EP4658661A1

EP4658661A1 - Macrocyclic aminopyridine compounds as egfr inhibitors

Info

Publication number: EP4658661A1
Application number: EP24760548.8A
Authority: EP
Inventors: Su Bin Choi; Hyunjoo Lee; Young Ae Yoon; Misong KIM; Sol Park; Kwan Hoon Hyun; Jae Young Sim; Marian C. Bryan; Scott Kuduk; James Campbell ROBERTSON
Original assignee: Yuhan Corp; Janssen Biotech Inc
Current assignee: Yuhan Corp; Janssen Biotech Inc
Priority date: 2023-02-22
Filing date: 2024-02-21
Publication date: 2025-12-10
Also published as: AR131910A1; WO2024177359A1; CN120731212A; TW202448895A; JP2026507653A; KR20250142978A

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 (IRESSA^TM), erlotinib (TARCEVA^TM), and afatinib (GIOTRIF^TM) 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

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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

R₁is hydrogen or C_1-3alkyl,

R₂is selected from the group consisting of

C_1-6alkoxy;

C_3-6cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of OH and halogen;

3-7 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, C_1-6alkyl substituted with one or more halogens, C_1-6alkoxy, C_1-6alkoxy substituted with one or more halogens, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C_1-6alkylcarbonylmethyl, and mono or di-C_1-6alkylaminolmethyl; and

-NR₃R₄, wherein R₃ and R₄ are, independently each other, hydrogen, C_1-6alkyl optionally substituted with one or more halogens, mono or di-(C_1-6alkyl)amino-C_1-6alkyl, or 3-7 membered heterocyclyl-C_1-3alkyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-6alkyl, and

L is a linear or branched C_3-6alkylene.

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, C_1-6alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. Unless otherwise defined, the alkyl refers to C_1-6alkyl, preferably C_1-4alkyl, more preferably C_1-3alkyl.

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 "hydroxyalkyl" refers to any hydroxyl derivative of alkyl radical. The term "hydroxyalkyl" includes any alkyl radical having one or more hydrogen atoms replaced by a hydroxy group.

As used herein, "amino" refers to -NH₂.

As used herein,the term "cycloalkyl" refers to a cyclic alkyl which may be substituted or unsubstituted, and for example, the C_3-20cycloalkyl represents a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, unless otherwise defined, the cycloalkyl may be C_3-8cycloalkyl, or C_3-6cycloalkyl.

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 memberedheterocycloalkyl, more preferably 4-7 heterocycloalkyl.

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

R₁is hydrogen or C_1-3alkyl,

R₂is selected from the group consisting of

C_1-6alkoxy;

L is a linear or branched C_3-6alkylene.

In certain embodiment, R₁may be hydrogen or methyl. Preferably, R₁may be methyl.

In certain embodiment, R₂ may be C_1-6alkoxy; C_3-6cycloalkyl; 3-7 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, C_1-6alkyl substituted with one or more halogens, C_1-6alkoxy substituted with one or more halogens, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C_1-6alkylcarbonylmethyl, and mono or di-C_1-6alkylaminolmethyl; or -NR₃R₄. In said embodiments, the 3-7 membered heterocyclyl may be selected from the group consisting of pyrrolidine, azetidine, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.3]hexane, 2,6-diazaspiro[3.4]octane, and 2,7-diazaspiro[3.5]nonane.

In certain embodiment, R₃ and R₄ may be, independently each other, hydrogen, C_1-6alkyl, halo-C_1-6alkyl, or di-(C_1-6alkyl)amino-C_1-6alkyl.

In further certain embodiment, R₃ may be hydrogen or C_1-6alkyl and R₄ may be 3-7 membered heterocyclyl-C_1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-6alkyl. In said embodiments, the 3-7 membered heterocyclyl-C_1-3alkyl may be selected from the group consisting of azetidinyl-C_1-3alkyl, piperazinyl-C_1-3alkyl, morpholinyl-C_1-3alkyl.

In certain embodiment, L may be n-propylene, 1-methylpropylene, 3-methylpropylene, 2,2-dimethylpropylene, or n-butylene.

Representative compounds of Formula (I) are listed below:

(1) (S)-Cyclopropyl(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(2) Cyclopropyl(1¹-methyl-1¹ H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4⁵-yl)methanone;

(3) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(4) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(5) (S)-1-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-N,N-dimethylmethanesulfonamide;

(6) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(7) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone;

(8) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

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

(10) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2,2,2-trifluoroethyl)azetidin-1-yl)methanone;

(11) Cyclopropyl(1¹-methyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(12) Methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate;

(13) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(pyrrolidin-1-yl)methanone;

(14) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(15) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone;

(16) (S)-N,N,1¹,6-Tetramethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(17) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-hydroxypyrrolidin-1-yl)methanone;

(18) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone;

(19) Methyl (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate;

(20) Methyl 1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate;

(21) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(22) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methanone;

(23) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-fluoro-2-azaspiro[3.3]heptan-2-yl)methanone;

(24) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(25) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(26) (S)-(3-(2,2-Difluoroethyl)-3-methylazetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(27) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2-fluoropropan-2-yl)azetidin-1-yl)methanone;

(28) (S)-N-(2-(3-Fluoroazetidin-1-yl)ethyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(29) (S)-N-(2-(3,3-Difluoroazetidin-1-yl)ethyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(30) (S)-N,1¹,6-Trimethyl-N-((1-methylazetidin-3-yl)methyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(31) (S)-N-(4-(Dimethylamino)butyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(32) (S)-N-(3-(Dimethylamino)propyl)-N,1¹,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(33) (S)-N-(3-(Dimethylamino)-2,2-dimethylpropyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(34) (S)-1¹,6-Dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(35) (S)-1¹,6-Dimethyl-N-(2-morpholinoethyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(36) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)methanone;

(37) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)methanone;

(38) (S)-N-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide;

(39) (S)-(3-(Difluoromethoxy)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(40) (S)-(6-(Difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(41) (S)-1-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-3-methylbutan-2-one;

(42) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone;

(43) ((S)-1¹,8-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(44) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(45) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(46) ((2R,3R)-2-Methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(47) (3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(48) (3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(49) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(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)methanone;

(50) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(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)methanone;

(51) (S)-(3-(Difluoromethoxy)azetidin-1-yl)(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)methanone; and

(52) (S)-N-(2,2-Difluoroethyl)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide.

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

(49) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(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)methanone; and

(50) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(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)methanone.

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

(49) (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(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)methanone or a pharmaceutically acceptable salt thereof; and

(50) (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(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)methanone 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 formic 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⁺(C_1-4alkyl)₄salts.

