99 (d, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.51 (s, 1H), 6.74 (s, 1H), 6.27 (d, 1H), 4.54-4.43 (m, 3H), 4.06-4.04 (m, 1H), 3.66 (s, 3H), 2.24-2.15 (m, 2H), 1.45 (d, 6H), 1.39 (d, 3H); MS (ESI) m/z = 507.0 (M + H)+
  • Step 3. (S)-45-((1-Isopropyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The mixture of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (25.00 mg, 0.049 mmol) prepared in step 2, Cs2CO3 (48.29 mg, 0.148 mmol), XPhos (9.42 mg, 0.020 mmol), and Pd2(dba)3 (9.05 mg, 0.010 mmol) in 1,4-dioxane (4 mL) was stirred at 100 oC 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-isopropyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (15.10 mg, 0.032 mmol, 65.09% yield). 1H-NMR (CD3OD, 400MHz) δ 8.27 (d, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 6.67 (d, 1H), 4.72-4.53 (m, 2H), 4.15-4.11 (m, 2H), 3.81 (s, 3H), 2.37-2.29 (m, 2H), 1.58 (d, 6H), 1.43 (d, 3H); MS (ESI) m/z = 470.2 (M + H)+
  • Example 19. (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The title compound as a solid (95.00 mg, 0.312 mmol, 50.90% yield) was prepared in the same fashion as step 1 in Example 18 except that 3-ethynyl-1-methyl-1H-pyrazole (65.00 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1H-pyrazole. 1H-NMR (CD3OD, 400MHz) δ 8.00 (d, 1H), 7.64 (d, 1H), 6.73 (s, 1H), 6.53 (d, 1H), 3.94 (s, 3H), 3.93-3.88 (m, 1H), 3.77-3.69 (m, 2H), 1.89-1.84 (m, 2H), 1.30 (d, 3H); MS (ESI) m/z = 305.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a solid (29.00 mg, 0.061 mmol, 25.40% yield) was prepared in the same fashion as step 2 in Example 18 except that (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (72.82 mg, 0.239 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 8.01-7.97 (m, 2H), 7.83 (s, 1H), 7.57 (s, 1H), 6.77 (s, 1H), 6.36 (s, 1H), 6.26 (d, 1H), 4.53-4.48 (m, 2H), 4.07-4.05 (m, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 2.26-2.17 (m, 2H), 1.47 (d, 3H); MS (ESI) m/z = 478.1 (M + H)+
  • Step 3. (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a solid (2.60 mg, 0.006 mmol, 11.92% yield) was prepared in the same fashion as step 3 in Example 18 except that (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (23.61 mg, 0.049 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.26 (d, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (s, 1H), 6.70 (d, 1H), 6.44 (d, 1H), 5.95 (s, 1H), 4.88-4.69 (m, 1H), 4.19-4.16 (m, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.23-2.19 (m, 2H), 1.30 (d, 3H); MS (ESI) m/z = 442.2 (M + H)+
  • Example 20. (S)-11,6-Dimethyl-45-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The title compound as a solid (170.00 mg, 0.456 mmol, 74.47% yield) was prepared in the same fashion as step 1 in Example 18 except that 4-ethynyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole (106.64 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1H-pyrazole. 1H-NMR (CD3OD, 400MHz) δ 8.06 (s, 1H), 6.76 (s, 1H), 3.99 (s, 3H), 3.95-3.92 (m, 1H), 3.76-3.68 (m, 2H), 1.85-1.81 (m, 2H), 1.30 (d, 3H); MS (ESI) m/z = 373.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a solid (25.00 mg, 0.046 mmol, 19.17% yield) was prepared in the same fashion as step 2 in Example 18 except that (S)-3-((2-chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (89.06 mg, 0.239 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 7.99-7.95 (m, 2H), 7.84 (s, 1H), 7.71 (s, 1H), 6.78 (s, 1H), 6.26 (d, 1H), 4.56-4.46 (m, 2H), 4.08-4.07 (m, 1H), 3.91 (s, 3H), 3.66 (s, 3H), 2.25-2.03 (m, 2H), 1.39 (d, 3H); MS (ESI) m/z = 546.1 (M + H)+
  • Step 3. (S)-11,6-Dimethyl-45-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a solid (6.60 mg, 0.013 mmol, 26.22% yield) was prepared in the same fashion as step 3 in Example 18 except that (S)-2-(5-(3-((2-chloro-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (26.97 mg, 0.049 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.33 (s, 1H), 8.24 (d, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 6.68 (d, 1H), 4.88-4.67 (m, 1H), 4.19-4.16 (m, 2H), 3.99 (s, 3H), 3.81 (s, 3H), 2.30-2.27 (m, 1H), 2.08-2.03 (m, 1H), 1.44 (d. 3H); MS (ESI) m/z = 510.2 (M + H)+
  • Example 21. (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The title compound as a solid (138.00 mg, 0.400 mmol, 65.34% yield) was prepared in the same fashion as step 1 in Example 18 except that 3-cyclopropyl-4-ethynyl-1-methyl-1H-pyrazole (89.53 mg, 0.612 mmol) was used instead of 4-ethynyl-1-isopropyl-1H-pyrazole. 1H-NMR (CD3OD, 400MHz) δ 7.95 (s, 1H), 7.58 (s, 1H), 6.71 (s, 1H), 3.91 (s, 3H), 3.89-3.67 (m, 2H), 1.96-1.82 (m, 3H), 1.30 (d, 3H), 1.18-1.06 (m, 4H); MS (ESI) m/z = 345.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a solid (22.00 mg, 0.042 mmol, 17.78% yield) was prepared in the same fashion as step 2 in Example 18 except that (S)-3-((2-chloro-5-((3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (82.39 mg, 0.239 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol. 1H-NMR (CD3OD, 400MHz) δ 7.98 (d, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 6.76 (s, 1H), 6.26 (d, 1H), 4.59-4.48 (m, 2H), 4.10-4.08 (m, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 2.28-2.24 (m, 2H), 1.41 (d, 3H), 1.02-0.98 (m, 4H); MS (ESI) m/z = 518.1 (M + H)+
  • Step 3. (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a solid (3.10 mg, 0.006 mmol, 13.03% yield) was prepared in the same fashion as step 3 in Example 18 except that (S)-2-(5-(3-((2-chloro-5-((3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (25.59 mg, 0.049 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400MHz) δ 8.33 (s, 1H), 8.24 (d, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 6.69 (d, 1H), 4.78-4.72 (m, 1H), 4.24-4.18 (m, 2H), 3.92 (s, 3H), 3.81 (s, 3H), 2.29-2.27 (m, 1H), 2.00-1.94 (m, 2H), 1.47 (d, 3H), 1.16-1.12 (m, 4H); MS (ESI) m/z = 482.2 (M + H)+
  • Example 22. (S)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol (155.72 mg, 0.471 mmol) prepared in Reference Example 1, 4-ethynyl-1-methylpyrazole (50 mg, 0.471 mmol), PdCl2(PPh3)2 (33.07 mg, 0.047 mmol), CuI (17.94 mg, 0.094 mmol) , and TEA (131.33 uL, 0.942 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (86.5 mg, 0.28 mmol, 59.49% yield) as pale pink solid. MS (ESI) m/z = 308.9 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The reaction mixture of　4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (48 mg, 0.251 mmol),　(Tributylphosphoranylidene)acetonitrile (164.66 uL, 0.628 mmol) and　(S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (77.51 mg, 0.251 mmol) prepared in step 1 in　toluene (1 mL) was stirred at　110　oC for　3 hours. The reaction mixture was cooled, concentrated. The crude product was purified by silica gel column chromatography　(MeOH/EA = 0-15%) to yield　(S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (46 mg, 0.095 mmol, 38.02 % yield) as pale yellow solid. 1H-NMR (DMSO-d 6, 400 MHz) δ 8.19 (d, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.60 (s, 1H), 6.19 (d, 1H), 5.85 (t, 1H), 5.13-4.96 (m, 1H), 4.82 (s, 2H), 4.74-4.60 (m, 2H), 3.91 (s, 3H), 3.87-3.69 (m, 5H)
  • Step 3. (S)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of Pd2(dba)3 (12.83 mg, 0.014 mmol), XPhos (13.35 mg, 0.028 mmol), Cs2CO3 (91.28 mg, 0.28 mmol) and (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.093 mmol) prepared in step 2 in 1,4-dioxane (1.0 mL) was stirred at 90 oC for 2 hours. The mixture was diluted in DCM, filtered through Celite, and then concentrated. The crude residue was purified by silica gel column chromatography　(EA/n-Hex = 0-100%)　　and then slurried with EA/IPE　for 0.5 hr (room temperature) and then filtered to yield (S)-7-fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (15.8 mg, 0.035 mmol, 37.98% yield) as pale yellow solid. 1H-NMR (DMSO-d 6, 400 MHz) δ 10.04 (s, 1H), 8.31 (d, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 8.01 (s,1 H), 7.98 (s, 1H), 7.70 (s,1 H), 6.79 (d, 1H), 6.68 (t, 1H), 4.84 (dd, 1H), 4.66 (dd, 1H), 4.40 (t, 1H), 4.17-4.09 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.66-3.56 (m, 1H); MS (ESI) m/z = 445.9 (M + H)+
  • Example 23. (S)-7-Fluoro-11-methyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • The title compound as a white solid (1166 mg) was prepared in the same fashion as step 1 in Example 22 except that 4-Ethynyl-1-(trifluoromethyl)-1H-pyrazole (50 mg, 0.312 mmol) was used instead of 4-ethynyl-1-methylpyrazole. 1H-NMR (CDCl3, 400 MHz) 8.17 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 6.58 (s, 1H), 5.56 (t, 1H), 4.90-4.73 (m, 1H), 4.02-3.83 (m, 2H), 3.68-3.58 (m, 2H), 2.21 (t, 1H)
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (41 mg) was prepared in the same fashion as step 2 in Example 22 except that (S)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (75.88 mg, 0.209 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 6.64 (s, 1H), 6.19 (d, 1H), 6.10 (t, 1H), 5.11-4.81 (m, 1H), 4.81 (s, 2H), 4.68-4.61 (m, 2H), 3.95-3.78 (m, 2H), 3.73 (s, 3H)
  • Step 3. (S)-7-Fluoro-11-methyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (9.9 mg) was prepared in the same fashion as step 3 Example 22 except that (S)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (35 mg, 0.065 mmol) was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (DMSO-d 6, 400 MHz) δ 10.05 (s, 1H), 8.89 (s, 1H), 8.32 (d, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 6.80 (d, 1H), 6.77 (t, 1H), 4.84 (dd, 1H), 4.66 (dd, 1H), 4.40 (t, 1H), 4.19-4.12 (m, 1H), 3.75 (s, 3H), 3.64-3.54 (m, 1H); MS (ESI) m/z = 499.8 (M + H)+
  • Example 24. (R)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol
  • The title compound as a white solid (80 mg) was prepared in the same fashion as step 1 in Example 22 except that (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol (155.72 mg, 0.471 mmol) prepared in Reference Example 2 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m/z = 308.9 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (72 mg) was prepared in the same fashion as step 2 in Example 22 except that (R)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol (77.51 mg, 0.251 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.19 (d, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.60 (s, 1H), 6.20 (d, 1H), 5.85 (t, 1H), 5.13-4.96 (m, 1H), 5.01 (s, 2H), 4.96-4.60 (m, 2H), 3.91 (s, 3H), 3.87-3.69 (m, 5H)
  • Step 3. (R)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (19.2 mg) was prepared in the same fashion as step 3 Example 22 except that (R)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.093 mmol) was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (DMSO-d 6, 400 MHz) δ 10.02 (s, 1H), 8.31 (d, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 8.01 (s,1 H), 7.98 (s, 1H), 7.70 (s,1 H), 6.79 (d, 1H), 6.67 (t, 1H), 4.84 (dd, 1H), 4.66 (dd, 1H), 4.40 (t, 1H), 4.17-4.09 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.66-3.57 (m, 1H); MS (ESI) m/z = 445.9 (M + H)+
  • Example 25. (S)-11,8-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a white solid (80.8 mg) was prepared in the same fashion as step 1 in Example 22 except that (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (153.85 mg, 0.471 mmol) prepared in Reference Example 3 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m/z = 305.0 (M + H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (54 mg) was prepared in the same fashion as step 2 in Example 22 except that (R)-4-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (76.52 mg, 0.251 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (d, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.33 (s, 1H), 6.94 (s, 1H), 6.70 (dd, 1H), 6.54 (s, 1H), 6.14 (d, 1H), 5.06-5.02 (m, 1H), 4.77 (s, 2H), 3.84 (s, 3H), 3.72-3.54 (m, 2H), 3.62 (s, 3H), 2.32-2.24 (m, 1H), 1.97-1.91 (m, 1H), 1.23 (d, 3H)
  • Step 3. (S)-11,8-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (7 mg) was prepared in the same fashion as step 3 in Example 22 except that (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (44.63 mg, 0.093 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400 MHz) δ 8.36 (s, 1H), 8.26 (d, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H), 6.69 (d, 1H), 5.44-5.36 (m, 1H), 3.97-3.91 (m, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.62-3.55 (m, 1H), 2.32-2.24 (m, 1H), 1.97-1.91 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 442.0 (M + H)+
  • Example 26. (S)-11,8-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a white solid (95 mg) was prepared in the same fashion as step 1 in Example 25 except that 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (50 mg, 0.312 mmol) was used instead of 4-ethynyl-1-methylpyrazole. 1H-NMR (CDCl3, 400 MHz) 8.11 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 6.50 (s, 1H), 6.05 (brs, 1H), 4.09 (brs, 1H), 3.47-3.29 (m, 2H), 1.94-1.76 (m, 2H), 1.33 (d, 3H)
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (35 mg) was prepared in the same fashion as step 2 in Example 22 except that (R)-4-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (75.06 mg, 0.209 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (d, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.44 (d, 1H), 7.13 (dd, 1H), 6.57 (s, 1H), 6.14 (d, 1H), 4.99-4.92 (m, 1H), 4.79 (s, 2H), 3.75-3.57 (m, 2H), 3.65 (s, 3H), 2.24-2.14 (m, 1H), 1.87-1.84 (m, 1H), 1.22 (d, 3H)
  • Step 3. (S)-11,8-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (2.2 mg) was prepared in the same fashion as step 3 Example 22 except that (S)-2-(5-((4-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (34.74 mg, 0.065 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400 MHz) δ 8.50 (s, 1H), 8.39 (s, 1H), 8.28 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 6.72 (d, 1H), 5.45-5.41 (m, 1H), 3.99-3.92 (m, 1H), 3.77 (s, 3H), 3.62-3.57 (m, 1H), 2.34-2.32 (m, 1H), 1.99-1.93 (m, 1H), 1.32 (d, 3H); MS (ESI) m/z = 495.9 (M + H)+
  • Example 27. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,8-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a white solid (103 mg) was prepared in the same fashion as step 1 in Example 25 except that 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (47.81 mg, 0.306 mmol) was used instead of 4-ethynyl-1-methylpyrazole. MS (ESI) m/z = 354.9 (M + H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (52 mg) was prepared in the same fashion as step 2 in Example 22 except that (R)-4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (92.78 mg, 0.262 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m/z = 527.9 (M + H)+
  • Step 3. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,8-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (9.9 mg) was prepared in the same fashion as step 3 Example 22 except that (S)-2-(5-((4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50 mg, 0.095 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.35 (d, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 6.37 (d, 1H), 6.13 (tt, 1H), 5.51-5.43 (m, 2H), 4.51 (td, 2H), 4.12-4.05 (m, 1H), 3.77 (s, 3H), 3.58-3.51 (m, 1H), 2.30-2.20 (m, 1H), 1.98-1.92 (m, 1H), 1.12 (d, 3H); MS (ESI) m/z = 491.9 (M + H)+
  • Example 28. (S)-11,8-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a white solid (112 mg) was prepared in the same fashion as step 1 in Example 25 except that 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (53.32 mg, 0.306 mmol) was used instead of 4-ethynyl-1-methylpyrazole. MS (ESI) m/z = 372.9 (M + H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (58 mg) was prepared in the same fashion as step 2 in Example 22 except that (R)-4-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (97.49 mg, 0.262 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m/z = 545.9 (M + H)+