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 invention may be synthesized by methods known in the art or by methods illustrated in Examples 1-52 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.

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

In one embodiment, the at least one mutant is at least one triple 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 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 and L are the same as defined in the above; and R₂'is C_1-6alkoxy or C_3-6cycloalkyl.

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-OH to obtain a compound of formula (III), reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V) and cyclizing the compound of formula (V) to obtain the compound of formula (Ia).

In the processes of Scheme 1, the compounds of formula (II), NH₂-L-OH and (IV) are commercially available. The reaction of the compound of formula (II) and NH₂-L-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^oC.

The compound of formula (III) is coupled with a compound of formula (IV) to obtain a compound of formula (V) by Mitsunobu reaction. The reaction of the compound of formula (III) and (IV) may be performed in the presence of a phosphorane　ylide such as (cyanomethylene)trimethylphosphorane, (cyanomethylene)tributylphosphorane, 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^oC.

The compound of formula (V) is cyclized by Buchwald-Hartwig reaction to obtain the compound of formula (Ia). The cyclization reaction of the compound of formula (V) may be performed in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. Further, the reaction may be performed in the presence of a palladium catalyst such as Pd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃)_4, Pd(dppf)Cl₂, BrettPhos Pd G1 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^oC.

Alternately, the compound of formula (I) may be prepared in accordance with the following Scheme 2:

Scheme 2.

In the Scheme 2, R₁ and L are the same as defined in the above; R₂'is C_1-6alkoxy; and R₂'' is 3-7 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, C_1-6alkyl substituted with one or more halogens, C_1-6alkoxy, C_1-6alkoxy substituted with one or more halogens, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C_1-6alkylcarbonylmethyl, and mono or di-C_1-6alkylaminolmethyl; or -NR₃R₄, wherein R₃ and R₄ are, independently each other, hydrogen, C_1-6alkyl optionally substituted with one or more halogens, mono or di-(C_1-6alkyl)amino-C_1-6alkyl, or 3-7 membered heterocyclyl-C_1-3alkyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-6alkyl.

Specifically, the compound of formula (Ib) may be prepared using a process which comprises: hydrolyzing a compound of formula (Ia) to obtain a compound of formula (VI) and reacting a compound of formula (VI) with R₂ ^''-H to obtain a compound of formula (Ib).

In the processes of Scheme 2, the compounds of formula R₂ ^''-H is commercially available. The hydrolysis reaction of the compound of formula (Ia) may be performed in the presence of a base, such as sodium hydride, potassium carbonate, cesium carbonate, potassium hydroxide, etc. Further, the reaction may be carried out in an organic solvent, such as THF, MeOH, H₂O, etc. and at room temperature or under heating, e.g., at a temperature of 40-100^oC.

The reaction of the compound of formula (VI) and R₂ ^''-H may be performed in the presence of a base, such as TEA, DIPEA, etc. and a amide coupling reagent such as HOBt, HBTU, BOP, PyBOP, HATU, etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., DCM, DMF, acetonitrile, etc. at room temperature or under heating, e.g. at a temperature of 30-100^oC.

In an embodiment, the compound of formula (IV) may be prepared in accordance with the following Scheme 3:

Scheme 3.

In the Scheme 3, R₁ is the same as defined in the above; X is halogen; and M is B(OH)₂ or BPin.

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

In the processes of Scheme 3, the compounds of formula (VII) is commercially available. The reaction of the compound of formula (VII) and (VIII) may be performed in the presence of a base, such as sodium carbonate, potassium carbonate, etc. and a ligand-coupled palladium catalyst such as Pd(dppf)Cl_2,Pd(PPh₃)_4,etc. Further, the reaction may be carried out in an anhydrous organic solvent, e.g., THF, 1,4-dioxane, etc. under heating, e.g. at a temperature of 40-100^oC.

The hydrogenolysis of the compound of formula (IX) may be done (or 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 another embodiment, the compound of formula (VIII) may be prepared in accordance with the following Scheme 4:

Scheme 4.

In the Scheme 4, R₁ is the same as defined in the above; X is halogen; and M is B(OH)₂ or BPin.

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

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

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

The borylation of the compound of formula (XII) may be performed in the presence of boron reagent such as B₂Pin₂, B₂Cat₂, i-proOBPin, etc. and organometallic reagents such 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)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid Step 1. Ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate

To a solution of ethyl 4,6-dichloronicotinate (5.0 g, 24.3 mmol) and (S)-3-aminobutan-1-ol (4.65 mL, 48.6 mmol) in acetonitrile (100 mL) was added DIPEA (12.7 mL, 72.9 mmol). The reaction mixture was continued to stir at 60 ℃ for 12 hours. After completion, the solvent was evaporated under reduced pressure. The residue was diluted by EA followed by washed with water and brine. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. It was then purified by use of flash column chromatography (EA/n-Hex = 0-50%) to obtain ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (5.02 g, 75.7%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 8.19 (d, 1H), 6.63 (s, 1H), 4.35-4.29 (m, 2H), 3.84-3.76 (m, 3H), 1.85-1.80 (m, 3H), 1.39-1.36 (m, 3H), 1.28 (d, 3H); MS (ESI) m/z = 273.1 (M + H)⁺

Step 2. (S)-Ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate

To a solution of　ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (3.0 g, 11.0 mmol) prepared in step 1 in toluene (22 mL)　were added (tributylphosphoranylidene)acetonitrile (8.65 mL, 33.0 mmol) and 4-(4-aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol (2.10 g, 11.0 mmol) prepared in Reference Example 8. The reaction mixture was continued to stir at 100 ℃ for 4 hours. After completion, the mixture was cooled and diluted with EA. The organic layer was washed with water, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude was then purified by use of flash column chromatography [MeOH/DCM = 0-5%, (containing 1% NH₄OH)] to obtain (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (3.37 g, 68.7%) as a brown solid. ¹H-NMR (CDCl_3,400 MHz) δ 8.66 (s, 1H), 8.22 (d, 1H), 8.15 (d, 1H), 7.96 (s, 1H), 6.64 (s, 1H), 6.18 (d, 1H), 4.83 (brs, 2H), 4.52-4.50 (m, 1H), 4.40-4.37 (m, 1H), 4.33-4.28 (m, 2H), 3.95-3.91 (m, 1H), 3.69 (s, 3H), 2.11-2.08 (m, 2H), 1.38-1.35 (m, 6H); MS (ESI) m/z = 446.1 (M + H)⁺

Step 3. Ethyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

To a solution of　(S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (3.37 g, 7.56 mmol) prepared in step 2 in 1,4-dioxane (300 mL)　were added Cs₂CO₃ (7.39 g, 22.7 mmol), Pd₂(dba)₃ (1.38 g, 1.51 mmol), and xphos (1.44 g, 3.02 mmol). The reaction mixture was continued to stir at 120 ℃ for 6 hours. After completion, the mixture was cooled and diluted with DCM. The organic layer was washed with water, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude was then purified by use of flash column chromatography [MeOH/DCM = 0-5%, (containing 1% NH₄OH)] to obtain ethyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (1.77 g, 57%) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.65 (s, 1H), 8.33 (d, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 8.12 (s, 1H), 7.66 (brs, 1H), 6.37 (d, 1H), 4.74-4.71 (m, 1H), 4.35-4.26 (m, 3H), 4.08-4.06 (m, 1H), 3.80 (s, 3H), 2.16-2.15 (m, 2H), 1.47-1.45 (d, 2H), 1.41-1.37 (m, 3H); MS (ESI) m/z = 409.1 (M + H)⁺

Step 4. (S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

The suspension of 3N NaOH solution (4.88 mL, 14.654 mmol) and ethyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (600 mg, 1.465 mmol) prepared in step 3 in THF (24.0 mL)/50% MeOH (12 mL) was stirred at 60 ^oC for 7 hours. The reaction mixture was cooled, and then added 9N HCl soln. to pH 2 and stirred for 15 minutes. The mixture was filtered and washed with water. The wetcake was dried to yield methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (543 mg, 1.424 mmol, 97.16 %) as a white solid. MS (ESI) m/z = 381.9 (M + H)⁺

Reference Example 2. (S)-1¹,8-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

Step 1. methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate

The title compound as an off-white solid (1010 mg) was prepared in the same fashion as step1 in Reference Example 1 except methyl-4,6-dichloronicotinate (1000 mg, 4.854 mmol) and (R)-4-aminobutan-2-ol (562.45 mg, 6.31 mmol) was used instead of ethyl 4,6-dichloronicotinate and (S)-3-aminobutan-1-ol. MS (ESI) m/z = 259.0 (M + H)⁺

Step 2. Methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate

The title compound as a white solid (171 mg) was prepared in the same fashion as step 2 in Reference Example 1 except that methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate (270.62 mg, 1.046 mmol) prepared in step 1 was used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate.¹H-NMR (CDCl₃, 400 MHz) δ 8.68 (s, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.05 (s, 1H), 5.24-5.16 (m, 1H), 4.80 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.58 (q, 2H), 2.24-2.16 (m, 1H), 2.10-2.02 (m, 1H), 1.28 (d, 3H).

Step 3. Methyl (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

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

Step 4. (S)-1¹,8-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

he title compound as an off-white solid (65 mg) was prepared in the same fashion as step 4 in Reference Example 1 except that methyl (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (100 mg, 0.253 mmol) prepared in step 3 was used instead of ethyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate. MS (ESI) m/z = 381.9 (M + H)⁺

Reference Example 3. 1¹,7,7-Trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

Step 1. Methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate

The title compound as a white solid (1166 mg) was prepared in the same fashion as step 1 in Reference Example 2 except that 3-amino-2,2-dimethylpropan-1-ol (650.91 mg, 6.31 mmol) was used instead of (R)-4-aminobutan-2-ol. ¹H-NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 8.46 (s, 1H), 6.64 (s, 1H), 3.91 (s, 3H), 3.51 (d, 2H), 3.13 (d, 2H), 1.83 (t, 1H), 1.05 (s, 6H).

Step 2. Methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate

The title compound as a white solid (382 mg) was prepared in the same fashion as step 2 in Reference Example 1 except that methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate (713.24 mg, 2.615mmol) prepared in step 1 was used instead of ethyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate. ¹H-NMR (CDCl₃, 400 MHz) δ 8.69 (s, 1H), 8.51 (s, 1H), 8.19 (d, 1H), 7.99 (s, 1H), 6.66 (s, 1H), 6.21 (d, 1H), 4.83 (s, 2H), 4.22 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.34 (d, 2H), 1.23 (s, 6H).

Step 3. Methyl 1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

The title compound as a white solid (49 mg) was prepared in the same fashion as step 3 in Reference Example 1 except that methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate (380 mg, 0.852 mmol) was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate.¹H-NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 8.48 (t, 1H), 8.37 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 6.39 (d, 1H), 4.79 (brs, 1H), 4.21 (brs, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.54 (brs, 1H), 2.94 (brs, 1H), 1.41 (brs, 3H), 1.00 (brs, 3H); MS (ESI) m/z = 410.0 (M + H)⁺

Step 4. 1¹,7,7-Trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

The title compound as an off-white solid (33 mg) was prepared in the same fashion as step 4 in Reference Example 1 except that methyl 1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (45 mg, 0.11 mmol) was used instead of ethyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate. MS (ESI) m/z = 396.0 (M + H)⁺

Reference Example 4. tert-Butyl(tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate

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

Reference Example 5. 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

Step 1. 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

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

Step 2. 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

To a solution of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (1.00 g, 4.38 mmol) prepared in step 1 in MeCN (14.60 mL) was added N-bromosuccinimide (740.46 mg, 4.16 mmol) at 0 ^oC. The reaction mixture was stirred at 0 ^oC for 30 minutes and diluted with sat. Na₂S₂O₃ and EA. The aqueous phase was extracted with EA. The combined organic phases were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH/DCM = 0-5%) to yield 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (668.0 mg, 2.2 mmol, 49.6% yield) as a pale yellowish solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.43 (s, 1H), 4.97 (s, 2H), 3.50-3.46 (m, 5H), 0.86 (q, 2H), 0.00 (s, 9H); MS (ESI) m/z = 307.0 (M+H)⁺

Reference Example 6. 4-(4-Aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1,2-dihydro-3H-pyrazol-3-one

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

Reference Example 7. (4-((3-((tert-Butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone

Step 1. (6-Chloro-4-((3-hydroxypropyl)amino)pyridin-3-yl)(cyclopropyl)methanone

To a solution of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (2.0 g, 9.26 mmol) in MeCN (9.20 mL) was added DIPEA (2.59 mL, 18.51 mmol) and 3-amino-1-propanol (0.78 mL, 10.18 mmol). The reaction mixture was stirred at 60 ^oC for overnight. Then, the reaction mixture was cooled to room temperature, 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 (6-chloro-4-((3-hydroxypropyl)amino)pyridin-3-yl)(cyclopropyl)methanone (1.74 g, 6.8 mmol, 73.9% yield). ¹H-NMR (CDCl₃, 400 MHz) δ 9.18 (s, 1H), 8.77 (s, 1H), 6.56 (d, 1H), 3.78 (s, 2H), 3.32 (d, 2H), 2.54 (d, 1H), 1.90 (d, 2H), 1.20 (d, 2H), 1.02 (d, 2H); MS (ESI) m/z = 255.1 (M+H)⁺