  • Step 3. (S)-11,8-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (9.5 mg) was prepared in the same fashion as step 3 Example 22 except that (S)-2-(5-((4-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (51.7 mg, 0.095 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine.1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 8.35 (d, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 6.37 (d, 1H), 5.51-5.43 (m, 2H), 475 (q, 2H), 4.12-4.05 (m, 1H), 3.77 (s, 3H), 3.58-3.52 (m, 1H), 2.30-2.22 (m, 1H), 1.98-1.92 (m, 1H), 1.12 (d, 3H); MS (ESI) m/z = 509.9 (M + H)+
  • Example 29. 1'-Methyl-5'-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Step 1. (1-(((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methanol
  • The title compound as a white solid (90.5 mg) was prepared in the same fashion as step 1 in Example 22 except that (1-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)cyclopropyl)methanol (159.51 mg, 0.471 mmol) prepared in Reference Example 4 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m/z = 316.9 (M + H)+
  • Step 2. 2-(5-((1-(((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (47 mg) was prepared in the same fashion as step 2 in Example 22 except that 3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (79.53 mg, 0.251 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (d, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.39 (s, 1H), 6.97 (s, 1H), 6.62 (t, 1H), 6.46 (s, 1H), 6.17 (d, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.78 (s, 3H), 3.64 (s, 3H), 3.41 (d, 2H), 0.86-0.79 (q, 4H)
  • Step 3. 1'-Methyl-5'-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • The title compound as an off-white solid (3 mg) was prepared in the same fashion as step 3 in Example 22 except that 2-(5-((1-(((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)cyclopropyl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.75 mg, 0.093 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 8.26 (d, 1H), 8.05 (s, 1H), 7.95 (s 1H), 7.87 (s, 1H), 7.69 (s, 1H), 6.70 (d, 1H), 4.23 ( brs, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.59 (brs, 2H), 0.92 (s, 3H), 0.74 (s, 3H); MS (ESI) m/z = 453.9 (M + H)+
  • Example 30. 11,7,7-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol
  • The title compound as a white solid (83 mg) was prepared in the same fashion as step 1 in Example 22 except that 3-((2-chloro-5-iodopyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (160.46 mg, 0.471 mmol) prepared in Reference Example 5 was used instead of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)-2-fluoropropan-1-ol. MS (ESI) m/z = 318.9 (M + H)+
  • Step 2. 2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a white solid (46 mg) was prepared in the same fashion as step 2 in Example 22 except that 3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropan-1-ol (80.04 mg, 0.251 mmol) prepared in step 1 was used instead of (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropan-1-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (d, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.30 (s, 1H), 6.86 (s, 1H), 6.84 (t, 1H), 6.55 (s, 1H), 6.15 (d, 1H), 4.73 (s, 2H), 4.09 (s, 2H), 3.79 (s, 3H), 3.66 (s, 3H), 3.40 (d, 2H), 1.17 (s, 6H)
  • Step 3. 11,7,7-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (10.2 mg) was prepared in the same fashion as step 3 in Example 22 except that 2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2,2-dimethylpropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.94 mg, 0.093 mmol) prepared in step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)-2-fluoropropoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (DMSO-d 6, 400 MHz) δ 9.93 (s, 1H), 8.29 (d, 1H), 8.17 (s, 1H), 8.05 (s,1 H), 7.96 (s, 2H), 7.70 (d, 1H), 6.77 (d, 1H), 6.29 (t, 1H), 4.59 (brs, 1H), 3.87 (brs, 4H), 3.78 (s, 3H), 3.67 (brs, 1H), 3.01 (brs, 1H), 1.30 (s, 3H), 0.89 (s, 3H); MS (ESI) m/z = 456.0 (M + H)+
  • Example 31. (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine (300 mg, 1.273 mmol) prepared in Reference Example 10, and (S)-3-aminobutan-1-ol (113.4 mg, 1.273 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.44 mL, 2.546 mmol) were added, the reaction mixture was stirred at 80 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (385 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13-8.12 (d, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 6.54 (s, 1H), 6.17-6.16 (d, 1H), 5.86-5.84 (d, 1H), 4.84 (s, 2H), 4.57-4.53 (q, 1H), 4.46-4.41 (q, 1H), 3.98-3.91 (q, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 2.25-2.20 (m, 1H), 2.10-2.05 (m, 1H), 1.45-1.40 (t, 3H); MS (ESI) m/z = 305.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (224 mg, 1.17 mmol) in prepared in Reference Example 7, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (385 mg, 1.263 mmol, 1.08 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (1.2 mL, 3.51 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-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 8.12-8.11 (d, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 6.54 (s, 1H), 6.16-6.15 (d, 1H), 5.85-5.83 (d, 1H), 4.91 (s, 2H), 4.56-4.53 (t, 1H), 4.46-4.42 (q, 1H), 3.96-3.92 (t, 1H), 3.81 (s, 3H), 3.64 (s, 3H), 2.22-2.19 (m, 1H), 2.10-2.05 (m, 1H), 1.41-1.39 (d, 3H); MS (ESI) m/z = 478.2 (M + H)+
  • Step 3. (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (209 mg, 0.348 mmol) prepared in step 2, Cs2CO3 (427 mg, 1.31 mmol), XPhos (83 mg, 0.17 mmol), and Pd2(dba)3 (80 mg, 0.087 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (10.9 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.32-8.31 (d, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.77-7.73 (d, 1H), 7.65-7.58 (m, 2H), 7.43-7.42 (d, 1H), 7.12-7.08 (d, 1H), 6.37-6.36 (d, 1H), 4.95-4.94 (d, 1H), 4.81-4.76 (t, 1H), 4.29-4.27 (d, 1H), 4.06-4.02 (m, 1H), 3.94-3.91 (d, 3H), 3.80 (s, 3H), 2.20-2.13 (m, 2H), 1.47-1.46 (d, 3H); MS (ESI) m/z = 442.2 (M + H)+
  • Example 32. (R)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridine (300 mg, 1.273 mmol) prepared in Reference Example 10, and (R)-3-aminobutan-1-ol (113.4 mg, 1.273 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.44 mL, 2.546 mmol) were added, the reaction mixture was stirred at 80 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (357 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.98-7.96 (d, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 6.46 (s, 1H), 5.75-5.73 (d, 1H), 3.84 (s, 3H), 3.80-3.76 (m, 3H), 1.90-1.87 (m, 1H), 1.77-1.73 (m, 1H), 1.27-1.21 (q, 3H); MS (ESI) m/z = 305.1 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (224 mg, 1.17 mmol) in prepared in Reference Example 7, (R)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (357 mg, 1.171 mmol, 1.0 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (1.2 mL, 3.51 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (158 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11-8.10 (d, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 6.53 (s, 1H), 6.16-6.14 (d, 1H), 5.85-5.83 (d, 1H), 4.99 (s, 2H), 4.55-4.51 (m, 1H), 4.45-4.41 (m, 1H), 3.95-3.91 (t, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.22-2.18 (m, 1H), 2.09-2.03 (m, 1H), 1.40-1.38 (d, 3H); MS (ESI) m/z = 478.2 (M + H)+
  • Step 3. (R)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (159 mg, 0.333 mmol) prepared in step 2, Cs2CO3 (427 mg, 1.31 mmol), XPhos (83 mg, 0.17 mmol), and Pd2(dba)3 (80 mg, 0.087 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (23.9 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31-8.30 (d, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.38-6.36 (d, 1H), 4.95-4.94 (d, 1H), 4.81-4.76 (t, 1H), 4.29-4.27 (d, 1H), 4.05-4.03 (t, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.20-2.13 (m, 2H), 1.47-1.45 (d, 3H); MS (ESI) m/z = 442.2 (M + H)+
  • Example 33. (R)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (150 mg, 0.525 mmol) prepared in Reference Example 11, and (R)-3-aminobutan-1-ol (46.8 mg, 0.525 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.18 mL, 1.05 mmol, 2.0 eq) were added, the reaction mixture was stirred at 80 oC 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (141 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.69-7.68 (d, 2H), 6.51 (s, 1H), 6.23-5.95 (t, 1H), 5.63-5.61 (d, 1H), 4.50-4.43 (m, 2H), 3.88-3.80 (m, 3H), 2.24 (s, 1H), 1.93-1.89 (q, 1H), 1.82-1.77 (q, 1H), 1.30-1.29 (d, 3H); MS (ESI) m/z = 355.1 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (30.8 mg, 0.161 mmol) in prepared in Reference Example 7, (R)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (140 mg, 0.395 mmol, 2.45 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.14 mL, 0.402 mmol, 2.5 eq) in toluene (2 mL) was stirred at 100 oC 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.3 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.09-8.08 (d, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 6.53 (s, 1H), 6.15-6.14 (d, 1H), 6.04-5.90 (m, 2H), 5.05 (s, 2H), 4.54-4.52 (d, 1H), 4.44-4.32 (m, 3H), 3.94-3.91 (t, 1H), 3.62 (s, 3H), 2.22-2.19 (q, 1H), 2.08-2.02 (m, 1H), 1.40-1.38 (d, 3H); MS (ESI) m/z = 528.2 (M + H)+
  • Step 3. (R)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45.3 mg, 0.087 mmol) prepared in step 2, Cs2CO3 (85 mg, 0.261 mmol), XPhos (17 mg, 0.035 mmol), and Pd2(dba)3 (16 mg, 0.017 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (2.7 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.33-8.32 (d, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 6.37-6.36 (d, 1H), 6.25-5.98 (t, 1H), 4.93-4.91 (d, 1H), 4.81-4.76 (t, 1H), 4.53-4.46 (m, 2H), 4.30-4.28 (d, 1H), 4.07-4.05 (d, 1H), 3.81 (s, 3H), 2.20-2.17 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m/z = 492.2 (M + H)+
  • Example 34. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (150 mg, 0.525 mmol) prepared in Reference Example 11, and (S)-3-aminobutan-1-ol (46.8 mg, 0.525 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.18 mL, 1.05 mmol, 2.0 eq) were added, the reaction mixture was stirred at 80 oC 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (141 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.02 (s, 1H), 7.68 (s, 2H), 6.50 (s, 1H), 6.22-5.94 (t, 1H), 5.66-5.64 (d, 1H), 4.49-4.42 (m, 2H), 3.88-3.79 (m, 3H), 1.92-1.89 (q, 1H), 1.82-1.75 (q, 1H), 1.29-1.27 (d, 3H); MS (ESI) m/z = 355.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (30.8 mg, 0.161 mmol) in prepared in Reference Example 7, (S)-3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (140 mg, 0.395 mmol, 2.45 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.14 mL, 0.402 mmol, 2.5 eq) in toluene (2 mL) was stirred at 100 oC 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-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70.8 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12-8.11 (d, 1H), 7.96 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.55 (s, 1H), 6.17 (d, 1H), 6.05-5.92 (m, 2H), 5.05 (s, 2H), 4.87 (s, 2H), 4.56-4.56 (d, 1H), 4.54-4.33 (m, 3H), 3.96-3.93 (t, 1H), 3.64 (s, 3H), 2.23-2.21 (t, 1H), 2.10-2.04 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m/z = 528.1 (M + H)+
  • Step 3. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (71.0 mg, 0.087 mmol) prepared in step 2, Cs2CO3 (85 mg, 0.261 mmol), XPhos (17 mg, 0.035 mmol), and Pd2(dba)3 (16 mg, 0.017 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-45-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (4.0 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.33-8.32 (d, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 6.37-6.36 (d, 1H), 6.24-5.90 (dd, 1H), 4.92 (s, 1H), 4.81-4.76 (t, 1H), 4.30-4.28 (d, 1H), 4.07-4.04 (d, 1H), 3.81 (s, 3H), 2.20-2.17 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m/z = 492.2 (M + H)+
  • Example 35. (6S)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (3S)-3-((2-Chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (100 mg, 0.306 mmol) prepared in Reference Example 6, 1-(2,2-difluorocyclopropyl)-4-ethynyl-1H-pyrazole (42.3 mg, 0.306 mmol), PdCl2(PPh3)2 (10.8 mg, 0.015 mmol), and CuI (11.7 mg, 0.061 mmol) was charged nitrogen gas for 10 minutes. After DMF (15 mL) and TEA (0.09 mL, 0.612 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (71.1 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.55 (s, 1H), 7.50 (s, 2H), 7.22-7.12 (m, 1H), 7.07-7.05 (d, 1H), 6.08 (s, 1H), 5.89-5.87 (d, 1H), 4.35 (s, 1H), 3.84-3.82 (d, 1H), 3.40-3.36 (q, 2H), 3.29 (s, 1H), 1.95-1.86 (m, 1H), 1.75-1.70 (q, 1H), 1.47-1.44 (q, 1H), 1.34-1.30 (q, 1H), 0.85-0.83 (d, 3H); MS (ESI) m/z = 367.1 (M + H)+
  • Step 2. 2-(5-((3S)-3-((2-Chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (30.8 mg, 0.161 mmol) in prepared in Reference Example 7, (3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (71.1 mg, 0.194 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.17 mL, 0.485 mmol, 2.5 eq) in toluene (2 mL) was stirred at 100 oC 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-((3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.7 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13-8.08 (q, 2H), 7.96 (s, 1H), 7.49 (s, 1H), 7.33 (s, 1H), 6.55 (s, 1H), 6.17-6.14 (t, 1H), 5.95-5.88 (m, 1H), 4.87 (s, 2H), 4.57-4.41 (m, 2H), 4.05-4.03 (d, 1H), 3.96-3.93 (t, 1H), 3.65 (s, 3H), 2.21-2.15 (m, 2H), 2.11-2.04 (m, 2H), 1.41-1.40 (d, 3H); MS (ESI) m/z = 540.2 (M + H)+
  • Step 3. (6S)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of 2-(5-((3S)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.7 mg, 0.094 mmol) prepared in step 2, Cs2CO3 (92 mg, 0.282 mmol), XPhos (17.9 mg, 0.038 mmol), and Pd2(dba)3 (17.2 mg, 0.019 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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 (6S)-45-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (9.9 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.31-8.30 (d, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.72-7.71 (d, 1H), 6.38-6.37 (d, 1H), 4.94-4.92 (d, 1H), 4.78 (t, 1H), 4.29-4.28 (d, 1H), 4.15-4.09 (q, 3H), 4.06-4.04 (t, 1H), 3.80 (s, 3H), 2.27-2.23 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m/z = 504.2 (M + H)+
  • Example 36. 11-Methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The mixture of 2-(5-(3-((2-chloro-5-iodopyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (200 mg, 0.412 mmol) prepared in Reference Example 12, 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (43.7 mg, 0.412 mmol, 1.0 eq), PdCl2(PPh3)2 (14.4 mg, 0.021 mmol, 0.05 eq), and CuI (15.7 mg, 0.082 mmol, 0.2 eq) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.11 mL, 0.824 mmol, 2.0 eq) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (191 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11-8.09 (d, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.55-6.53 (d, 2H), 6.16-6.15 (d, 1H), 5.00 (s, 2H), 4.64-4.62 (d, 2H), 4.42-4.40 (t, 2H), 3.60-3.59 (d, 2H), 3.18-3.14 (t, 2H), 2.16-2.14 (t, 2H), 1.47-1.44 (t, 3H); MS (ESI) m/z = 532.1 (M + H)+