Step 2. (4-((3-((tert-Butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone

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

Reference Example 8. 4-(4-Aminopyrimidin-2-yl)-2-methyl-pyrazol-3-ol

Step 1. 5-(Benzyloxy)-1-methyl-1H-pyrazole

To a solution of 1-methyl-1H-pyrazol-5-ol (50.0 g, 0.51 mol) in DMF (500 mL) 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) 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) 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 MgSO_4, 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) 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 9. 4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-ol

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

To a solution of 1,3-dimethyl-1H-pyrazol-5-ol (13.0 g, 116 mmol) in THF (500 mL) 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) 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) 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 MgSO_4, 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) 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)⁺

Example 1. (S)-Cyclopropyl(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

Step 1. (S)-(6-Chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone

The mixture of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (2.00 g, 9.257 mmol), (S)-3-aminobutan-1-ol (825.14 mg, 9.257 mmol), and DIPEA (2.59 mL, 18.513 mmol) in MeCN (10 mL) was stirred at 60 ^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)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (2.08 g, 7.740 mmol, 83.61% yield). ¹H-NMR (CDCl₃, 400MHz) δ 8.77 (s, 1H), 6.67 (s, 1H), 3.87-3.74 (m, 3H), 2.58-2.52 (m, 1H), 2.24-2.22 (m, 1H), 1.85-1.78 (m, 2H), 1.27 (d, 3H), 1.21-1.15 (m, 2H), 1.05-1.01 (m, 2H); MS (ESI) m/z = 269.1 (M + H)⁺

Step 2. (S)-(4-((4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone

The mixture of (S)-(6-chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (1.23 g, 4.593 mmol) prepared in step 1, tert-butylchlorodimethylsilane (830.79 mg, 5.512 mmol), DMAP (56.12 mg, 0.459 mmol) and TEA (1.28 mL, 9.187) in DCM (4 mL) was stirred at rt for 3 hours. After the reaction mixture was 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)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (1.70 g, 4.439 mmol, 96.63% yield). ¹H-NMR (CDCl₃, 400MHz) δ 9.12 (brs, 1H), 8.81 (s, 1H), 6.69 (s, 1H), 3.83-3.77 (m, 1H), 3.69-3.63 (m, 2H), 2.60-2.54 (m, 1H), 1.81-1.63 (m, 2H), 1.25 (d ,3H), 1.20-1.16 (m, 2H), 1.04-1.00 (m, 2H), 0.91 (s, 9H), 0.03 (s, 6H); MS (ESI) m/z = 384.1 (M + H)⁺

Step 3. (S)-(6-((2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone

The mixture of (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (68.07 mg, 0.178 mmol) prepared in step 2, 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (50.00 mg, 0.178 mmol), cesium carbonate (173.74 mg, 0.533 mmol), XPhos (33.89 mg, 0.071 mmol), and Pd₂(dba)₃ (32.55 mg, 0.036 mmol) in 1,4-dioxane (1 mL) was stirred at 130 ^oC for 2 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)-(6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (20.00 mg, 0.032 mmol, 17.92% yield). MS (ESI) m/z = 628.1 (M + H)⁺

Step 4. (S)-(4-((4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone

The mixture of (S)-(6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (20.00 mg, 0.032 mmol) prepared in step 3, 10% Pd/C (40.00 mg) in MeOH (1 mL) was stirred under H₂ gas at rt for 2 hours. The reaction mixture was filtered through celite pad, and then concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-20%) to yield (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (7.50 mg, 0.014 mmol, 42.53% yield). MS (ESI) m/z = 538.1 (M + H)⁺

Step 5. (S)-Cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone

The mixture of (S)-(4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone (15.52 mg, 0.029 mmol) prepared in step 4 and TBAF in THF 1.0M (0.43 mL, 0.433 mmol) in THF (1 mL) was stirred at 50 ^oC for 7 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)-cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone (7.50 mg, 0.018 mmol, 61.36% yield). ¹H-NMR (CD₃OD, 400MHz) δ 9.01 (s, 1H), 8.14 (d, 1H), 7.80 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 3.98-3.93 (m, 1H), 3.73-3.67 (m, 2H), 3.51 (s, 3H), 2.81-2.77 (m, 1H), 1.88-1.83 (m, 2H), 1.33 (d, 3H), 1.15-1.11 (m, 4H); MS (ESI) m/z = 424.1 (M + H)⁺

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

The mixture of (S)-cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)methanone (7.50 mg, 0.018 mmol) prepared in step 5 and (tributylphosphoranylidene)acetonitrile (0.12 mL, 0.117 mmol) in　Toluene (1 mL) was stirred at 130 ^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)-cyclopropyl(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone (2.80 mg, 0.007 mmol, 38.99% yield). ¹H-NMR (CD₃OD, 400MHz) δ 8.86 (brs, 1H), 8.42-8.40 (m, 3H), 8.03 (s, 1H), 6.74 (d, 1H), 4.70-4.64 (m, 1H), 4.25-4.20 (m, 2H), 3.81 (s, 3H), 2.76-2.72 (m, 1H), 2.22-2.13 (m, 1H), 1.43 (d, 3H), 1.13-1.08 (m, 2H), 1.05-1.00 (m, 2H); MS (ESI) m/z = 406.1 (M + H)⁺

Example 2. Cyclopropyl(1¹-methyl-1¹ H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4⁵-yl)methanone

Step 1. (6-Chloro-4-((4-hydroxybutyl)amino)pyridin-3-yl)(cyclopropyl)methanone

The mixture of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (2.00 g, 9.257 mmol), 4-aminobutan-1-ol (907.66 mg, 10.182 mmol), and DIPEA (2.59 mL, 18.513 mmol) in MeCN (10 mL) was stirred at 60 ^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 (6-chloro-4-((4-hydroxybutyl)amino)pyridin-3-yl)(cyclopropyl)methanone (2.00 g, 7.442 mmol, 80.40% yield). ¹H-NMR (CD₃OD, 400MHz) δ 9.33 (brs, 1H), 8.84 (s, 1H), 6.79 (s, 1H), 3.63-3.59 (m, 2H), 3.32-3.27 (m, 3H), 2.78-2.72 (m, 1H), 1.77-1.60 (m, 4H), 1.15-1.14 (m, 4H); MS (ESI) m/z = 269.1 (M + H)⁺

Step 2. (4-((4-((tert-Butyldimethylsilyl)oxy)butyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone

The mixture of (6-chloro-4-((4-hydroxybutyl)amino)pyridin-3-yl)(cyclopropyl)methanone (1.23 g, 4.593 mmol) prepared in step 1, tert-butylchlorodimethylsilane (830.79 mg, 5.512 mmol), DMAP (56.12 mg, 0.459 mmol) and TEA (1.28 ml, 9.187 mmol) in DCM (4 ml) was stirred at rt for 3 hours. After the reaction mixture was diluted in EA, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-15%) to yield (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (1.70 g, 4.439 mmol, 96.63% yield). ¹H-NMR (CDCl₃, 400MHz) δ 9.14 (brs, 1H), 8.82 (s, 1H), 6.56 (s, 1H), 3.67-3.64 (m, 2H), 3.23-3.18 (m, 2H), 2.60-2.54 (m, 1H), 1.77-1.58 (m, 4H), 1.21-1.17 (m ,2H), 1.05-1.00 (m, 2H), 0.91 (s, 9H), 0.03 (s, 6H); MS (ESI) m/z = 384.1 (M + H)⁺

Step 3. (6-((2-(5-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)pyridin-3-yl)(cyclopropyl)methanone

The mixture of (4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (204.22 mg, 0.533 mmol) prepared in step 2, 2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (150.00 mg, 0.533 mmol), cesium carbonate (521.22 mg, 1.600 mmol), XPhos (101.68 mg, 0.213 mmol), and Pd₂(dba)₃ (97.66 mg, 0.107 mmol) in 1,4-dioxane (1 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 (6-((2-(5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-((tert-butyldimethylsilyl)oxy)butyl)amino)pyridin-3-yl)(cyclopropyl)methanone (80.00 mg). MS (ESI) m/z = 628.1 (M + H)⁺

Step 4. (4-((4-((tert-Butyldimethylsilyl)oxy)butyl)amino)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)(cyclopropyl)methanone

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

Step 5. Cyclopropyl(6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutyl)amino)pyridin-3-yl)methanone

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

Step 6. Cyclopropyl(1¹-methyl-1¹ H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4⁵-yl)methanone

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

Example 3. ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone

The mixture of (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (30.00 mg, 0.079 mmol) prepared in Reference Example 1, (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (47.12 mg, 0.236 mmol), HATU (59.82 mg, 0.157 mmol) and DIPEA (0.04 ml, 0.236 mmol) in DMF (3 mL) 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 (MeOH/DCM = 0-20%) to yield ((S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (2.70 mg, 0.005 mmol, 6.52% yield). ¹H-NMR (CD₃OD, 400MHz) δ 8.30 (s, 3H), 8.28-8.26 (d, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 6.71 (d, 1H), 4.72-4.69 (m, 1H), 4.68-4.56 (m, 2H), 4.24-4.18 (m, 2H), 4.02 (s, 1H), 3.81 (s, 3H), 3.58-3.48 (m, 2H), 3.00 (s, 3H), 2.22-2.15 (m, 2H), 1.51 (d, 3H), 1.41 (d, 3H); MS (ESI) m/z = 527.1 (M + H)⁺

Example 4. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone

The title compound as a white solid (3.50 mg) was prepared in the same fashion as Example 3 except that 3-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (15.71 mg, 0.079 mmol) was used instead of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride. ¹H-NMR (DMSO-d ₆, 400MHz) δ 8.30 (d, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 6.80 (d, 1H), 4.52-4.48 (m, 1H), 4.32-4.29 (m, 2H), 4.01-3.96 (m, 2H), 3.78 (s, 3H), 3.02 (s, 3H), 2.13-1.99 (m, 3H), 1.53 (s, 3H), 1.37 (d, 3H); MS (ESI) m/z = 527.3 (M + H)⁺

Example 5. (S)-1-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-N,N-dimethylmethanesulfonamide formate

The title compound as a white solid (4.00 mg) was prepared in the same fashion as Example 3 except that azetidin-3-ylmethanesulfonyl fluoride hydrochloride (14.92 mg, 0.079 mmol) was used instead of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride. ¹H-NMR (DMSO-d ₆, 400MHz) δ 10.06 (s, 1H), 8.30 (d, 1H), 8.21 (s, 1H), 8.13 (d, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 6.80 (d, 1H), 4.51-4.47 (m, 1H), 4.33-4.29 (m, 2H), 4.02-3.96 (m, 2H), 3.48 (d, 2H), 3.11-3.06 (m, 1H), 2.13-1.98 (m, 2H), 1.37 (d, 3H); MS (ESI) m/z = 542.2 (M + H)⁺

Example 6. ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone

The reaction mixture of (S)-1¹,6-dimethyl-1¹H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (30.0 mg, 0.079 mmol) prepared in Reference Example 1, (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol), HATU (59.82 mg, 0.157 mmol) and DIPEA (0.04 mL, 0.236 mmol) in DMF (2 mL) was stirred at 80 ^oC for 3 hours. The crude reaction mixture was concentrated under reduced pressure, and purified by column chromatography (MeOH/EA = 0-30%) and recrystallization (EA/IPE) to yield ((S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (6 mg, 0.011 mmol, 14.48% yield) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.38 (d, 1H), 8.34 (s, 1H), 8.20 (d, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.63 (brs, 1H), 6.43 (d, 1H), 4.99-4.95 (m, 1H), 4.77-4.72 (m, 1H), 4.47-4.41 (m, 1H), 4.26-4.24 (m, 1H), 4.12-4.09 (m, 1H), 3.82 (s, 3H), 3.44-3.31 (m, 2H), 2.98 (s, 2H), 2.17-2.13 (m, 2H), 1.49-1.45 (m, 6H); MS (ESI) m/z = 527.2 (M + H)⁺

Example 7. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone

The title compound as a white solid (2 mg) was prepared in the same fashion as Example 6, except that 2-(azetidin-3-yl)propan-2-ol hydrochloride (15.9 mg, 0.105 mmol) was used instead of (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.35 (d, 1H), 8.30 (s, 1H), 8.22 (d, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.49 (s, 1H), 6.38 (d, 1H), 4.77-4.73 (m, 1H), 4.26-4.22 (m, 4H), 4.10-4.06 (m, 1H), 2.73-2.18 (m, 2H), 1.45 (d, 3H), 1.28 (t, 1H), 1.24 (s, 6H); MS (ESI) m/z = 479.3 (M + H)⁺