  • Step 2. 11-Methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of 2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)propoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (191 mg, 0.359 mmol) prepared in step 1, Cs2CO3 (350 mg, 1.077 mmol), XPhos (68.5 mg, 0.144 mmol), and Pd2(dba)3 (65.7 mg, 0.072 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (12.7 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.34-8.32 (d, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.75-7.73 (d, 1H), 6.37-6.36 (d, 1H), 5.54-5.52 (t, 1H), 4.77-4.70 (q, 2H), 4.43-4.40 (t, 2H), 3.79 (s, 3H), 3.77 (s, 2H), 2.23 (s, 2H); MS (ESI) m/z = 496.2 (M + H)+
  • Example 37. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (500 mg, 1.841 mmol) prepared in Reference Example 13, and (S)-3-aminobutan-1-ol (164 mg, 1.841 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.64 mL, 3.681 mmol, 2.0 eq) were added, the reaction mixture was stirred at 80 oC 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (517 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.33-7.03 (t, 1H), 6.52 (s, 1H), 5.69-5.67 (d, 1H), 3.91 (s, 1H), 3.86-3.81 (m, 2H), 1.94-1.91 (m, 1H), 1.82-1.80 (m, 1H), 1.31-1.29 (d, 3H); MS (ESI) m/z = 341.1 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (56.1 mg, 0.293 mmol) in prepared in Reference Example 7, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100 mg, 0.293 mmol, 1.0 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.30 mL, 0.88 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105.4 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.10-8.08 (t, 2H), 7.95 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.11-6.96 (t, 1H), 6.56 (s, 1H), 6.15-6.13 (d, 1H), 5.96-5.93 (d, 1H), 4.55-4.50 (m, 1H), 4.45-4.41 (m, 1H), 3.97-3.94 (t, 1H), 3.67 (s, 3H), 2.20-2.18 (t, 1H), 2.09-2.03 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m/z = 514.1 (M + H)+
  • Step 3. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (105 mg, 0.204 mmol) prepared in step 2, Cs2CO3 (199 mg, 0.613 mmol, 3.0 eq), XPhos (38.9 mg, 0.082 mmol, 0.4 eq), and Pd2(dba)3 (37 mg, 0.041 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-45-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (31.3 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.37 (s, 1H), 8.29-8.28 (d, 1H), 8.12-8.10 (d, 2H), 8.01 (s, 1H), 7.79 (s, 1H), 7.35-7.05 (t, 1H), 6.38-6.36 (d, 1H), 4.91-4.89 (d, 1H), 4.77-4.76 (d, 1H), 4.27 (d, 1H), 4.04-4.02 (t, 1H), 3.79 (s, 3H), 2.20-2.12 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m/z = 478.1 (M + H)+
  • Example 38. (R)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-fluoropyridine (500 mg, 1.841 mmol) prepared in Reference Example 13, and (R)-3-amino-1-butanol (164 mg, 1.841 mmol) was charged nitrogen gas for 10 minutes. After DMF (6 mL) and DIPEA (0.64 mL, 3.681 mmol, 2.0 eq) were added, the reaction mixture was stirred at 80 oC 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (535 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.02-8.00 (d, 2H), 7.76 (s, 1H), 7.32-7.02 (t, 1H), 6.49 (s, 1H), 5.76-5.74 (d, 1H), 3.89-3.87 (t, 1H), 3.84-3.80 (q, 2H), 1.96-1.90 (m, 1H), 1.80-1.77 (m, 1H), 1.29-1.28 (d, 3H); MS (ESI) m/z = 341.1 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (56.1 mg, 0.293 mmol) in prepared in Reference Example 7, (R)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (100 mg, 0.293 mmol, 1.0 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.30 mL, 0.88 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (88.2 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 8.09-8.08 (d, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.26-6.96 (t, 1H), 6.56 (s, 1H), 6.15-6.14 (d, 1H), 5.95-5.93 (d, 1H), 4.56-4.53 (m, 1H), 4.51-4.40 (m, 1H), 3.98-3.94 (t, 1H), 3.66 (s, 3H), 2.22-2.19 (q, 1H), 2.10-2.04 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m/z = 514.1 (M + H)+
  • Step 3. (R)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (88 mg, 0.171 mmol) prepared in step 2, Cs2CO3 (199 mg, 0.613 mmol), XPhos (38.9 mg, 0.082 mmol), and Pd2(dba)3 (37 mg, 0.041 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (22.9 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.32-8.30 (d, 1H), 8.12-8.10 (m, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.35-7.05 (t, 1H), 6.38-6.37 (d, 1H), 4.91-4.89 (d, 1H), 4.79-4.75 (q, 1H), 4.30-4.27 (q, 1H), 4.06-4.03 (t, 1H), 3.80 (s, 3H), 2.20-2.13 (m, 2H), 1.48-1.46 (d, 3H); MS (ESI) m/z = 478.2 (M + H)+
  • Example 39. (R)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol) prepared in Reference Example 14, 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (133.3 mg, 0.766 mmol), PdCl2(PPh3)2 (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (R)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (260 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.73-7.73 (d, 2H), 7.43-7.43 (d, 1H), 6.53 (s, 1H), 5.60-5.59 (d, 1H), 4.75-4.69 (q, 2H), 3.92-3.81 (m, 2H), 1.92-1.90 (m, 1H), 1.83-1.81 (m, 1H), 1.31-1.30 (d, 3H); MS (ESI) m/z = 373.1 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) in prepared in Reference Example 7, (R)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (260 mg, 0.697 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (98 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.10-8.09 (d, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 6.54 (s, 1H), 6.16-6.15 (d, 1H), 5.95-5.93 (d, 1H), 4.65-4.53 (m, 2H), 4.45-4.41 (m, 1H), 3.96-3.92 (t, 1H), 3.63 (s, 3H), 2.24-2.20 (m, 1H), 2.09-2.05 (m, 1H), 1.41-1.39 (d, 3H); MS (ESI) m/z = 546.1 (M + H)+
  • Step 3. (R)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (98 mg, 0.180 mmol) prepared in step 2, Cs2CO3 (175 mg, 0.539 mmol), XPhos (34.2 mg, 0.072 mmol), and Pd2(dba)3 (32.8 mg, 0.036 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (28.3 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.33-8.32 (d, 1H), 8.14 (s, 1H), 7.76-7.74 (d, 2H), 6.39-6.38 (d, 1H), 4.94-4.93 (d, 1H), 4.81-4.72 (m, 3H), 4.31-4.29 (q, 1H), 4.15-4.13 (d, 1H), 4.07-4.05 (t, 1H), 3.81 (s, 3H), 2.22-2.21 (m, 2H), 1.49-1.48 (d, 3H); MS (ESI) m/z = 510.1 (M + H)+
  • Example 40. (R)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol) prepared in Reference Example 14, 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (122.5 mg, 0.766 mmol), PdCl2(PPh3)2 (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (R)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (275 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.02 (s, 2H), 7.86 (s, 1H), 6.50 (s, 1H), 5.84-5.82 (d, 1H), 3.91-3.88 (q, 1H), 3.85-3.80 (m, 2H), 1.95-1.87 (m, 1H), 1.81-1.78 (m, 1H), 1.30-1.28 (d, 3H); MS (ESI) m/z = 359.1 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) in prepared in Reference Example 7, (R)-3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (275 mg, 0.767 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (169 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.10-8.08 (t, 2H), 7.95 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 6.57 (s, 1H), 6.15-6.14 (d, 1H), 6.09-6.07 (d, 1H), 4.86 (s, 2H), 4.57-4.52 (m, 1H), 4.43-4.38 (m, 1H), 3.99-3.67 (q, 1H), 3.67 (s, 3H), 2.22-2.20 (m, 1H), 2.09-2.04 (m, 1H), 1.43-1.41 (d, 3H); MS (ESI) m/z = 532.1 (M + H)+
  • Step 3. (R)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-(3-((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (169 mg, 0.318 mmol) prepared in step 2, Cs2CO3 (175 mg, 0.539 mmol), XPhos (34.2 mg, 0.072 mmol), and Pd2(dba)3 (32.8 mg, 0.036 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (35.6 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.32-8.31 (d, 1H), 8.13-8.12 (d, 2H), 8.03 (s, 1H), 7.90 (s, 1H), 6.40-6.39 (d, 1H), 4.91-4.89 (d, 1H), 4.78-4.75 (t, 1H), 4.31-4.29 (q, 1H), 4.07-4.04 (t, 1H), 3.80 (s, 3H), 2.22-2.14 (m, 2H), 1.49-1.48 (d, 3H); MS (ESI) m/z = 496.1 (M + H)+
  • Example 41. (6R)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (3R)-3-((2-Chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol) prepared in Reference Example 14, 1-(2,2,-difluorocyclopropyl)-4-ethynyl-1H-pyrazole (128.6 mg, 0.766 mmol), PdCl2(PPh3)2 (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (180 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 6.45 (s, 1H), 5.73-5.72 (d, 1H), 4.08-4.06 (q, 1H), 3.86-3.77 (m, 1H), 2.24-2.16 (m, 2H), 2.14-2.06 (m, 1H), 1.93-1.91 (t, 1H), 1.89-1.87 (t, 1H), 1.30-1.28 (d, 3H); MS (ESI) m/z = 367.1 (M + H)+
  • Step 2. 2-(5-((3R)-3-((2-Chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) in prepared in Reference Example 7, (3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (180 mg, 0.491 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-((3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (107 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13-8.07 (m, 2H), 7.96-7.96 (d, 1H), 7.49-7.48 (d, 1H), 7.33 (s, 1H), 6.55 (s, 1H), 6.17-6.14 (q, 1H), 5.95-5.88 (q, 1H), 4.90-4.88 (d, 2H), 4.60-4.42 (m, 2H), 4.05-4.03 (q, 1H), 3.96-3.93 (t, 1H), 3.65-3.64 (d, 3H), 2.23-2.15 (m, 2H), 2.11-2.04 (m, 2H), 1.42-1.41 (d, 3H); MS (ESI) m/z = 540.1 (M + H)+
  • Step 3. (6R)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of 2-(5-((3R)-3-((2-chloro-5-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (107 mg, 0.198 mmol) prepared in step 2, Cs2CO3 (193 mg, 0.594 mmol), XPhos (37.8 mg, 0.079 mmol), and Pd2(dba)3 (36.2 mg, 0.04 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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 (6R)-45-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (22 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31-8.29 (d, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.73-7.72 (d, 2H), 6.39-6.38 (d, 1H), 4.95-4.93 (d, 1H), 4.78-4.76 (t, 1H), 4.28-4.28 (d, 1H), 4.16-4.11 (m, 2H), 4.06-4.03 (t, 1H), 3.80 (s, 3H), 2.27-2.12 (m, 4H), 1.48-1.47 (d, 3H); MS (ESI) m/z = 504.2 (M + H)+
  • Example 42. (R)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-3-((2-Chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (R)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (250 mg, 0.766 mmol) prepared in Reference Example 14, 4-ethynyl-1-(2-fluoroethyl)-1H-pyrazole (105.6 mg, 0.766 mmol), PdCl2(PPh3)2 (26.8 mg, 0.038 mmol), and CuI (29.1 mg, 0.153 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.21 mL, 1.531 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (R)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (189 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 6.46 (s, 1H), 5.71-5.69 (d, 1H), 4.79-4.77 (t, 1H), 4.67-4.65 (t, 1H), 4.41-4.39 (t, 1H), 4.34-4.32 (t, 1H), 3.84-3.74 (m, 3H), 1.89-1.86 (m, 1H), 1.77-1.75 (m, 1H), 1.26-1.24 (d, 3H); MS (ESI) m/z = 337.1 (M + H)+
  • Step 2. (R)-2-(5-(3-((2-Chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (133.3 mg, 0.697 mmol) in prepared in Reference Example 7, (R)-3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (189 mg, 0.561 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.71 mL, 2.092 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (139 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11-8.07 (m, 2H), 7.96 (s, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 6.17-6.15 (d, 1H), 5.85-5.83 (d, 1H), 4.79-4.77 (t, 1H), 4.67-4.65 (t, 1H), 4.54-4.51 (q, 2H), 4.46-4.42 (q, 1H), 4.38-4.30 (q, 1H), 3.94 (s, 1H), 3.65 (s, 3H), 2.37-2.19 (t, 1H), 2.10-2.09 (d, 1H), 1.41-1.39 (d, 3H); MS (ESI) m/z = 510.1 (M + H)+
  • Step 3. (R)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-(3-((2-chloro-5-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (139 mg, 0.273 mmol) prepared in step 2, Cs2CO3 (193 mg, 0.594 mmol), XPhos (37.8 mg, 0.079 mmol), and Pd2(dba)3 (36.2 mg, 0.04 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-(2-fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (50.8 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.31-8.29 (d, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.72-7.72 (d, 2H), 6.40-6.38 (d, 1H), 4.97-4.95 (d, 1H), 4.87-4.85 (t, 1H), 4.81-4.73 (m, 2H), 4.50-4.47 (t, 1H), 4.43-4.41 (t, 1H), 4.30-4.28 (t, 1H), 4.06-4.03 (t, 1H), 3.81 (s, 3H), 2.22-2.13 (m, 2H), 1.48-1.47 (d, 3H); MS (ESI) m/z = 474.1 (M + H)+
  • Example 43. (S)-6-Methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (68 mg, 0.262 mmol) in prepared in Reference Example 15, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (80 mg, 0.262 mmol, 1.0 eq) prepared in step 1 in Example 31, and (tributylphosphoranylidene)acetonitrile (0.27 mL, 0.787 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (62 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.14-8.13 (d, 1H), 8.09-8.08 (d, 2H), 7.48 (s, 1H), 6.53 (s, 1H), 6.21-6.20 (d, 1H), 5.63-5.60 (d, 1H), 4.70-4.67 (q, 1H), 4.55-4.48 (m, 3H), 3.93-3.90 (t, 1H), 3.85 (s, 3H), 2.21-2.19 (m, 1H), 2.11-2.08 (m, 1H), 1.42-1.40 (d, 3H); MS (ESI) m/z = 545.8 (M + H)+
  • Step 2. (S)-6-Methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (62 mg, 0.114 mmol) prepared in step 1, Cs2CO3 (111 mg, 0.341 mmol), XPhos (21.6 mg, 0.045 mmol), and Pd2(dba)3 (20.8 mg, 0.023 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-6-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (7.5 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36-8.34 (t, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 6.54-6.52 (d, 1H), 5.15 (t, 1H), 5.07-5.06 (d, 1H), 4.72-4.68 (t, 1H), 4.59-4.53 (q, 1H), 4.35-4.33 (q, 1H), 4.03-3.96 (q, 1H), 3.87 (s, 3H), 2.24-2.10 (m, 2H), 1.49-1.48 (d, 3H); MS (ESI) m/z = 510.9 (M + H)+
  • Example 44. (S)-11-Ethyl-6-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol (53.8 mg, 0.262 mmol) in prepared in Reference Example 16, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (80 mg, 0.262 mmol, 1.0 eq) prepared in step 1 in Example 31, and (tributylphosphoranylidene)acetonitrile (0.27 mL, 0.787 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (91 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12-8.10 (d, 1H), 8.07 (s, 2H), 7.99 (s, 1H), 7.44 (s, 1H), 7.20 (s, 1H), 6.54 (s, 1H), 6.17-6.15 (d, 1H), 5.80-5.78 (d, 1H), 5.02 (s, 2H), 4.53-4.50 (q, 1H), 4.45-4.41 (m, 1H), 4.00-3.93 (m, 3H), 3.81 (s, 3H), 2.26-2.20 (m, 2H), 2.09-2.04 (m, 1H), 1.41-1.39 (d, 3H); MS (ESI) m/z = 491.9 (M + H)+
  • Step 2. (S)-11-Ethyl-6-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (91 mg, 0.185 mmol) prepared in step 1, Cs2CO3 (180 mg, 0.555 mmol), XPhos (35.2 mg, 0.074 mmol), and Pd2(dba)3 (33.8 mg, 0.037 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-ethyl-6-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (40.5 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.28-8.27 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.44-6.42 (d, 1H), 5.00-4.98 (t, 1H), 4.86-4.81 (t, 1H), 4.29-4.28 (d, 1H), 4.13-4.03 (m, 2H), 3.93 (s, 3H), 2.20-2.10 (m, 2H), 1.49-1.45 (t, 3H), 1.28-1.24 (t, 3H); MS (ESI) m/z = 455.9 (M + H)+
  • Example 45. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-6-methyl-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-ol (57 mg, 0.22 mmol) in prepared in Reference Example 15, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (75 mg, 0.22 mmol, 1.0 eq) prepared in step 1 in Example 37, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.66 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (82 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13-8.11 (t, 2H), 8.07 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.30-7.00 (t, 1H), 6.56 (s, 1H), 6.20-6.19 (d, 1H), 5.67-5.64 (d, 1H), 4.95 (s, 2H), 4.69-4.67 (q, 1H), 4.56-4.49 (m, 3H), 3.94-3.94 (q, 1H), 2.29-2.21 (m, 2H), 2.12-2.11 (m, 1H), 1.43-1.42 (d, 3H); MS (ESI) m/z = 581.8 (M + H)+