Example 8. ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone formate

The title compound as a white solid (11.9 mg) was prepared in the same fashion as Example 6, except that (2S,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71 mg, 0.079 mmol) was used instead of (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.49-8.47 (m, 2H), 8.42 (s, 1H), 8.38 (d, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 6.67 (d, 1H), 4.70-4.64 (m, 2H), 4.57-4.55 (m, 1H), 4.27-4.25 (m, 1H), 4.12-4.10 (m, 1H), 4.06-4.02 (m, 1H), 3.81 (s, 3H), 3.40-3.32 (m, 2H), 2.97 (s, 3H), 2.88-2.86 (m, 1H), 2.18-2.14 (m, 2H), 1.57 (d, 3H), 1.49 (d, 3H); MS (ESI) m/z = 526.9 (M + H)⁺

Example 9. (S)-(1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

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

Example 10. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2,2,2-trifluoroethyl)azetidin-1-yl)methanone

The title compound as a white solid (4.5 mg) was prepared in the same fashion as Example 6, except that 3-(2,2,2-trifluoroethyl)azetidine hydrochloride (17.72 mg, 0.101 mmol) was used instead of (2S,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 8.34 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 6.43 (d, 1H), 4.74-4.72 (d, 1H), 4.51-4.49 (m, 2H), 4.27-4.24 (m, 1H), 4.12-4.07 (m, 3H), 3.82 (s, 3H), 3.09-3.05 (m, 1H), 2.53-2.46 (m, 2H), 2.20-2.14 (m, 2H), 1.47 (d, 3H); MS (ESI) m/z = 503.2 (M + H)⁺

Example 11. Cyclopropyl(1¹-methyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone 2,2,2-trifluoroacetate

Step 1. 4-(4-((4-((3-((tert-Butyldimethylsilyl)oxy)propyl)amino)-5-(cyclopropanecarbonyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

To a solution of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (20.0 mg, 0.06 mmol) prepared in Reference Example 6 in 1,4-dioxane (1.5 mL) was added (4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-6-chloropyridin-3-yl)(cyclopropyl)methanone (29.84 mg, 0.08 mmol) prepared in Reference Example 7, Pd₂(dba)₃ (11.39 mg, 0.01 mmol), Xphos (11.86 mg, 0.02 mmol) and cesium carbonate (60.82 mg, 0.19 mmol). The reaction mixture was charged N₂ for 30 minutes and stirred at 100 ^oC for 2 hours. The reaction mixture was diluted with DCM and water. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH/DCM = 5-10%) to yield 4-(4-((4-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-5-(cyclopropanecarbonyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (12.0 mg, 0.02 mmol, 29.5% yield). MS (ESI) m/z = 654.3 (M+H)⁺

Step 2. 4-(4-((5-(Cyclopropanecarbonyl)-4-((3-hydroxypropyl)amino)pyridin-2-yl)amino) pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one

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

Step 3. Cyclopropyl(1¹-methyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

To a solution 4-(4-((5-(cyclopropanecarbonyl)-4-((3-hydroxypropyl)amino)pyridin-2-yl) amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one (2.22 mg, 0.01 mmol) in toluene (1.08 mL) was added (tributylphosphoranylidene)acetonitrile solution (1.0 M in toluene, 0.04 mL, 0.04 mmol). The reaction mixture was stirred at 130 ^oC for 12 hours, concentrated and purified by silica gel column chromatography (MeOH/DCM = 0-30%) to yield cyclopropyl(1¹-methyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone. (0.80 mg, 0.002 mmol, 29.1% yield) as TFA salt form. ¹H-NMR (CDCl₃, 400 MHz) δ 11.44 (s, 1H), 9.95 (t, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.43 (d, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 6.79 (d, 1H), 4.39 (s, 2H), 3.79 (s, 3H), 3.76 (s, 2H), 2.24-2.23 (m, 3H), 1.23 (t, 2H), 1.07 (t, 2H); MS (ESI) m/z = 392.1 (M+H)⁺

Example 12. Methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

Step 1. Methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate

To a solution of methyl-4,6-dichloronicotinate (3.70 g, 17.96 mmol) in DMA (29.12 mL) was added (S)-3-aminobutan-1-ol (1.60 g, 17.96 mmol), DIPEA (5.02 mL, 35.92 mmol). The reaction mixture was stirred at 80 ^oC for 3 hours. The reaction mixture was cooled to room temperature, 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 (EA/n-Hex = 0-30%) to yield methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (2.93 g, 11.3 mmol, 63.2% yield). ¹H-NMR (CDCl₃, 400 MHz) δ 8.57 (s, 1H), 8.15 (d, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.83-3.67 (m, 3H), 2.69-2.51 (m, 1H), 1.90-1.75 (m, 2H), 1.28 (d, 3H); MS (ESI) m/z = 259.0 (M+H)⁺

Step 2. Methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate

To a solution of methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate (105.0 mg, 0.41 mmol) in toluene (1.78 mL) was added 4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (77.60 mg, 0.41 mmol) prepared in Reference Example 8 and (tributylphosphoranylidene)acetonitrile (1.0 M in toluene, 305.76 mg, 1.01 mmol). 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 methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (121.60 mg, 0.28 mmol, 69.4% yield). ¹H-NMR (CDCl₃, 400 MHz) δ 8.65 (s, 1H), 8.19 (d, 1H), 8.14 (d, 1H), 7.96 (s, 1H), 6.64 (s, 1H), 6.17 (d, 1H), 5.03 (s, 2H), 4.54-4.36 (m, 2H), 3.93 (quin, 1H), 3.84 (s, 3H), 3.68 (s, 3H), 2.09 (sep, 2H), 1.35 (d, 3H)

Step 3. Methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

To a solution of methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (120.0 mg, 0.28 mmol) in 1,4-dioxane (5.56 mL) was added cesium carbonate (271.59 mg, 0.83 mmol), Pd₂(dba)₃ (50.89 mg, 0.06 mmol) and XPhos (52.98 mg, 0.11 mmol). The reaction mixture was stirred at 130 ^oC for 3 hours. The reaction mixture was added to water and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (EA/n-Hex = 0-100%) & (MeOH/DCM = 0-30%) to yield methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (63.0 mg, 0.16 mmol, 57.34% yield). ¹H-NMR (CDCl₃, 400 MHz) δ 8.65 (s, 1H), 8.45 (s, 1H), 8.34 (d, 1H), 8.31 (s, 1H), 8.26 (d, 1H), 8.12 (s, 1H), 6.42 (d, 1H), 4.73 (q, 1H), 4.29 (t, 1H), 4.09-4.06 (m, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.17 (d, 2H), 1.48 (d, 3H); MS (ESI) m/z = 396.2 (M+H)⁺

Example 13. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(pyrrolidin-1-yl)methanone

Step 1. (S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

To a solution of methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (73.0 mg, 0.18 mmol) prepared in Example 12 in THF (2.0 mL) and water (2.0 mL) was added 1.0 N NaOH (2.0 mL). The reaction mixture was stirred at 60 ^oC for 12 hours. The reaction mixture was added 9.0 N HCl to pH 3~4. The mixture was filtered and washed with water. Filter cake was dried to yield (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (56.0 mg, 0.15 mmol, 79.5% yield) as a pale yellowish solid. ¹H-NMR (DMSO-d ₆, 400 MHz) δ 10.06 (s, 1H), 8.51 (s, 1H), 8.30-8.27 (m, 2H), 8.20 (s, 1H), 7.91 (s, 1H), 6.78 (d, 1H), 4.49 (t, 1H), 4.30 (s, 1H), 4.02 (s, 1H), 3.77 (s, 4H), 2.14-2.03 (m, 2H), 1.38 (d, 3H); MS (ESI) m/z = 382.1 (M+H)⁺

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

To a solution of (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (15.0 mg, 0.04 mmol) prepared in step 1 in DMF (4.28 mL) was added HATU (29.91 mg, 0.08 mmol) and DIPEA (20.55 uL, 0.12 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then, pyrrolidine (5.59 mg, 0.08 mmol) was added. The reaction mixture was stirred at 80 ^oC for 6 hours and extracted with DCM/water. The organic layers was dried over MgSO₄, filtered, and concentrated. The crude was purified by C18 column chromatography (MeCN/water = 0-100%) to yield (S)-(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(pyrrolidin-1-yl)methanone (8.40 mg, 0.02 mmol, 49.2% yield). ¹H-NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.30 (d, 1H), 6.39 (d, 1H), 4.73 (t, 1H), 4.23 (s, 1H), 4.09 (d, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 2.15-1.96 (m, 8H), 1.43 (d, 3H); MS (ESI) m/z = 435.2 (M+H)⁺

Example 14. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-((methylsulfonyl)methyl)azetidin-1-yl) methanone

The title compound as solid (26.0 mg) was prepared in the same fashion as step 2 in Example 13 except that 3-(methylsulfonylmethyl)azetidine hydrochloride (29.21 mg, 0.16 mmol) was used instead of pyrrolidine. ¹H-NMR (DMSO-d ₆, 400 MHz) δ 9.19 (s, 1H), 8.28 (d, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 6.78 (d, 1H), 4.49 (t, 1H), 4.30-3.95 (m, 6H), 3.76 (s, 3H), 3.55 (d, 2H), 3.18-3.16 (m, 1H), 2.96 (s, 3H), 2.11-2.00 (m, 2H), 1.35 (d, 3H); MS (ESI) m/z = 513.2 (M+H)⁺

Example 15. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone

The title compound as solid (2.10 mg) was prepared in the same fashion as step 2 in Example 13 except that 2-oxa-6-azaspiro[3.3]heptane (3.90 mg, 0.04 mmol) was used instead of pyrrolidine. ¹H-NMR (CD₃OD, 400 MHz) δ 8.28 (s, 1H), 8.28 (d, 1H), 8.12 (s, 3H), 8.02 (s, 1H), 6.72 (d, 1H), 4.82 (s, 4H), 4.67 (t, 1H), 4.46 (s, 4H), 4.23-4.17 (m, 2H), 3.81 (s, 3H), 2.23-2.08 (m, 2H), 1.41 (d, 3H); MS (ESI) m/z = 463.2 (M+H)⁺

Example 16. (S)-N,N,1¹,6-Tetramethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as solid (9.80 mg) was prepared in the same fashion as step 2 in Example 13 except that methyl 1H-pyrrole-3-carboxylate (4.92 mg, 0.04 mmol) was used instead of pyrrolidine. ¹H-NMR (CD₃OD, 400 MHz) δ 8.31 (s, 1H), 8.27 (d, 1H), 8.14 (s, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 6.70 (d, 1H), 4.64 (t, 1H), 4.22-4.19 (m, 2H), 3.79 (s, 3H), 3.11 (s, 6H), 2.18-2.11 (m, 2H), 1.41 (d, 3H); MS (ESI) m/z = 409.2 (M+H)⁺

Example 17. ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-hydroxypyrrolidin-1-yl)methanone

The title compound as solid (1.80 mg) was prepared in the same fashion as step 2 in Example 13 except that 3-pyrrolidinol (3.43 mg, 0.04 mmol) was used instead of pyrrolidine. ¹H-NMR (CD₃OD, 400 MHz) δ 8.33(s, 1H), 8.29 (d, 1H), 8.11 (s, 2H), 8.03 (s, 1H), 8.01 (s, 1H), 6.73 (d, 1H), 4.66 (t, 1H), 4.45 (s, 1H), 4.25-4.22 (m, 2H), 3.83-3.49 (m, 8H), 2.20-2.00 (m, 4H), 1.42 (d, 3H); MS (ESI) m/z = 451.2 (M+H)⁺

Example 18. ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone

The title compound as solid (3.50 mg) was prepared in the same fashion as step 2 in Example 13 except that pyrrolidin-3-ylmethanol (3.98 mg, 0.04 mmol) was used instead of pyrrolidine. ¹H-NMR (CD₃OD, 400 MHz) δ 8.32 (s, 1H), 8.28 (d, 1H), 8.13 (s, 2H), 8.02 (s, 1H), 8.00 (s, 1H), 6.72 (d, 1H), 4.69 (t, 1H), 4.24-4.22 (m, 2H), 3.81 (s, 3H), 3.77-3.41 (m, 6H), 2.47 (s, 1H), 2.24-2.08 (m, 3H), 1.81-1.76 (m, 1H), 1.41 (d, 3H); MS (ESI) m/z = 465.2 (M+H)⁺

Example 19. Methyl (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

Step 1. Methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate

The reaction mixture of methyl-4,6-Dichloronicotinate (1000 mg, 4.854 mmol), (R)-4-aminobutan-2-ol (562.45 mg, 6.31 mmol), DIPEA (2.11 mL, 12.134 mmol) in DMA (16.18 mL) was stirred at　90 ^oC for 4 hours. The reaction mixture was cooled to room temperature, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex = 0-40%) to yield methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate (1010 mg, 3.904 mmol, 80.44 % yield) as pale yellow solid. MS (ESI) m/z = 259.0 (M + H)⁺