  • Step 2. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-6-methyl-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of yield (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (82 mg, 0.141 mmol) prepared in step 1, Cs2CO3 (137 mg, 0.423 mmol), XPhos (26.8 mg, 0.056 mmol), and Pd2(dba)3 (25.8 mg, 0.028 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-45-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-6-methyl-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (4.5 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36-8.35 (d, 1H), 8.32-8.30 (d, 2H), 8.11 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.37-7.22 (t, 1H), 6.43-6.42 (d, 1H), 5.16-5.13 (d, 1H), 4.96-4.95 (d, 1H), 4.72-4.68 (t, 1H), 4.60-4.56 (t, 1H), 4.36-4.34 (d, 1H), 4.03-4.01 (q, 1H), 2.30-2.21 (m, 2H), 2.13-2.11 (d, 1H), 1.30-1.28 (d, 3H); MS (ESI) m/z = 545.9 (M + H)+
  • Example 46. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-ethyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1-ethyl-1H-pyrazol-5-ol (45.1 mg, 0.22 mmol) in prepared in Reference Example 16, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (75 mg, 0.22 mmol, 1.0 eq) prepared in step 1 in Example 37, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.66 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (29 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11-8.09 (t, 2H), 7.97 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.28-7.12 (t, 1H), 6.57 (s, 1H), 6.16-6.15 (d, 1H), 5.88-5.86 (d, 1H), 4.53-4.53 (q, 1H), 4.44-4.42 (m, 1H), 4.01-3.96 (q, 3H), 2.22-2.20 (m, 2H), 2.09-2.07 (m, 1H), 1.43-1.41 (d, 3H), 1.36-1.34 (d, 3H); MS (ESI) m/z = 527.9 (M + H)+
  • Step 2. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-ethyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (29 mg, 0.055 mmol) prepared in step 1, Cs2CO3 (53.7 mg, 0.165 mmol), XPhos (10.5 mg, 0.022 mmol), and Pd2(dba)3 (10.1 mg, 0.011 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-45-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-ethyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (5.2 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.36-8.34 (d, 1H), 8.18 (s, 1H), 8.03-8.00 (d, 2H), 7.80 (s, 1H), 7.37-7.07 (t, 1H), 6.53-6.52 (d, 1H), 5.00-4.99 (d, 1H), 4.88-4.83 (q, 1H), 4.35-4.34 (d, 1H), 4.17-4.01 (m, 4H), 2.22-2.14 (m, 2H), 1.54-1.49 (q, 3H), 1.29-1.26 (t, 3H); MS (ESI) m/z = 492.9 (M + H)+
  • Example 47. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-isopropyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1-isopropyl-1H-pyrazol-5-ol (48.2 mg, 0.22 mmol) in prepared in Reference Example 17, (S)-3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (75 mg, 0.22 mmol, 1.0 eq) prepared in step 1 in Example 37, and (tributylphosphoranylidene)acetonitrile (0.23 mL, 0.66 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.14-8.12 (t, 2H), 8.01 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.28-7.12 (t, 1H), 6.59 (s, 1H), 6.17-6.16 (d, 1H), 5.86-5.84 (d, 1H), 4.81 (s, 2H), 4.54-4.49 (m, 2H), 4.45-4.41 (m, 1H), 4.02-3.99 (t, 1H), 2.29-2.22 (m, 1H), 2.10-2.06 (m, 1H), 1.45-1.44 (d, 6H), 1.43-1.39 (q, 3H); MS (ESI) m/z = 541.9 (M + H)+
  • Step 2. (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-isopropyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg, 0.135 mmol) prepared in step 1, Cs2CO3 (131.6 mg, 0.404 mmol), XPhos (25.7 mg, 0.054 mmol), and Pd2(dba)3 (24.7 mg, 0.027 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-45-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-isopropyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (20.6 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.31-8.30 (d, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.37-7.07 (t, 1H), 6.40-6.39 (d, 1H), 4.93-4.88 (q, 2H), 4.50-4.46 (t, 1H), 4.33-4.32 (d, 1H), 3.94-3.92 (t, 1H), 2.12-2.10 (m, 2H), 1.59-1.57 (d, 3H), 1.50-1.48 (d, 6H); MS (ESI) m/z = 506.9 (M + H)+
  • Example 48. (S)-11,25,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine
  • The suspension of 4-(4-amino-5-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (101 mg, 0.492 mmol) in prepared in Reference Example 18, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (150 mg, 0.492 mmol, 1.0 eq) prepared in step 1 in Example 31, and (tributylphosphoranylidene)acetonitrile (0.50 mL, 1.477 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine (164 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.97-7.96 (d, 2H), 7.45 (s, 1H), 7.16 (s, 1H), 6.55 (s, 1H), 5.89-5.87 (d, 1H), 4.88 (s, 2H), 4.56-4.52 (m, 1H), 4.46-4.42 (m, 1H), 3.96-3.93 (t, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 2.23-2.20 (m, 1H), 2.10-2.05 (m, 1H), 1.42-1.41 (d, 3H); MS (ESI) m/z = 491.9 (M + H)+
  • Step 2. (S)-11,25,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-5-methylpyrimidin-4-amine (164 mg, 0.333 mmol) prepared in step 1, Cs2CO3 (325 mg, 1.00 mmol), XPhos (63.5 mg, 0.133 mmol), and Pd2(dba)3 (61 mg, 0.067 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-11,25,6-trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (39.9 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 4.96-4.94 (d, 1H), 4.80-4.74 (m, 1H), 4.28-4.27 (d, 1H), 4.05-4.01 (m, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 2.23 (s, 3H), 2.21-2.18 (m, 1H), 2.13-2.10 (m, 1H), 1.47-1.45 (d, 3H); MS (ESI) m/z = 456.0 (M + H)+
  • Example 49. (S)-11,26,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine
  • The suspension of 4-(4-amino-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (101 mg, 0.492 mmol) in prepared in Reference Example 19, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (150 mg, 0.492 mmol, 1.0 eq) prepared in step 1 in Example 31, and (tributylphosphoranylidene)acetonitrile (0.50 mL, 1.477 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine (135 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.23 (s, 1H), 6.55 (s, 1H), 6.07-6.07 (d, 1H), 4.77 (s, 2H), 4.55-4.49 (m, 2H), 3.95-3.92 (t, 1H), 3.84-3.83 (d, 3H), 3.66-3.65 (d, 3H), 2.32 (s, 3H), 2.22-2.20 (m, 1H), 2.13-2.11 (m, 1H), 1.43-1.41 (d, 3H); MS (ESI) m/z = 491.9 (M + H)+
  • Step 2. (S)-11,26,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-amine (135 mg, 0.274 mmol) prepared in step 1, Cs2CO3 (325 mg, 1.00 mmol), XPhos (63.5 mg, 0.133 mmol), and Pd2(dba)3 (61 mg, 0.067 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-11,26,6-trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (33.7 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 6.23 (s, 1H), 4.94-4.92 (d, 1H), 4.81-4.75 (m, 1H), 4.29-4.27 (m, 1H), 4.05-4.01 (m, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 2.40 (s, 3H), 2.20-2.12 (m, 2H), 1.47-1.45 (d, 3H); MS (ESI) m/z = 455.9 (M + H)+
  • Example 50. (S)-11,13,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (101 mg, 0.492 mmol) in prepared in Reference Example 8, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (150 mg, 0.492 mmol, 1.0 eq) prepared in step 1 in Example 31, and (tributylphosphoranylidene)acetonitrile (0.50 mL, 1.477 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (118 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.17-8.16 (d, 1H), 8.08 (s, 1H), 7.48-7.48 (d, 1H), 7.22 (s, 1H), 6.53 (s, 1H), 6.18-6.16 (d, 1H), 5.81-5.79 (d, 2H), 4.83 (s, 2H), 4.45-4.41 (m, 1H), 4.34-4.30 (m, 1H), 3.93-3.90 (t, 1H), 3.83 (s, 3H), 3.60 (s, 3H), 2.48 (s, 3H), 2.17-2.15 (m, 1H), 2.07-2.04 (m, 1H), 1.38-1.36 (d, 3H); MS (ESI) m/z = 491.9 (M + H)+
  • Step 2. (S)-11,13,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (118 mg, 0.240 mmol) prepared in step 1, Cs2CO3 (325 mg, 1.00 mmol), XPhos (63.5 mg, 0.133 mmol), and Pd2(dba)3 (61 mg, 0.067 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-11,13,6-trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (27.7 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36-8.35 (d, 1H), 8.30 (s, 1H), 8.11-8.09 (brs, 2H), 7.66 (s, 1H), 7.59 (s, 1H), 6.37-6.36 (d, 1H), 4.95-4.93 (d, 1H), 4.82-4.77 (t, 1H), 4.28-4.26 (d, 1H), 4.00-3.97 (m, 1H), 3.95 (s, 3H), 3.74-3.72 (d, 3H), 2.59 (s, 3H), 2.26-2.06 (m, 2H), 1.46-1.45 (d, 3H); MS (ESI) m/z = 456.0 (M + H)+
  • Example 51. 1'-Methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Step 1. (3-(((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol
  • The mixture of (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (160 mg, 0.451 mmol) prepared in Reference Example 20, 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (78.6 mg, 0.451 mmol), PdCl2(PPh3)2 (15.8 mg, 0.023 mmol), and CuI (17.2 mg, 0.09 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.13 mL, 0.903 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (3-(((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (172 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.75-7.72 (d, 1H), 7.68-7.63 (m, 1H), 7.50-7.45 (m, 1H), 6.59 (s, 1H), 6.30 (s, 1H), 4.73-4.67 (q, 2H), 4.57-4.56 (d, 1H), 4.52-4.50 (d, 1H), 4.14-4.08 (t, 2H), 3.62-3.60 (d, 2H); MS (ESI) m/z = 400.9 (M + H)+
  • Step 2. 2-(5-((3-(((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (97.1 mg, 0.508 mmol) in prepared in Reference Example 7, (3-(((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (172 mg, 0.429 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.44 mL, 1.287 mmol) in toluene (2 mL) was stirred at 100 oC 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-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (148 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11-8.10 (d, 2H), 7.99 (s, 1H), 7.42 (s, 1H), 7.06 (s, 1H), 6.64 (s, 1H), 6.42-6.42 (t, 1H), 6.19-6.17 (d, 1H), 5.19 (s, 2H), 4.87 (s, 2H), 4.81-4.79 (d, 2H), 4.67-4.57 (m, 4H), 3.82-3.81 (d, 2H), 3.66 (s, 3H); MS (ESI) m/z = 573.8 (M + H)+
  • Step 3. 1'-Methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • The suspension of 2-(5-((3-(((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (148 mg, 0.258 mmol) prepared in step 2, Cs2CO3 (252 mg, 0.774 mmol), XPhos (49.2 mg, 0.103 mmol), and Pd2(dba)3 (47.2 mg, 0.052 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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 1'-methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane] (25.3 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.33-8.31 (t, 2H), 8.20 (s, 1H), 8.10 (s, 1H), 7.78-7.77 (d, 2H), 6.39-6.37 (d, 1H), 5.65-5.62 (t, 1H), 4.79-4.68 (m, 5H), 4.58-4.56 (d, 2H), 4.06-4.04 (d, 2H), 3.86 (s, 3H); MS (ESI) m/z = 537.9 (M + H)+
  • Example 52. 1'-Methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • Step 1. (3-(((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol
  • The mixture of (3-(((2-chloro-5-iodopyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (160 mg, 0.451 mmol) prepared in Reference Example 20, 4-ethynyl-1-(trifluoromethyl)-1H-pyrazole (72.3 mg, 0.451 mmol), PdCl2(PPh3)2 (15.8 mg, 0.023 mmol), and CuI (17.2 mg, 0.09 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.13 mL, 0.903 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (148 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 6.67-6.65 (t, 1H), 6.54 (s, 1H), 4.56-4.55 (d, 2H), 4.48-4.47 (d, 2H), 4.11-4.06 (t, 2H), 3.61-3.60 (d, 2H); MS (ESI) m/z = 386.9 (M + H)+
  • Step 2. 2-(5-((3-(((2-Chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (97.1 mg, 0.508 mmol) in prepared in Reference Example 7, (3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methanol (148 mg, 0.383 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.44 mL, 1.287 mmol) in toluene (2 mL) was stirred at 100 oC 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-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (81 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12-8.10 (t, 2H), 7.99 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 6.71 (s, 1H), 6.68-6.66 (t, 1H), 6.17-6.16 (d, 1H), 4.99 (s, 2H), 4.79-4.78 (d, 4H), 4.67-4.65 (d, 2H), 3.88-3.86 (d, 2H), 3.74 (s, 3H); MS (ESI) m/z = 559.8 (M + H)+
  • Step 3. 1'-Methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane]
  • The suspension of 2-(5-((3-(((2-chloro-5-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)methyl)oxetan-3-yl)methoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (81 mg, 0.145 mmol) prepared in step 2, Cs2CO3 (252 mg, 0.774 mmol), XPhos (49.2 mg, 0.103 mmol), and Pd2(dba)3 (47.2 mg, 0.052 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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 1'-methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane] (19.3 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36-8.33 (t, 2H), 8.21 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 6.40-6.39 (d, 1H), 5.61-5.58 (t, 1H), 4.75 (s, 2H), 4.70-4.68 (d, 2H), 4.58-4.57 (d, 2H), 4.07-4.05 (d, 2H), 3.87 (s, 3H); MS (ESI) m/z = 524.9 (M + H)+
  • Example 53. (S)-11,6-Dimethyl-45-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. 2-Chloro-4-fluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridine
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.42 g, 5.52 mmol), 3-ethynyl-1-methyl-1,2,4-triazole (0.563 g, 5.257 mmol), PdCl2(PPh3)2 (184.5 mg, 0.263 mmol), and CuI (200.3 mg, 1.051 mmol) was charged nitrogen gas for 10 minutes. After DMF (50 mL) and TEA (1.47 mL, 10.514 mmol) were added, the reaction mixture was stirred at 50 oC 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 = 0-40%) to yield 2-chloro-4-fluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridine (669 mg) as an off-white solid. MS (ESI) m/z = 237.0 (M + H)+
  • Step 2. (S)-3-((2-Chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridine (120 mg, 0.507 mmol) prepared in step 1, and (S)-3-aminobutan-1-ol (45.2 mg, 0.507 mmol) was charged nitrogen gas for 10 minutes. After DMF (20 mL) and DIPEA (0.18 mL, 1.014 mmol) were added, the reaction mixture was stirred at 80 oC 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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (177 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.78 (s, 1H), 6.68-6.66 (d, 1H), 6.45 (s, 1H), 4.48 (s, 1H), 3.95 (s, 3H), 3.91-3.88 (q, 1H), 3.83-3.78 (m, 2H), 2.00-1.94 (m, 1H), 1.74-1.68 (m, 1H), 1.26-1.26 (d, 3H); MS (ESI) m/z = 306.0 (M + H)+
  • Step 3. (S)-2-(5-(3-((2-Chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (110 mg, 0.579 mmol) in prepared in Reference Example 7, (S)-3-((2-chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (177 mg, 0.579 mmol, 1.0 eq) prepared in step 2, and (tributylphosphoranylidene)acetonitrile (0.59 mL, 1.737 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg) as a yellow solid. 1H-NMR (CDCl3, 600 MHz) δ 8.16 (s, 1H), 8.09-8.08 (d, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 6.62 (s, 1H), 6.15-6.14 (d, 1H), 5.95-5.93 (d, 1H), 5.07 (s, 2H), 4.47-4.42 (m, 2H), 3.99-3.97 (d, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.18-2.12 (m, 2H), 1.44-1.40 (d, 3H); MS (ESI) m/z = 479.0 (M + H)+
  • Step 4. (S)-11,6-Dimethyl-45-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (73 mg, 0.152 mmol) prepared in step 3, Cs2CO3 (148.9 mg, 0.457 mmol), XPhos (29 mg, 0.061 mmol), and Pd2(dba)3 (27.9 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (4.3 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.38-8.37 (d, 1H), 8.17-8.15 (d, 2H), 7.96 (s, 1H), 7.63-7.63 (m, 1H), 6.42-6.40 (d, 1H), 5.01-4.99 (d, 1H), 4.77-4.74 (q, 1H), 4.35-4.32 (q, 1H), 4.05 (s, 3H), 3.82 (s, 3H), 2.22-2.16 (m, 2H), 1.51-1.49 (d, 3H)
  • Example 54. (S)-11,6-Dimethyl-45-((5-methylpyrazin-2-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of 2-chloro-4-fluoro-5-iodopyridine (1.097 g, 4.262 mmol), 2-ethynyl-5-methylpyrazine (479 mg, 4.059 mmol), PdCl2(PPh3)2 (142.5 mg, 0.203 mmol), and CuI (154.6 mg, 0.812 mmol) was charged nitrogen gas for 10 minutes. After DMF (50 mL) and TEA (1.13 mL, 8.118 mmol) were added, the reaction mixture was stirred at 50 oC 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 = 0-40%) to yield 2-((6-chloro-4-fluoropyridin-3-yl)ethynyl)-5-methylpyrazine (821 mg) as an off-white solid. The mixture of 2-((6-chloro-4-fluoropyridin-3-yl)ethynyl)-5-methylpyrazine (126 mg, 0.507 mmol) and (S)-3-aminobutan-1-ol (45.2 mg, 0.507 mmol) was charged nitrogen gas for 10 minutes. After DMF (20 mL) and DIPEA (0.18 mL, 1.014 mmol) were added, the reaction mixture was stirred at 80 oC 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-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (136 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.64-8.64 (d, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 6.53 (s, 1H), 6.45-6.43 (d, 1H), 3.98-3.95 (q, 1H), 3.90-3.84 (m, 2H), 2.59 (s, 3H), 2.05-1.97 (m, 2H), 1.36-1.35 (d, 3H); MS (ESI) m/z = 317.0 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (110 mg, 0.579 mmol) in prepared in Reference Example 7, (S)-3-((2-chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (136 mg, 0.429 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.59 mL, 1.737 mmol) in toluene (2 mL) was stirred at 100 oC 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-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.43-8.43 (d, 1H), 8.32-8.31 (d, 1H), 8.18 (s, 1H), 8.10-8.09 (d, 1H), 7.88 (s, 1H), 6.59 (s, 1H), 6.16-6.15 (d, 1H), 5.98-5.96 (d, 1H), 5.05 (s, 2H), 4.52-4.49 (q, 1H), 4.46-4.42 (m, 1H), 3.99-3.96 (t, 1H), 3.73 (s, 3H), 2.57 (s, 3H), 2.23-2.20 (q, 1H), 2.14-2.12 (q, 1H), 1.42-1.41 (d, 3H); MS (ESI) m/z = 490.0 (M + H)+
  • Step 3. (S)-11,6-Dimethyl-45-((5-methylpyrazin-2-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((5-methylpyrazin-2-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (45 mg, 0.092 mmol) prepared in step 2, Cs2CO3 (148.9 mg, 0.457 mmol), XPhos (29 mg, 0.061 mmol), and Pd2(dba)3 (27.9 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-((5-methylpyrazin-2-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (4.4 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.66-8.66 (d, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.37-8.36 (d, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 6.41-6.39 (d, 1H), 5.09-5.08 (d, 1H), 4.79-4.78 (d, 1H), 4.34-4.32 (q, 1H), 4.15-4.09 (m, 1H), 3.82 (s, 3H), 2.63 (s, 2H), 2.22-2.19 (q, 2H), 1.52-1.50 (d, 3H)
  • Example 55. (S,E)-11,6-Dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • To a solution of (S)-11,6-dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane in prepared in Example 31 (55 mg, 0.125 mmol) in methanol (4 mL) was added Lindlar cat. (15 mg) and stirred under H2 atmosphere 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 (S,E)-11,6-dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (7.1 mg) as a gray solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.30-8.29 (d, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 7.18 (s, 1H), 6.63-6.60 (d, 1H), 6.39-6.38 (d, 1H), 6.18-6.16 (d, 1H), 4.81-4.75 (q, 1H), 4.31-4.29 (d, 1H), 4.21-4.20 (d, 1H), 4.06-4.01 (m, 1H), 3.79 (s, 6H), 2.09-2.06 (t, 1H), 1.95-1.92 (m, 1H), 1.22-1.21 (s, 3H)
  • Example 56. (S)-11,6-Dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • To a solution of (S)-11,6-dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane in prepared in Example 31 (55 mg, 0.125 mmol) in methanol (4 mL) was added Pd/C (15 mg) and stirred under H2 atmosphere 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 (S)-11,6-dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (3.0 mg) as a gray solid.1H-NMR (CDCl3, 400 MHz) δ 8.31-8.29 (d, 2H), 8.14 (s, 1H), 7.73 (s, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 6.35-6.34 (d, 1H), 4.77-4.75 (t, 1H), 4.23-4.21 (t, 1H), 4.09-4.06 (t, 1H), 3.92-3.90 (d, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 2.81-2.76 (m, 2H), 2.68-2.63 (m, 2H), 2.11-2.04 (m, 2H), 1.39-1.37 (s, 3H)
  • Example 57. (S)-11,13,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (500 mg, 1.531 mmol) prepared in Reference Example 6, 4-ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (266.6 mg, 1.531 mmol), PdCl2(PPh3)2 (53.7 mg, 0.077 mmol), and CuI (58.4 mg, 0.306 mmol) was charged nitrogen gas for 10 minutes. After DMF (5 mL) and TEA (0.43 mL, 3.062 mmol) were added, the reaction mixture was stirred at 50 oC 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 column chromatography (EA/n-Hex = 0-40%) to yield (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (495 mg) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.74 (s, 2H), 6.55 (s, 1H), 5.61-5.59 (d, 1H), 4.77-4.70 (q, 2H), 3.91-3.82 (m, 3H), 1.93-1.91 (m, 1H), 1.85-1.84 (m, 1H), 1.33-1.31 (d, 3H); MS (ESI) m/z = 372.9 (M + H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (110.1 mg, 0.537 mmol) in prepared in Reference Example 8, (S)-3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (200 mg, 0.537 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.55 mL, 1.61 mmol, 3 eq) in toluene (2 mL) was stirred at 100 oC 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-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (134 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.17-8.15 (d, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 7.33 (s, 1H), 6.54 (s, 1H), 6.18-6.17 (d, 1H), 5.92-5.90 (d, 1H), 4.81 (s, 2H), 4.67-4.61 (q, 2H), 4.49-4.44 (q, 1H), 4.36-4.32 (q, 1H), 3.94-3.91 (t, 1H), 3.60 (s, 3H), 2.48 (s, 3H), 2.20-2.18 (t, 1H), 2.07-2.03 (q, 1H), 1.39-1.38 (d, 3H); MS (ESI) m/z = 559.9 (M + H)+
  • Step 3. (S)-11,13,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (134 mg, 0.239 mmol) prepared in step 2, Cs2CO3 (233 mg, 0.718 mmol), XPhos (45.6 mg, 0.096 mmol), and Pd2(dba)3 (43.8 mg, 0.048 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-11,13,6-trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (34.9 mg) as an white solid. 1H-NMR (CDCl3, , 400 MHz) δ 8.37-8.34 (t, 2H), 8.31 (s, 1H), 8.10 (s, 1H), 7.75-7.74 (d, 1H), 6.38-6.36 (d, 1H), 4.92-4.91 (d, 1H), 4.82-4.72 (m, 3H), 4.29-4.27 (d, 1H), 4.00-3.98 (q, 1H), 3.74 (s, 3H), 2.59 (s, 3H), 2.26 (m, 1H), 2.09-2.04 (m, 1H), 1.47-1.43 (t, 3H); MS (ESI) m/z = 523.9 (M + H)+
  • Example 58. (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-N-(4-((4-(4-Aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine
  • The suspension of 4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-ol (71.8 mg, 0.377 mmol) in prepared in Reference Example 21, (S)-3-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (115 mg, 0.377 mmol, 1.0 eq) prepared in step 1 in Example 31, and (tributylphosphoranylidene)acetonitrile (0.34 mL, 1.0 mmol, 2.65 eq) in toluene (4 mL) was stirred at 100 oC 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)-N-(4-((4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine (34 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13-8.11 (d, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 6.69 (s, 1H), 6.52 (s, 1H), 6.35-6.34 (d, 1H), 5.72-5.70 (d, 1H), 4.33 (s, 3H), 4.27-4.25 (t, 1H), 3.90-3.87 (t, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.14-2.13 (d, 1H), 2.05-2.02 (t, 1H), 1.36-1.34 (d, 3H); MS (ESI) m/z = 476.9 (M + H)+
  • Step 2. (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-N-(4-((4-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)-2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine (34 mg, 0.071 mmol) prepared in step 1, Cs2CO3 (69.7 mg, 0.214 mmol), XPhos (13.6 mg, 0.029 mmol), and Pd2(dba)3 (13.0 mg, 0.014 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane (2.9 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.41-8.39 (d, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.06-7.03 (m, 1H), 6.72 (s, 1H), 6.64 (s, 1H), 4.95-4.92 (d, 1H), 4.35-4.31 (t, 1H), 4.27-4.25 (d, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.70 (m, 1H), 2.46 (s, 1H), 2.06-1.98 (m, 2H), 1.47-1.46 (d, 3H)
  • Example 59. (S)-(4-Hydroxypiperidin-1-yl)(4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)phenyl)methanone
  • Step 1. (S)-(4-((6-Chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone
  • The mixture of (4-((6-chloro-4-fluoropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (152 mg, 0.424 mmol) prepared in Reference Example 22, and (S)-3-aminobutan-1-ol (37.8 mg, 0.424 mmol) was charged nitrogen gas for 10 minutes. After DMF (20 mL) and DIPEA (0.15 mL, 0.847 mmol) were added, the reaction mixture was stirred at 80 oC 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)-(4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (163 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.57-7.55 (d, 1H), 7.42-7.40 (d, 1H), 6.56 (s, 1H), 5.77-5.76 (d, 1H), 4.02-3.94 (m, 1H), 3.88-3.84 (m, 3H), 3.72 (s, 1H), 3.49-3.23 (brs, 4H), 1.96-1.94 (d, 2H), 1.85-1.84 (d, 2H), 1.34-1.33 (d, 3H); MS (ESI) m/z = 427.9 (M + H)+
  • Step 2. (S)-(4-((4-((4-((4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (78.2 mg, 0.381 mmol) in prepared in Reference Example 8, (S)-(4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (163 mg, 0.381 mmol, 1.0 eq) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (0.39 mL, 1.143 mmol, 3.0 eq) in toluene (2 mL) was stirred at 100 oC 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)-(4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (96.2 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13-8.11 (t, 2H), 7.34-7.32 (d, 2H), 7.26 (s, 2H), 6.56 (s, 1H), 6.11-6.10 (d, 1H), 5.79-5.77 (d, 1H), 4.93 (s, 1H), 4.43-4.40 (q, 1H), 4.35-4.31 (m, 1H), 4.00-3.92 (m, 2H), 3.61 (s, 3H), 3.57 (s, 3H), 3.48-3.10 (m, 2H), 2.17-2.15 (q, 1H), 2.09-2.04 (q, 1H), 1.64-1.62 (m, 2H), 1.54 (brs, 2H), 1.40-1.38 (d, 3H); MS (ESI) m/z = 617.9 (M + H)+
  • Step 3. (S)-(4-Hydroxypiperidin-1-yl)(4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)phenyl)methanone
  • The suspension of (S)-(4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone (96.2 mg, 0.156 mmol) prepared in step 2, Cs2CO3 (152.8 mg, 0.469 mmol), XPhos (29.8 mg, 0.063 mmol), and Pd2(dba)3 (28.6 mg, 0.031 mmol) in 1,4-dioxane (2 mL) was stirred at 130 oC 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)-(4-hydroxypiperidin-1-yl)(4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)phenyl)methanone (24.3 mg) as an white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.38-8.37 (d, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.57-7.55 (d, 1H), 7.44-7.42 (d, 1H), 6.40-6.38 (d, 1H), 5.00-4.98 (d, 1H), 4.83-4.78 (t, 1H), 4.32-4.27 (m, 2H), 4.04-3.99 (m, 2H), 3.76-3.75 (d, 3H), 3.46-3.23 (brs, 2H), 2.60 (s, 3H), 2.28-2.25 (d, 1H), 2.11-2.05 (m, 5H), 1.50-1.48 (d, 3H); MS (ESI) m/z = 578.9 (M + H)+
  • Example 60. (S)-11,13,8-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a deep yellow solid (282.3 mg) was prepared in the same fashion as Step 2 in Example 3 except that 4-ethynyl-1-methyl-1H-pyrazole (120.0 mg, 1.13 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.49 (s, 1H), 5.91 (t, 1H), 4.10-4.03 (m, 1H), 3.94 (s, 3H), 3.44-3.31 (m, 2H), 1.89-1.78 (m, 2H), 1.62 (d, 1H), 1.32 (d, 3H); MS (ESI) m/z = 304.9 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • To a solution of (R)-4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (74.25 mg, 0.24 mmol) prepared in Step 1 in toluene (1.0 mL) were added 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50.0 mg, 0.24 mmol) prepared in Reference example 8 and cyanomethylenetributylphosphorane (0.15 mL, 0.56 mmol). The reaction mixture was stirred at 110 oC for 6 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (MeOH/DCM = 0-20%), slurried with DCM/IPE for 0.5 hr, and then filtered to yield (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.10 mg, 0.10 mmol, 41.8% yield) as a pale brown solid. 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.08 (s, 1H), 7.32 (s, 1H), 6.94 (s, 1H), 6.77 (d, 1H), 6.53 (s, 1H), 6.16 (d, 1H), 4.82-4.79 (m, 1H), 4.74 (s, 2H), 3.83 (s, 3H), 3.68-3.60 (m, 1H), 3.58 (s, 3H), 3.56-3.48 (m, 1H), 2.48 (s, 3H), 2.16-2.04 (m, 2H), 1.20 (d, 3H); MS (ESI) m/z = 491.9 (M+H)+
  • Step 3. (S)-11,13,8-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as a pale yellow solid (18.2 mg) was prepared in the same fashion as Step 4 in Example 2 except that (S)-2-(5-((4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.0 mg, 0.10 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.37 (d, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 6.35 (d, 1H), 5.49 (t, 1H), 5.30 (q, 1H), 4.09-4.01 (m, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 3.71-3.57 (m, 1H), 2.62 (s, 3H), 2.06-2.04 (m, 1H), 1.97-1.94 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 456.0 (M+H)+
  • Example 61. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The title compound as a deep yellow solid (135.5 mg) was prepared in the same fashion as Step 2 in Example 3 except that 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole (71.72 mg, 0.46 mmol) was used instead of 4-ethynyl-1-(oxan-4-yl)-1H-pyrazole. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 6.50 (s, 1H), 6.11 (tt, 1H), 5.91 (s, 1H), 4.50 (td, 2H), 4.07 (sex, 1H), 3.45-3.31 (m, 2H), 1.89-1.79 (m, 2H), 1.53 (d, 1H), 1.31 (d, 3H); MS (ESI) m/z = 354.9 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The title compound as a pale yellow solid (75.8 mg) was prepared in the same fashion as Step 2 in Example 60 except that (R)-4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (86.44 mg, 0.24 mmol) prepared in Step 1 was used instead of (R)-4-((2-chloro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 8.08 (s, 1H), 7.36 (s, 1H), 7.04 (s, 1H), 6.81 (d, 1H), 6.53 (s, 1H), 6.16 (d, 1H), 6.06 (tt, 1H), 4.83-4.79 (m, 1H), 4.76 (s, 2H), 4.38 (td, 2H), 3.63-3.60 (m, 1H), 3.55 (s, 3H), 3.53-3.47 (m, 1H), 2.47 (s, 3H), 2.16-2.12 (m, 1H), 1.93-1.89 (m, 1H), 1.20 (d, 3H); MS (ESI) m/z = 541.9 (M+H)+
  • Step 3. (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The title compound as an off-white solid (27.1 mg) was prepared in the same fashion as Step 4 in Example 2 except (S)-2-(5-((4-((2-chloro-5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (71.8 mg, 0.13 mmol) prepared in Step 2 was used instead of (S)-2-(5-(3-((2-chloro-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)pyridine-4-yl)amino)butoxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine. 1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.38 (d, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.07 (s, 1H), 7.22 (s, 1H), 6.34 (d, 1H), 6.12 (tt, 1H), 5.47 (t, 1H), 5.30-5.28 (m, 1H), 4.50 (td, 2H), 4.07-4.03 (m, 1H), 3.72 (s, 3H), 3.61-3.58 (m, 1H), 2.63 (s, 3H), 2.22-2.18 (m, 1H), 1.98-1.92 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 505.9 (M+H)+
  • Example 62. (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (223.38 mg, 0.68 mmol) prepared in Reference Example 6, and 5-cyclopropyl-4-ethynyl-1-methyl-1H-pyrazole (100 mg, 0.68 mmol), PdCl2(PPh3)2 (48.1 mg, 0.068 mmol), CuI (26.05 mg, 0.14 mmol), and TEA (190.69 uL, 1.37 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (S)-3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (221 mg, 0.64 mmol, 93.69% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.51 (s, 1H), 6.54 (s, 1H), 5.41 (d, 1H), 3.91 (s, 3H), 3.87-3.81 (m, 3H), 2.25 (s, 1H), 1.94-1.74 (m, 3H), 1.31 (d, 3H), 1.13-1.04 (m, 4H); MS (ESI) m/z = 345.0 (M+H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Reference Example 8, (S)-3-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (168.03 mg, 0.49 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (319.58 uL, 1.22 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-90%) to yield (S)-2-(5-(3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (94 mg, 0.18 mmol, 36.26% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.20 (d, 1H), 8.10 (s, 1H), 7.38 (s, 1H), 6.56 (s, 1H), 6.18 (d, 1H), 5.41 (d, 1H), 4.75 (s, 2H), 4.41-4.29 (m, 2H), 3.97-3.91 (m, 1H), 3.88 (s, 3H), 3.64 (s, 3H), 2.48 (s, 3H), 2.14-2.02 (m, 2H), 1.73-1.67 (m, 1H), 1.38 (d, 3H), 1.05-0.96 (m, 4H); MS (ESI) m/z = 532.0 (M+H)+
  • Step 3. (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75 mg, 0.14 mmol) prepared in step 2, Pd2(dba)3 (25.82 mg, 0.028 mmol), XPhos (26.88 mg, 0.056 mmol), and Cs2CO3 (137.79 mg, 0.42 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-100%) to yield (S)-45-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (26 mg, 0.052 mmol, 37.22% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.54 (s, 1H), 7.53 (d, 1H), 6.35 (d, 1H), 4.96 (d, 1H), 4.83 (t, 1H), 4.32-4.26 (m, 1H), 4.02-3.98 (m, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.60 (s, 3H), 2.30-2.24 (m, 1H), 2.09-2.03 (m, 1H), 1.86-1.80 (m, 1H), 1.47 (d, 3H), 1.18-1.06 (m, 4H); MS (ESI) m/z = 496.0 (M+H)+
  • Example 63. (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (223.38 mg, 0.68 mmol) prepared in Reference Example 3, and 5-cyclopropyl-4-ethynyl-1-methyl-1H-pyrazole (100 mg, 0.68 mmol), PdCl2(PPh3)2 (48.1 mg, 0.068 mmol), CuI (26.05 mg, 0.14 mmol), and TEA (190.69 uL, 1.37 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (R)-4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (216 mg, 0.63 mmol, 91.57% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.51 (s, 1H), 6.50 (s, 1H), 5.78 (s, 1H), 4.04 (brs, 1H), 3.91 (s, 3H), 3.45-3.30 (m, 2H), 1.91-1.74 (m, 3H), 1.30 (d, 3H), 1.13-1.04 (m, 4H); MS (ESI) m/z = 345.0 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Reference Example 8, (R)-4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (168.03 mg, 0.49 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (319.58 uL, 1.22 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-90%) to yield (S)-2-(5-((4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75 mg, 0.14 mmol, 28.93% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.19 (d, 1H), 8.07 (s, 1H), 7.06 (s, 1H), 6.59 (t, 1H), 6.54 (s, 1H), 6.16 (d, 1H), 4.77 (s, 3H), 3.84 (s, 3H), 3.67-3.53 (m, 2H), 3.59 (s, 3H), 2.42 (s, 3H), 2.19-2.07 (m, 1H), 1.89-1.85 (m, 1H), 1.62-1.55 (m, 1H), 1.19 (d, 3H), 0.93-0.89 (m, 4H); MS (ESI) m/z = 532.0 (M+H)+
  • Step 3. (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (75mg, 0.14 mmol) prepared in step 2, Pd2(dba)3 (25.82 mg, 0.028 mmol), XPhos (26.88 mg, 0.056 mmol), and Cs2CO3 (137.79 mg, 0.42 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-100%) to yield (S)-45-((5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (22 mg, 0.044 mmol, 31.49% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.37 (d, 1H), 8.07 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.35 (d, 1H), 5.50 (t, 1H), 5.34-5.30 (m, 1H), 4.11-4.03 (m, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 3.60-3.54 (m, 1H), 2.63 (s, 3H), 2.26-2.19 (m, 1H), 1.98-1.92 (m, 1H), 1.85-1.79 (m, 1H), 1.17-1.05 (m, 6H); MS (ESI) m/z = 496.0 (M+H)+
  • Example 64. (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (173.56 mg, 0.53 mmol) prepared in Reference Example 6, and 4-ethynyl-3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazole (100 mg, 0.53 mmol), PdCl2(PPh3)2 (37.31 mg, 0.053 mmol), CuI (20.24 mg, 0.11 mmol), and TEA (148.16 uL, 1.06 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 (S)-3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (197 mg, 0.51 mmol, 95.83% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 6.58 (s, 1H), 5.45 (d, 1H), 3.91-3.81 (m, 3H), 3.51 (s, 1H), 2.53 (s, 3H), 2.37 (s, 3H), 1.96-1.77 (m, 2H), 1.33 (d, 3H); MS (ESI) m/z = 386.9 (M+H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Reference Example 8, (S)-3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (188.48 mg, 0.49 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (319.58 uL, 1.22 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-40%) to yield (S)-2-(5-(3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (42 mg, 0.073 mmol, 15.02% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 8.13 (s, 1H), 6.60 (s, 1H), 6.16 (d, 1H), 5.79 (d, 1H), 4.70 (s, 2H), 4.47-4.41 (m, 1H), 4.33-4.28 (m, 1H), 4.01-3.95 (m, 1H), 3.64 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H), 2.19-2.13 (m, 1H), 2.10-2.02 (m, 1H), 1.41 (d, 3H); MS (ESI) m/z = 573.9 (M+H)+
  • Step 3. (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (40 mg, 0.07 mmol) prepared in step 2, Pd2(dba)3 (12.76 mg, 0.014 mmol), XPhos (13.29 mg, 0.028 mmol), and Cs2CO3 (68.12 mg, 0.21 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-50%) to yield (S)-45-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (19 mg, 0.035 mmol, 50.72% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.33 (s, 1H), 6.36 (d, 1H), 4.91 (d, 1H), 4.82 (t, 1H), 4.33-4.28 (m, 1H), 4.03-3.99 (m, 1H), 3.76 (s, 3H), 2.61 (s, 1H), 2.56 (s, 3H), 2.40 (s, 3H), 2.31-2.23 (m, 1H), 2.08-2.03 (m, 1H), 1.47 (d, 3H); MS (ESI) m/z = 537.9 (M+H)+
  • Example 65. (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (223.38 mg, 0.68 mmol) prepared in Reference Example 3, and 4-ethynyl-3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazole (100 mg, 0.53 mmol), PdCl2(PPh3)2 (37.31 mg, 0.053 mmol), CuI (20.24 mg, 0.11 mmol), and TEA (148.16 uL, 1.063 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 (R)-4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (193 mg, 0.50 mmol, 93.88% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 6.52 (s, 1H), 5.82 (s, 1H), 4.08-4.04 (m, 1H), 3.47-3.31 (m, 2H), 2.53 (d, 3H), 2.37 (s, 3H), 1.93-1.75 (m, 2H), 1.56 (d, 1H), 1.31 (d, 3H); MS (ESI) m/z = 386.9 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (100 mg, 0.49 mmol) prepared in Reference Example 8, (R)-4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (188.48 mg, 0.49 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (319.58 uL, 1.22 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-40%) to yield (S)-2-(5-((4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (102 mg, 0.18 mmol, 36.47% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (d, 1H), 8.09 (s, 1H), 6.98 (dd, 1H), 6.57 (s, 1H), 6.13 (d, 1H), 4.77 (s, 2H), 4.77-4.74 (m, 1H), 3.70-3.63 (m, 1H), 3.59 (s, 3H), 3.59-3.51 (m, 1H), 2.39 (s, 3H), 2.18 (s, 3H), 2.18-2.09 (m, 1H), 2.04 (s, 3H), 1.84-1.81 (m, 1H), 1.18 (d, 3H); MS (ESI) m/z = 573.9 (M+H)+
  • Step 3. (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (90 mg, 0.16 mmol) prepared in step 2, Pd2(dba)3 (28.72 mg, 0.031 mmol), XPhos (29.9 mg, 0.026 mmol), and Cs2CO3 (153.26 mg, 0.47 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-50%) to yield (S)-45-((3,5-dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (15.4 mg, 0.029 mmol, 18.27% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 8.39 (d, 1H), 8.10 (s, 1H), 7.35 (s, 1H), 6.36 (d, 1H), 5.43 (t 1H), 5.33-5.29 (m, 1H), 4.11-4.03 (m, 1H), 3.72 (s, 3H), 3.60-3.29 (m, 1H), 2.63 (s, 3H), 2.55 (s, 3H), 2.39 (s, 3H), 2.27-2.19 (m, 1H), 1.98-1.92 (m, 1H), 1.12 (d, 3H); MS (ESI) m/z = 537.9 (M+H)+
  • Example 66. (S)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile
  • Step 1. (R)-4-((6-Chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (249.04 mg, 0.76 mmol) prepared in Reference Example 3, and 4-ethynyl-1-methyl-1H-pyrazole-3-carbonitrile (100 mg, 0.76 mmol), PdCl2(PPh3)2 (53.53 mg, 0.076 mmol), CuI (29.05 mg, 0.15 mmol), and TEA (212.59 uL, 1.53 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (R)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (141 mg, 0.43 mmol, 56.07% yield) as a pale yellow solid. MS (ESI) m/z = 329.9 (M+H)+
  • Step 2. (S)-4-((4-((3-((4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (85 mg, 0.41 mmol) prepared in Reference Example 8, (R)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (136.59 mg, 0.41 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (271.64 uL, 1.035 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (76 mg, 0.15 mmol, 35.49% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.87 (d, 1H), 6.57 (s, 1H), 6.19 (d, 1H), 4.83-4.79 (m, 1H), 4.77 (s, 2H), 3.91 (s, 1H), 3.67-3.63 (m, 1H), 3.62 (s, 3H), 3.56-3.48 (m, 1H), 2.44 (s, 3H), 2.20-2.12 (m, 1H), 1.95-1.89 (m, 1H), 1.21 (d, 3H); MS (ESI) m/z = 516.9 (M+H)+
  • Step 3. (S)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile
  • The suspension of (S)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (90 mg, 0.16 mmol) prepared in step 2, Pd2(dba)3 (24.8 mg, 0.027 mmol), XPhos (25.82 mg, 0.054 mmol), and Cs2CO3 (132.35 mg, 0.41 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-1-methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile (15.4 mg, 0.032 mmol, 23.67% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.38 (d, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 6.36 (d 1H), 5.70 (t, 1H), 5.32-5.26 (m, 1H), 4.08-4.01 (m, 1H), 4.01 (s, 3H), 3.71 (s, 3H), 3.65-3.60 (m, 1H), 2.62 (s, 3H), 2.26-2.18 (m, 1H), 2.00-1.94 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 480.9 (M+H)+
  • Example 67. (S)-11,13,8-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (181.2 mg, 0.56 mmol) prepared in Reference Example 3, and 1-ethynyl-4-(methylsulfonyl)benzene (100 mg, 0.56 mmol), PdCl2(PPh3)2 (38.95 mg, 0.055 mmol), CuI (21.13 mg, 0.11 mmol), and TEA (154.68 uL, 1.11 mmol) was charged nitrogen gas for 10 minutes. After DMF (2.22 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (R)-4-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-ol (169 mg, 0.45 mmol, 80.39% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.93 (d, 2H), 7.71 (d, 2H), 6.51 (s, 1H), 6.28 (s, 1H), 4.13-4.11 (m, 1H), 3.49-3.42 (m, 1H), 3.38-3.30 (m, 1H), 3.09 (s, 3H), 2.10 (d, 1H), 1.95-1.78 (m, 2H), 1.34 (d, 3H); MS (ESI) m/z = 378.9 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (85 mg, 0.41 mmol) prepared in Reference Example 8, (R)-4-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-ol (156.92 mg, 0.41 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (271.64 uL, 1.035 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-100%) to yield (S)-2-(5-((4-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (57 mg, 0.10 mmol, 24.31% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (d, 1H), 8.13 (s, 1H), 7.72 (d, 2H), 7.18 (d, 3H), 6.59 (s, 1H), 6.12 (d, 1H), 4.83-4.76 (m, 1H), 4.76 (s, 2H), 3.72-3.66 (m, 1H), 3.59-3.55 (m, 1H), 3.55 (s, 3H), 3.08 (s, 3H), 2.39 (s, 3H), 2.20-2.12 (m, 1 H), 1.88-1.84 (m, 1H), 1.19 (d, 3H); MS (ESI) m/z = 566.9 (M+H)+
  • Step 3. (S)-11,13,8-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.097 mmol) prepared in step 2, Pd2(dba)3 (17.79 mg, 0.019 mmol), XPhos (18.53 mg, 0.039 mmol), and Cs2CO3 (94.97 mg, 0.29 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-11,13,8- trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (25 mg, 0.047 mmol, 48.58% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 8.40 (d, 1H), 8.15 (s, 1H), 7.96 (d, 2H), 7.72 (d, 2H), 7.35 (s, 1H), 6.37 (d, 1H), 5.48 (t, 1H), 5.32-5.28 (m, 1H), 4.12-4.05 (m, 1H), 3.73 (s, 3H), 3.68-3.63 (m, 1H), 3.11 (s, 3H), 2.63 (s, 3H), 2.26-2.23 (m, 1H), 2.01-1.95 (m, 1H), 1.13 (d, 3H); MS (ESI) m/z = 529.9 (M+H)+
  • Example 68. (S)-11,13,6-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (181.2 mg, 0.56 mmol) prepared in Reference Example 6, and 1-ethynyl-4-(methylsulfonyl)benzene (100 mg, 0.56 mmol), PdCl2(PPh3)2 (38.95 mg, 0.055 mmol), CuI (21.13 mg, 0.11 mmol), and TEA (154.68 uL, 1.11 mmol) was charged nitrogen gas for 10 minutes. After DMF (2.22 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (S)-3-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-1-ol (159 mg, 0.42 mmol, 75.63% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.94 (d, 2H), 7.71 (d, 2H), 6.57 (s, 1H), 5.96 (d, 1H), 4.00-3.84 (m, 3H), 3.09 (s, 3H), 2.06 (s, 1H), 2.03-1.80 (m, 2H), 1.35 (d, 3H); MS (ESI) m/z = 378.9 (M+H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (85 mg, 0.41 mmol) prepared in Reference Example 8, (S)-3-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-1-ol (156.92 mg, 0.41 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (271.64 uL, 1.035 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-100%) to yield (S)-2-(5-(3-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (107 mg, 0.19 mmol, 45.64% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 8.15 (s, 1H), 7.76 (d, 2H), 7.39 (d, 2H), 6.60 (s, 1H), 6.20 (d, 1H), 6.15 (d, 1H), 4.72 (s, 2H), 4.58-4.52 (m, 1H), 4.36-4.31 (m, 1H), 4.02-3.96 (m, 1H), 3.59 (s, 3H), 3.09 (s, 3H), 2.46 (s, 3H), 2.33-2.23 (m, 1H), 2.11-2.03 (m, 1H), 1.44 (d, 3H); MS (ESI) m/z = 567.8 (M+H)+
  • Step 3. (S)-11,13,6-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.097 mmol) prepared in step 2, Pd2(dba)3 (17.79 mg, 0.019 mmol), XPhos (18.53 mg, 0.039 mmol), and Cs2CO3 (94.97 mg, 0.29 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-11,13,6- trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (18.8 mg, 0.035 mmol, 36.54% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.40 (d, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.97 (d, 2H), 7.70 (d, 2H), 7.38 (s, 1H), 6.37 (d, 1H), 4.94 (d, 1H), 4.81 (t, 1H), 4.34-4.29 (m, 1H), 4.05-4.01 (m, 1H), 3.77 (s, 3H), 3.11 (s, 3H), 2.61 (s, 3H), 2.32-2.26 (m, 1H), 2.14-2.07 (m, 1H), 1.51 (d, 3H); MS (ESI) m/z = 529.9 (M+H)+
  • Example 69. (S)-11,13,6-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (174.41 mg, 0.53 mmol) prepared in Reference Example 6, and 4-(4-ethynylphenyl)morpholine (100 mg, 0.53 mmol), PdCl2(PPh3)2 (37.49 mg, 0.053 mmol), CuI (20.34 mg, 0.11 mmol), and TEA (148.88 uL, 1.068 mmol) was charged nitrogen gas for 10 minutes. After DMF (2.14 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (S)-3-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-1-ol (155 mg, 0.40 mmol, 75.21% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.44 (d, 2H), 6.88 (d, 2H), 6.55 (s, 1H), 5.57 (d, 1H), 3.92-3.80 (m, 7H), 3.24 (t, 4H), 1.97-1.80 (m, 2H), 1.78 (t, 1H), 1.32 (d, 3H); MS (ESI) m/z = 386.0 (M+H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (70 mg, 0.34 mmol) prepared in Reference Example 8, (S)-3-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-1-ol (131.63 mg, 0.34 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (223.71 uL, 0.85 mmol) in toluene (1.36 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-100%) to yield (S)-2-(5-(3-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (136 mg, 0.24 mmol, 69.57% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.20 (d, 1H), 8.14 (s, 1H), 7.26 (d, 2H), 6.77 (d, 2H), 6.56 (s, 1H), 6.18 (d, 1H), 5.58 (d, 1H), 4.70 (s, 2H), 4.44-4.32 (m, 2H), 3.97-3.92 (m, 1H), 3.89-3.97 (m, 4H), 3.63 (s, 3H), 3.23-3.21 (m, 4H), 2.48 (s, 3H), 2.21-2.04 (m, 2H), 1.39 (d, 3H); MS (ESI) m/z = 573.9 (M+H)+
  • Step 3. (S)-11,13,6-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (125 mg, 0.22 mmol) prepared in step 2, Pd2(dba)3 (39.95 mg, 0.044 mmol), XPhos (41.59 mg, 0.087 mmol), and Cs2CO3 (213.21 mg, 0.65 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-11,13,6-trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (47.3 mg, 0.088 mmol, 40.41% yield) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, 1H), 8.32 (s, 1H), 8.11 (s 1H), 7.50 (s, 1H), 7.46 (d, 2H), 6.91 (d, 2H), 6.35 (d, 1H), 5.01 (d, 1H), 4.82 (t, 1H), 4.31-4.26 (m, 1H), 4.02-4.00 (m, 1H), 3.91-3.88 (m, 4H), 3.96 (s, 3H), 3.52 (s, 3H), 3.26-3.24 (m, 4H), 2.61 (s, 3H), 2.30-2.24 (m, 1H), 2.10-2.04 (m, 1H), 1.48 (d, 3H); MS (ESI) m/z = 536.9 (M+H)+
  • Example 70. (S)-11,13,8-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (174.41 mg, 0.53 mmol) prepared in Reference Example 3, and 4-(4-ethynylphenyl)morpholine (100 mg, 0.53 mmol), PdCl2(PPh3)2 (37.49 mg, 0.053 mmol), CuI (20.34 mg, 0.11 mmol), and TEA (148.88 uL, 1.068 mmol) was charged nitrogen gas for 10 minutes. After DMF (2.14 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (R)-4-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-2-ol (138 mg, 0.36 mmol, 66.96% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.45 (d, 2H), 6.88 (d, 2H), 6.50 (s, 1H), 5.89 (s, 1H), 4.10-4.04 (m, 1H), 3.89 (t, 4H), 3.46-3.31 (m, 2H), 3.24 (t, 4H), 1.57-1.50 (m, 2H), 1.32 (d, 3H); MS (ESI) m/z = 386.0 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (70 mg, 0.34 mmol) prepared in Reference Example 8, (R)-4-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-2-ol (131.63 mg, 0.34 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (223.71 uL, 0.85 mmol) in toluene (1.36 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-100%) to yield (S)-2-(5-((4-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (126 mg, 0.22 mmol, 64.46% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H), 8.11 (s, 1H), 7.06 (d, 2H), 6.70 (d, 2H), 6.54 (s, 1H), 6.50 (s, 1H), 6.14 (d, 1H), 4.80-4.77 (m, 1H), 4.73 (s, 2H), 3.88-3.86 (m, 4H), 3.64-3.50 (m, 5H), 3.21-3.18 (m, 4H), 2.45 (s, 3H), 2.19-2.10 (m, 1H), 1.95-1.91 (m, 1H), 1.21 (d, 3H); MS (ESI) m/z = 573.9 (M+H)+
  • Step 3. (S)-11,13,8-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((4-morpholinophenyl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (125 mg, 0.22 mmol) prepared in step 2, Pd2(dba)3 (39.95 mg, 0.044 mmol), XPhos (41.59 mg, 0.087 mmol), and Cs2CO3 (213.21 mg, 0.65 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (S)-11,13,8-trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (42.4 mg, 0.079 mmol, 36.22% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.38 (d, 1H), 8.10 (s, 1H), 7.47 (d, 2H), 6.90 (d, 2H), 6.34 (d, 1H), 5.53 (t, 1H), 5.34-5.30 (m, 1H), 4.10-4.02 (m, 1H), 3.91-3.89 (m, 4H), 3.72 (s, 3H), 3.61-3.57 (m, 1H), 3.26-3.24 (m, 4H), 2.63 (s, 3H), 2.27-2.18 (m, 1H), 1.98-1.92 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 536.9 (M+H)+
  • Example 71. (S)-1-Methyl-4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile
  • Step 1. (S)-4-((6-Chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (249.04 mg, 0.76 mmol) prepared in Reference Example 6, and 4-ethynyl-1-methyl-1H-pyrazole-3-carbonitrile (100 mg, 0.76 mmol), PdCl2(PPh3)2 (53.53 mg, 0.076 mmol), CuI (29.05 mg, 0.15 mmol), and TEA (212.59 uL, 1.53 mmol) was charged nitrogen gas for 10 minutes. After DMF (1 mL) was added, the reaction mixture was stirred at 70 oC for 2 hour. 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 = 0-70%) to yield (S)-4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (76 mg, 0.23 mmol, 30.22% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.07 (s, 1H), 6.75 (s, 1H), 6.27 (d, 1H), 4.71 (t, 1H), 3.99 (s, 3H), 3.91-3.84 (m, 1H), 3.59-3.49 (m, 2H), 1.75-1.69 (m, 2H), 1.20 (d, 3H); MS (ESI) m/z = 329.9 (M+H)+
  • Step 2. (S)-4-((4-((4-((4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (45 mg, 0.22 mmol) prepared in Reference Example 8, (S)-4-((6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (72.31 mg, 0.22 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (143.81 uL, 0.55 mmol) in toluene (1 mL) was stirred at 110 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (82.4 mg, 0.16 mmol, 72.69% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H), 8.12 (s, 1H), 6.59 (s, 1H), 6.20 (d, 1H), 5.91(d, 1H), 4.73 (s, 2H), 4.49-4.43 (m, 1H), 4.34-4.29 (m, 1H), 4.02-3.96 (m, 1H), 3.96 (s, 3H), 3.65 (s, 3H), 2.48 (s, 3H), 2.27-2.19 (m, 1H), 2.15-2.08 (m, 1H), 1.41 (d, 3H).
  • Step 3. (S)-1-Methyl-4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile
  • The suspension of (S)-4-((4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (80 mg, 0.16 mmol) prepared in step 2, Pd2(dba)3 (28.34 mg, 0.031 mmol), XPhos (29.51 mg, 0.062 mmol), and Cs2CO3 (151.26 mg, 0.46 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (S)-1-methyl-4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile (14.8 mg, 0.031 mmol, 19.9% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (d, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 6.36 (d, 1H), 5.12 (d, 1H), 4.79 (t, 1H), 4.32-4.27 (m, 1H), 4.03 (s, 3H), 4.03-3.99 (m, 1H), 3.76 (s, 3H), 2.60 (s, 3H), 2.31-2.24 (m, 1H), 2.15-2.09 (m, 1H), 1.52 (d, 3H); MS (ESI) m/z = 481.0 (M+H)+
  • Example 72. (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (299.82 mg, 0.92 mmol) prepared in Reference Example 3, and 4-ethynyl-3-methoxy-1-methyl-1H-pyrazole (125 mg, 0.92 mmol), PdCl2(PPh3)2 (64.44 mg, 0.092 mmol), CuI (34.97 mg, 0.18 mmol), and TEA (255.94 uL, 1.84 mmol) was charged nitrogen gas for 10 minutes. After DMF (3 mL) was added, the reaction mixture was stirred at 70 oC for 3 hour. 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 = 0-60%) to yield (R)-4-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (133 mg, 0.40 mmol, 43.27% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.36 (s, 1H), 6.54 (s, 1H), 5.61 (d, 1H), 4.00 (s, 3H), 3.92-3.81(m, 3H), 3.78 (s, 3H), 1.96-1.78 (m, 2H), 1.72 (t, 1H), 1.32 (d, 3H); MS (ESI) m/z = 334.9 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50 mg, 0.24 mmol) prepared in Reference Example 8, (R)-4-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (81.57 mg, 0.24 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (159.79 uL, 0.61 mmol) in toluene (1 mL) was stirred at 115 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-2-(5-((4-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (102 mg, 0.20 mmol, 80.2% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H), 8.09 (s, 1H), 7.11 (s, 1H), 6.53 (s, 1H), 6.19 (d, 1H), 5.66 (d, 1H), 4.72 (s, 2H), 4.44-4.31 (m, 2H), 3.96-3.88 (m, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.64 (s, 3H), 2.50 (s, 3H), 2.24-1.98 (m, 2H), 1.38 (d, 3H); MS (ESI) m/z = 521.9 (M+H)+
  • Step 3. (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (100 mg, 0.19 mmol) prepared in step 2, Pd2(dba)3 (35.09 mg, 0.038 mmol), XPhos (36.53 mg, 0.077 mmol), and Cs2CO3 (187.26 mg, 0.58 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (S)-45-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (32.4 mg, 0.067 mmol, 34.83% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.37 (d, 1H), 8.06 (s, 1H), 7.37 (s, 1H), 6.33 (d, 1H), 5.59 (t, 1H), 5.32-5.28 (m, 1H), 4.08-4.01 (m, 1H), 4.01 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H), 3.59-3.55 (m, 1H), 2.63 (s, 3H), 2.25-2.17 (m, 1H), 1.98-1.92 (m, 1H), 1.10 (d, 3H); MS (ESI) m/z = 486.0 (M+H)+
  • Example 73. (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (299.82 mg, 0.92 mmol) prepared in Reference Example 6, and 4-ethynyl-3-methoxy-1-methyl-1H-pyrazole (125 mg, 0.92 mmol), PdCl2(PPh3)2 (64.44 mg, 0.092 mmol), CuI (34.97 mg, 0.18 mmol), and TEA (255.94 uL, 1.84 mmol) was charged nitrogen gas for 10 minutes. After DMF (3 mL) was added, the reaction mixture was stirred at 70 oC for 3 hour. 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 = 0-60%) to yield (S)-3-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (151 mg, 0.45 mmol, 49.12% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.37 (s, 1H), 6.48 (s, 1H), 5.96 (s, 1H), 4.09-4.04 (m, 1H), 4.00 (s, 3H), 3.78 (s, 3H), 3.45-3.29 (m, 2H), 1.92-1.76 (m, 2H), 1.71 (d, 1H), 1.32 (d, 3H); MS (ESI) m/z = 334.9 (M+H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50 mg, 0.24 mmol) prepared in Reference Example 8, (S)-3-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (81.57 mg, 0.24 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (159.79 uL, 0.61 mmol) in toluene (1 mL) was stirred at 115 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (S)-2-(5-(3-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (112 mg, 0.22 mmol, 88.06% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H), 8.09 (s, 1H), 6.80 (s, 1H), 6.51 (s, 1H), 6.47 (dd, 1H), 6.16 (d, 1H), 4.83-4.78 (m,1 H), 4.75 (s, 2H), 3.89 (s, 3H), 3.68 (s, 3H), 3.64-3.46 (m, 2H), 3.56 (s, 3H), 2.50 (s, 3H), 2.19-2.09 (m, 1H), 1.96-1.92 (m, 1H), 1.21 (d, 3H); MS (ESI) m/z = 521.9 (M+H)+
  • Step 3. (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (100 mg, 0.19 mmol) prepared in step 2, Pd2(dba)3 (35.09 mg, 0.038 mmol), XPhos (36.53 mg, 0.077 mmol), and Cs2CO3 (187.26 mg, 0.58 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (S)-45-((3-methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (47.3 mg, 0.097 mmol, 50.85% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 6.34 (d, 1H), 5.14 (d, 1H), 4.81 (t, 1H), 4.30-4.25 (m, 1H), 4.01 (s, 3H), 4.01-3.98 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.60 (s, 3H), 2.30-2.24 (m, 1H), 2.11-2.05 (m, 1H), 1.47 (d, 3H); MS (ESI) m/z = 486.0 (M+H)+
  • Example 74. (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-3-((2-Chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol
  • The mixture of (S)-3-((2-chloro-5-iodopyridin-4-yl)amino)butan-1-ol (407.69 mg, 1.25 mmol) prepared in Reference Example 6, and 4-ethynyl-1,3-dimethyl-1H-pyrazole (150 mg, 1.25 mmol), PdCl2(PPh3)2 (87.63 mg, 0.13 mmol), CuI (47.55 mg, 0.25 mmol), and TEA (348.02 uL, 2.50 mmol) was charged nitrogen gas for 10 minutes. After DMF (4.16 mL) was added, the reaction mixture was stirred at 70 oC for 3 hour. 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 = 0-100%) to yield (S)-3-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (307.8 mg, 0.97 mmol, 77.34% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.47 (s, 1H), 6.53 (s, 1H), 5.42 (d, 1H), 3.84 (s, 3H), 3.82-3.80 (m, 3H), 2.33 (s, 3H), 1.93-1.75 (m, 3H), 1.29 (d, 3H); MS (ESI) m/z = 319.1 (M+H)+
  • Step 2. (S)-2-(5-(3-((2-Chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50 mg, 0.24 mmol) prepared in Reference Example 8, (S)-3-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-1-ol (77.67 mg, 0.24 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (159.79 uL, 0.61 mmol) in toluene (1 mL) was stirred at 115 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%) to yield (S)-2-(5-(3-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54 mg, 0.11 mmol, 43.8% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H), 8.08 (s, 1H), 7.13 (s, 1H), 6.53 (s, 1H), 6.16 (d, 1H), 5.70 (d, 1H), 4.70 (s, 2H), 4.45-4.40 (m,1 H), 4.33-4.28 (m, 1H), 3.95-3.89 (m,1 H), 3.76 (s, 3H), 3.61 (s, 3H), 2.48 (s, 3H), 2.23 (s, 3H), 2.19-2.12 (m, 1H), 2.07-1.99 (m, 1H), 1.37 (d, 3H); MS (ESI) m/z = 507.2 (M+H)+
  • Step 3. (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-(3-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butoxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47 mg, 0.093 mmol) prepared in step 2, Pd2(dba)3 (17.01 mg, 0.019 mmol), XPhos (17.71 mg, 0.037 mmol), and Cs2CO3 (90.79 mg, 0.28 mmol) in 1,4-dioxane (1 mL) was stirred at 90 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (S)-45-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (13.1 mg, 0.028 mmol, 30.04% yield) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.36 (d, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 6.33 (d, 1H), 4.96 (d, 1H), 4.79 (t, 1H), 4.29-4.23 (m, 1H), 4.00-3.96 (m, 1H), 3.86 (s, 3H), 3.73 (s, 3H), 2.58 (s, 3H), 2.37 (s, 3H), 2.28-2.22 (m, 1H), 2.06-2.00 (m, 1H), 1.44 (d, 3H); MS (ESI) m/z = 470.2 (M+H)+
  • Example 75. (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (R)-4-((2-Chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (R)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (407.69 mg, 1.25 mmol) prepared in Reference Example 3, 4-ethynyl-1,3-dimethyl-1H-pyrazole (150 mg, 1.25 mmol), PdCl2(PPh3)2 (87.63 mg, 0.13 mmol), CuI (47.55 mg, 0.25 mmol), and TEA (348.02 uL, 2.50 mmol) was charged nitrogen gas for 10 minutes. After DMF (4.16 mL) was added, the reaction mixture was stirred at 70 oC for 3 hour. 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 = 0-100%) to yield (R)-4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (305.6 mg, 0.96 mmol, 76.78% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.46 (s, 1H), 6.47 (s, 1H), 5.80 (s, 1H), 4.04-4.02 (m, 1H), 3.84 (s, 3H), 3.43-3.28 (m, 2H), 2.33 (s, 3H), 1.89-1.73 (m, 3H), 1.29 (d, 3H); MS (ESI) m/z = 319.1 (M+H)+
  • Step 2. (S)-2-(5-((4-((2-Chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50 mg, 0.24 mmol) prepared in Reference Example 8, (R)-4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (77.67 mg, 0.24 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (159.79 uL, 0.61 mmol) in toluene (1 mL) was stirred at 115 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%) to yield (S)-2-(5-((4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (48 mg, 0.095 mmol, 38.94% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H), 8.06 (s, 1H), 6.79 (s, 1H), 6.67 (t, 1H), 6.52 (s, 1H), 6.13 (d, 1H), 4.80-4.77 (m, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 3.64-3.47 (m, 5H), 2.45 (s, 3H), 2.16 (s, 3H), 2.13-2.07 (m, 1H), 1.91-1.87 (m, 1H), 1.18 (d, 3H); MS (ESI) m/z = 507.1 (M+H)+
  • Step 3. (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (S)-2-(5-((4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (47 mg, 0.093 mmol) prepared in step 2, Pd2(dba)3 (17.01 mg, 0.019 mmol), XPhos (17.71 mg, 0.037 mmol), and Cs2CO3 (90.79 mg, 0.28 mmol) in 1,4-dioxane (1 mL) was stirred at 90 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (S)-45-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (11.4 mg, 0.024 mmol, 26.14% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.36 (d, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 7.31 (s, 1H), 6.33 (d, 1H), 5.47 (t, 1H), 5.31-5.27 (m, 1H), 4.07-3.99 (m, 1H), 3.86 (s, 3H), 3.70 (s, 1H), 3.58-3.54 (m, 1H), 2.60 (s, 3H), 2.36 (s, 3H), 2.24-2.15 (m, 1H), 1.95-1.89 (m, 1H), 1.09 (d, 3H); MS (ESI) m/z = 470.2 (M+H)+
  • Example 76. (R)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile
  • Step 1. (S)-4-((2-Chloro-5-iodopyridin-4-yl)amino)butan-2-ol
  • The suspension of 2-chloro-4-fluoro-5-iodopyridine (1000 mg, 3.89 mmol), (S)-4-aminobutan-2-ol (450.15 mg, 5.05 mmol), and DIPEA (1.69 mL, 9.71 mmol) in DMA (12.95 mL) was stirred at 90 oC for 3 hours. 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 (EA/n-Hex = 0-50%) to yield (S)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (1121 mg, 3.43 mmol, 88.37% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 6.44 (s, 1H), 5.56 (s, 1H), 4.07 (s, 1H), 3.45-3.29 (m, 2H), 1.94-1.77 (m, 2H), 1.65 (d, 1H), 1.33 (d, 3H).
  • Step 2. (S)-4-((6-Chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile
  • The mixture of (S)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (373.55 mg, 1.14 mmol) prepared in step 1, and 4-ethynyl-1-methyl-1H-pyrazole-3-carbonitrile (150 mg, 1.14 mmol), PdCl2(PPh3)2 (80.29 mg, 0.11 mmol), CuI (43.57 mg, 0.23 mmol), and TEA (318.88 uL, 2.29 mmol) was charged nitrogen gas for 10 minutes. After DMF (3.81 mL) was added, the reaction mixture was stirred at 70 oC for 3 hour. 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 = 0-90%) to yield (S)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (278 mg, 0.84 mmol, 73.69% yield) as a pale yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.65 (s, 1H), 6.52 (s, 1H), 6.08 (s, 1H), 4.08 (brs, 1H), 4.02 (s, 3H), 3.50-3.30 (m, 2H), 2.23 (d, 1H), 1.94-1.86 (m, 1H), 1.83-1.75 (m, 1H), 1.30 (d, 3H).
  • Step 3. (R)-4-((4-((3-((4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (50 mg, 0.24 mmol) prepared in Reference Example 8, (S)-4-((6-chloro-4-((3-hydroxybutyl)amino)pyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (80.35 mg, 0.24 mmol) prepared in step 2, and (tributylphosphoranylidene)acetonitrile (159.79 uL, 0.61 mmol) in toluene (1 mL) was stirred at 115 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%) to yield (R)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (84 mg, 0.16 mmol, 66.69% yield) as a pale yellow foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.14 (d, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 6.57 (s, 1H), 6.19 (d, 1H), 1.82-4.79 (m, 3H), 3.91 (s, 3H), 3.68-3.60 (m, 1H), 3.58 (s, 3H), 3.55-3.49 (m, 1H), 2.44 (s, 3H), 2.21-2.12 (m, 1H), 1.93-1.90 (m, 1H), 1.20 (d, 3H).
  • Step 4. (R)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile
  • The suspension of (R)-4-((4-((3-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloropyridin-3-yl)ethynyl)-1-methyl-1H-pyrazole-3-carbonitrile (82 mg, 0.16 mmol) prepared in step 3, Pd2(dba)3 (29.05 mg, 0.032 mmol), XPhos (30.25 mg, 0.063 mmol), and Cs2CO3 (155.04 mg, 0.48 mmol) in 1,4-dioxane (1 mL) was stirred at 90 oC for 1.5 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-80%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (R)-1-methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile (17.2 mg, 0.036 mmol, 22.57% yield) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s 1H), 8.39 (d, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.33 (s, 1H), 6.35 (d, 1H), 5.70 (t, 1H), 5.30-5.26 (m, 1H), 4.09-4.03 (m, 1H), 4.03 (s, 3H), 3.72 (s, 3H), 3.65-3.60 (m, 1H), 2.63 (s, 3H), 2.26-2.19 (m, 1H), 2.01-1.95 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 481.2 (M+H)+
  • Example 77. (R)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • Step 1. (S)-4-((2-Chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol
  • The mixture of (S)-4-((2-chloro-5-iodopyridin-4-yl)amino)butan-2-ol (407.69 mg, 1.25 mmol) prepared in step 1 in Example 76, and 4-ethynyl-1,3-dimethyl-1H-pyrazole (150 mg, 1.25 mmol), PdCl2(PPh3)2 (87.63 mg, 0.13 mmol), CuI (47.55 mg, 0.25 mmol), and TEA (348.02 uL, 2.50 mmol) was charged nitrogen gas for 10 minutes. After DMF (4.16 mL) was added, the reaction mixture was stirred at 70 oC for 3 hour. 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 = 0-100%) to yield (S)-4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (309 mg, 0.97 mmol, 77.64% yield) as a pale red foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.48 (s, 1H), 6.49 (s, 1H), 5.82 (s, 1H), 4.05 (brs, 1H), 3.86 (s, 3H), 3.45-3.29 (m, 2H), 2.35 (s, 3H), 1.90-1.74 (m, 3H), 1.31 (d, 3H); MS (ESI) m/z = 319.1 (M+H)+
  • Step 2. (R)-2-(5-((4-((2-Chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine
  • The suspension of 4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol (70 mg, 0.34 mmol) prepared in Reference Example 8, (S)-4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-ol (108.74 mg, 0.34 mmol) prepared in step 1, and (tributylphosphoranylidene)acetonitrile (223.71 uL, 0.85 mmol) in toluene (1.5 mL) was stirred at 120 oC for 3 hours. The reaction mixture was cooled, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%) to yield (R)-2-(5-((4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70.9 mg, 0.14 mmol, 41.08% yield) as a pale brown foamy solid. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H), 8.08 (s, 1H), 6.82 (s, 1H), 6.69 (d, 1H), 6.54 (s, 1H), 6.15 (d, 1H), 4.82-4.79 (m, 1H), 4.75 (s, 2H), 3.76 (s, 3H), 3.66-3.49 (m, 2H), 3.57 (s, 3H), 2.47 (s, 3H), 2.17 (s, 3H), 2.15-2.09 (m, 1H), 1.94-1.90 (m, 1H), 1.20 (d, 3H); MS (ESI) m/z = 507.2 (M+H)+
  • Step 3. (R)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane
  • The suspension of (R)-2-(5-((4-((2-chloro-5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)amino)butan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (70 mg, 0.14 mmol) prepared in step 2, Pd2(dba)3 (25.34 mg, 0.028 mmol), XPhos (26.38 mg, 0.055 mmol), and Cs2CO3 (112.69 mg, 0.35 mmol) in 1,4-dioxane (1 mL) was stirred at 95 oC for 2 hours. The reaction mixture was cooled, filtered through celite, and then concentrated. The crude product was purified by amine column chromatography (EA/n-Hex = 0-60%), and then slurried with　EA/IPE for 0.5hr at room temperature, filtered to yield (R)-45-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane (31 mg, 0.066 mmol, 47.72% yield) as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.38 (d, 1H), 8.07 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.35 (d, 1H), 5.49 (t, 1H), 5.33-5.29 (m, 1H), 4.09-4.02 (m, 1H), 3.88 (s, 3H), 3.72 (s, 3H), 3.59-3.56 (m,1 H), 2.63 (s, 3H), 2.38 (s, 3H), 2.26-2.18 (m, 1H), 1.97-1.91 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 470.2 (M+H)+
  • BIOLOGICAL ASSAYS
  • 1. Biochemical EGFR inhibition assays
  • Biochemical EGFR kinase assays were conducted using Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology from Perkin-Elmer. Compounds of the invention were initially diluted to 20 mM in 100 % DMSO for storage and made into kinase buffer solution to create a compound concentration ranging from 0.003 μM and 10 μM.
  • Briefly, each EGFR enzyme wildtype (EGFR WT), double mutant [del19/C797S (EGFR D19CS) and L858R/C797S (EGFR LRCS)], triple mutant [del19/T790M/C797S (EGFR D19TMCS) and L858R/T790M/C797S (EGFR LRTMCS)], serial diluted EGFR inhibitors, substrate of ULight-poly-GT peptide (PerkinElmer; TRF0100-M) and different concentrations of ATP (Km and 100 μM final assay concentration) were mixed in kinase assay buffer (50 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT and 0.01% Tween-20) and were added to a 384-well plate (OptiplateTM 384, white, PerkinEImer; 6007290).
  • Each kinase reactions were incubated at room temperature for 1 hour and then stopped by the addition of 4 μL of stop solution (10 mM EDTA). The specific Europium-labeled-anti-phosphopeptide antibody (PerkinElmer, AD0069) diluted in LANCE detection buffer was then added to a final concentration of 2 nM. After 60 minutes incubation at room temperature the LANCE signal was measured on an EnVision Multilabel Reader (Perkin-Elmer). Excitation wavelength was set at 320 nm and emission monitored at 615 nm (donor) and 665 nm (acceptor). The IC50 values were determined using GraphPad prism software (GraphPad Software, Inc., San Diego, CA, USA).
  • The IC50 values of compounds of formula (I) on the activity of each EGFR kinase evaluated as above are shown in Tables 3 to 5 below.
  • Legend: A = IC50 < 10 nM
  • B = 10 nM ≤ IC50 < 100 nM
  • C = 100 nM ≤ IC50 < 1000 nM
  • D = IC50 ≥ 1000 nM
  • Table 3
  • Table 4
  • Table 5
  • As shown in the above results, the macrocyclic aminopyridine compounds containing -O-alkylene-NH- as a linking moiety or pharmaceutically acceptable salts thereof exhibit excellent inhibition activity against the EGFR triple/double mutants.
  • 2. Kinase Selectivity
  • Biochemical selectivity kinase assays were conducted using Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology from Perkin-Elmer. Compounds of the invention were initially diluted to 20 mM in 100 % DMSO for storage and made into kinase buffer solution to create a compound concentration ranging from 0.003 μM and 10 μM.
  • Briefly, each kinase enzyme LCK, JAK2, FLT3, HGK(MAP4K4), IRAK4, serial diluted EGFR inhibitors, substrate of ULight peptide (JAK1, TK, GT and p70S6K, PerkinElmer) and different concentrations of ATP (Km and 1mM final assay concentration) were mixed in kinase assay buffer (50 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM EGTA, 10mM MnCl2, 2 mM DTT and 0.01% Tween-20) and were added to a 384-well plate (OptiplateTM 384, white, PerkinEImer; 6007290).
  • Each kinase reactions were incubated at room temperature for 1 hour and then stopped by the addition of 4 μL of stop solution (10 mM EDTA). The specific Europium-labeled-anti-phosphopeptide antibody (PerkinElmer, AD0069) diluted in LANCE detection buffer was then added to a final concentration of 2 nM. After 60 minutes incubation at room temperature the LANCE signal was measured on an EnVision Multilabel Reader (Perkin-Elmer). Excitation wavelength was set at 320 nm and emission monitored at 615 nm (donor) and 665 nm (acceptor). The IC50 values were determined using GraphPad prism software (GraphPad Software, Inc., San Diego, CA, USA).
  • Table 6
  • As shown in the above results, the compounds of the present invention exhibit excellent kinase selectivity.
  • 3. Pharmacokinetic Study
  • Pharmacokinetics and oral bioavailability of test compound were evaluated after single oral intravenous and oral administration in mice. Test compound was dissolved in 5% DMSO : 5% solutol-ethanol (1:1) and 90% normal saline and then intravenously administered at a dose of 1 mg/5 mL/kg. Test compounds were suspended or dissolved in 0.5% methyl cellulose containing 0.2% Tween 80 or 50% polyethylene glycol 400 and then orally administered at a dose of 3 mg/10 mL/kg. Blood samples were collected from the mice in predetermined times through composite sampling design (2 times/head; n=3/time point) and plasma was separated from blood samples after centrifugation. The concentration of test compound in each sample was analyzed to obtain the plasma concentration profiles. Oral bioavailability was calculated as following equation;
  • The compounds of the present invention show excellent bioavailability according to the oral administration, along with improved pharmacokinetic characteristics.
    •

Claims (23)

  1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
    wherein
    R1 is hydrogen, halogen, C1-6 alkyl, or halo-C1-6 alkyl,
    R2 and R3 are, independently each other, hydrogen or C1-6 alkyl optionally substituted with one or more halogens,
    B is C2-3 alkylene, C2-3 alkenylene or C2-3 alkynylene,
    A is C6-10 aryl or 5-10 membered heteroaryl,
    R4 is selected from the group consisting of
    hydrogen,
    halogen,
    -CN,
    -S(O)2-C1-6 alkyl,
    4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
    -CO-4-7 membered heterocyclyl optionally substituted by one or more halogens or OH;
    C1-6 alkoxy optionally substituted by one or more halogens;
    C1-6 alkyl optionally substituted by one or more halogens; and
    C3-6 cycloalkyl optionally substituted by one or more halogens,
    n is 0, 1, 2 or 3;
    L is a linear or branched C3-6 alkylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene,
    R5 is hydrogen or halogen, and
    Y is CH or N.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, halogen, or methyl.
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen or methyl.
  4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
  5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is -CH2CH2-, -CH=CH-, or -C≡C-.
  6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, pyrazolyl, triazolyl, pyrazinyl, or pyridinyl.
  7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is n-propylene, 1-methylpropylene, 3-methylpropylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, cyclopropane-1,1-dimethylene, or oxetane-3,3-dimethylene.
  8. The compound of claim 1, which is selected from any one of the compounds as described below, or a pharmaceutically acceptable salt thereof:
    (1) (S)-25-Fluoro-11,6-dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (2) (S)-11,6-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (3) (S)-11,8-Dimethyl-45-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (4) (S)-11,6-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (5) (S)-11,8-Dimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (6) (S)-11,13,6-Trimethyl-45-(pyridin-3-ylethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (7) 11,7,7-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (8) 11,6,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (9) (R)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (10) (S)-7-Fluoro-11-methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (11) (S)-6-Methyl-11-(2,2,2-trifluoroethyl)-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (12) (S)-11,13,6-Trimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (13) (S)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (14) (S)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (15) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (16) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (17) (S)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (18) (S)-45-((1-Isopropyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (19) (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (20) (S)-11,6-Dimethyl-45-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (21) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (22) (S)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (23) (S)-7-Fluoro-11-methyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (24) (R)-7-Fluoro-11-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (25) (S)-11,8-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (26) (S)-11,8-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (27) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,8-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (28) (S)-11,8-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (29) 1'-Methyl-5'-((1-methyl-1H-pyrazol-4-yl)ethynyl)spiro[cyclopropane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];
    (30) 11,7,7-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (31) (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (32) (R)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (33) (R)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (34) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (35) (6S)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (36) 11-Methyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (37) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (38) (R)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (39) (R)-11,6-Dimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (40) (R)-11,6-Dimethyl-45-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (41) (6R)-45-((1-(2,2-Difluorocyclopropyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (42) (R)-45-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,6-dimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (43) (S)-6-Methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (44) (S)-11-Ethyl-6-methyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (45) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-6-methyl-11-(2,2,2-trifluoroethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (46) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-ethyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (47) (S)-45-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11-isopropyl-6-methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (48) (S)-11,25,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (49) (S)-11,26,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (50) (S)-11,13,6-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (51) 1'-Methyl-5'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];
    (52) 1'-Methyl-5'-((1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)spiro[oxetane-3,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane];
    (53) (S)-11,6-Dimethyl-45-((1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (54) (S)-11,6-Dimethyl-45-((5-methylpyrazin-2-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (55) (S,E)-11,6-Dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (56) (S)-11,6-Dimethyl-45-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (57) (S)-11,13,6-Trimethyl-45-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (58) (S)-11,6-Dimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2,4(2,4)-dipyridina-1(4,5)-pyrazolacyclononaphane;
    (59) (S)-(4-Hydroxypiperidin-1-yl)(4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)phenyl)methanone;
    (60) (S)-11,13,8-Trimethyl-45-((1-methyl-1H-pyrazol-4-yl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (61) (S)-45-((1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (62) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (63) (S)-45-((5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (64) (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (65) (S)-45-((3,5-Dimethyl-1-(trifluoromethyl)-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (66) (S)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
    (67) (S)-11,13,8-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (68) (S)-11,13,6-Trimethyl-45-((4-(methylsulfonyl)phenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (69) (S)-11,13,6-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (70) (S)-11,13,8-Trimethyl-45-((4-morpholinophenyl)ethynyl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (71) (S)-1-Methyl-4-((11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile;
    (72) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (73) (S)-45-((3-Methoxy-1-methyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (74) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,6-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (75) (S)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane;
    (76) (R)-1-Methyl-4-((11,13,8-trimethyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-45-yl)ethynyl)-1H-pyrazole-3-carbonitrile; and
    (77) (R)-45-((1,3-Dimethyl-1H-pyrazol-4-yl)ethynyl)-11,13,8-trimethyl-11 H-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 amount of 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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WO2022133037A1 (en) * 2020-12-17 2022-06-23 Blossomhill Therapeutics, Inc. Macrocycles and their use

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