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

The suspension of tris(dibenzylideneacetone)dipalladium(0) (54.07 mg, 0.059 mmol), XPhos (56.3 mg, 0.118 mmol), cesium carbonate (384.77 mg, 1.181 mmol) and methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate (50 mg, 0.209 mmol) prepared in step 2 in 1,4-dioxane (1.0 mL) was stirred at 90 ^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 0.5hr(room temperature) and then filtered to yield methyl (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (64 mg, 0.162 mmol, 41.12% yield) as pale yellow solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.65 (s, 1H), 8.50 (t, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.68 (brs, 1H), 6.39 (d, 1H), 5.48-5.41 (m, 1H), 4.07-4.00 (m, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.59-3.49 (m, 1H), 2.31-2.22 (m, 1H), 1.95-1.89 (m, 1H), 1.12 (d, 3H); MS (ESI) m/z = 396.0 (M + H)⁺

Example 20. Methyl 1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

Step 1. Methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate

The title compound as a white solid (1166 mg) was prepared in the same fashion as step 1 in Example 19 except that 3-amino-2,2-dimethylpropan-1-ol (650.91 mg, 6.31 mmol) was used instead of (R)-4-aminobutan-2-ol. ¹H-NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 8.46 (s, 1H), 6.64 (s, 1H), 3.91 (s, 3H), 3.51 (d, 2H), 3.13 (d, 2H), 1.83 (t, 1H), 1.05 (s, 6H).

The title compound as a white solid (382 mg) was prepared in the same fashion as step 2 in Reference Example 2 except that methyl 6-chloro-4-((3-hydroxy-2,2-dimethylpropyl)amino)nicotinate (713.24 mg, 2.615mmol) prepared in step 1 was used instead of methyl (R)-6-chloro-4-((3-hydroxybutyl)amino)nicotinate. ¹H-NMR (CDCl₃, 400 MHz) δ 8.69 (s, 1H), 8.51 (s, 1H), 8.19 (d, 1H), 7.99 (s, 1H), 6.66 (s, 1H), 6.21 (d, 1H), 4.83 (s, 2H), 4.22 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.34 (d, 2H), 1.23 (s, 6H).

The title compound as a white solid (49 mg) was prepared in the same fashion as step 3 in Example 19 except that methyl 4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)-2,2-dimethylpropyl)amino)-6-chloronicotinate (380 mg, 0.852 mmol) prepared in step 2 was used instead of methyl (S)-4-((3-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butyl)amino)-6-chloronicotinate.¹H-NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 8.48 (t, 1H), 8.37 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 6.39 (d, 1H), 4.79 (brs, 1H), 4.21 (brs, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.54 (brs, 1H), 2.94 (brs, 1H), 1.41 (brs, 3H), 1.00 (brs, 3H); MS (ESI) m/z = 410.0 (M + H)⁺

Example 21. ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone

The reaction mixture of (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (30 mg, 0.0079 mmol) prepared in Reference Example 1, HATU (59.82 mg, 0.157 mmol) and DIPEA (30.5 mg, 0.236 mmol) in DMF (1 mL) was stirred at room temperature for 20 minutes, and then (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71mg, 0.079 mmol)　　was added.　The reaction mixture was stirred at　80　^oC　for　2 hours.　The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex = 0-100%) to yield ((S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (7.2 mg, 0.014 mmol, 24% yield) as an off-white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 9.93 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 8.00 (brs, 1H), 7.92 (s, 1H), 6.80 (d, 1H), 4.79 (brs, 1H), 4.51-4.46 (m, 1H), 4.34-4.30 (m, 3H), 4.02-3.96 (m, 1H), 3.78 (s, 3H), 3.65-3.59 (m, 1H), 3.48-3.44 (m, 1H), 3.00 (s, 3H), 2.16-1.95 (m, 1H), 1.35 (d, 3H), 1.31 (d, 3H); MS (ESI) m/z = 526.9 (M + H)⁺

Example 22. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methanone

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

Example 23. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-fluoro-2-azaspiro[3.3]heptan-2-yl)methanone

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

Example 24. (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (29 mg) was prepared in the same fashion as Example 21 except that 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (24.66 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.45 (s, 1H), 8.32 (s, 1H), 8.31 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 6.38 (d, 1H), 5.89 (tt, 1H), 4.78-4.73 (m, 1H), 4.47 (brs, 2H), 4.27-4.22 (m, 1H), 4.10-4.06 (m, 3H), 3.81 (s, 3H), 3.03-2.97 (m, 1H), 2.30-2.15 (m, 4H), 1.46 (d, 3H); MS (ESI) m/z = 485.0 (M + H)⁺

Example 25. (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (27 mg) was prepared in the same fashion as Example 21 except that 3-(2,2-difluoropropyl)azetidine hydrochloride (18 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.52 (s, 1H), 8.32 (s, 1H), 8.31 (d, 1H), 8.24 (d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 6.38 (d, 1H), 4.79-4.73 (m, 1H), 4.47 (brs, 2H), 4.28-4.21 (m, 1H), 4.10-4.06 (m, 3H), 3.81 (s, 3H), 3.09-3.02 (m, 1H), 2.29-2.15 (m, 4H), 1.63 (t, 3H), 1.46 (d, 3H); MS (ESI) m/z = 498.9 (M + H)⁺

Example 26. (S)-(3-(2,2-Difluoroethyl)-3-methylazetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (28 mg) was prepared in the same fashion as Example 21 except that 3-(2,2-difluoroethyl)-3-methylazetidine hydrochloride (18 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.40 (s, 1H), 8.32 (s, 1H), 8.31 (d, 1H), 8.25 (d, 1H),8.14 (s, 1H), 8.06 (s, 1H), 6.38 (d, 1H), 5.94 (tt, 1H), 4.76 (td, 1H), 4.28-4.01 (m, 6H), 3.81 (s, 3H), 2.27-2.14 (m, 4H), 1.47 (s, 3H), 1.46 (d, 3H); MS (ESI) m/z = 498.9 (M + H)⁺

Example 27. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2-fluoropropan-2-yl)azetidin-1-yl)methanone

The title compound as an off-white solid (24 mg) was prepared in the same fashion as Example 21 except that 3-(2-fluoropropan-2-yl)azetidine hydrochloride (16.11 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 8.32 (s, 1H), 8.18 (d, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 6.38 (d, 1H), 4.77 (td, 1H), 4.27-4.21 (m, 5H), 4.11-4.06 (m, 1H), 3.82 (s, 3H), 2.87-2.73 (m, 1H), 2.22-2.11 (m, 2H), 1.46 (d, 3H), 1.39 (s, 3H), 1.33 (s, 3H); MS (ESI) m/z = 481.0 (M + H)⁺

Example 28. (S)-N-(2-(3-Fluoroazetidin-1-yl)ethyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as a pale yellow solid (6.3 mg) was prepared in the same fashion as Example 21 except that 2-(3-fluoroazetidin-1-yl)ethan-1-amine (12.39 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.43 (d, 1H), 8.35 (d, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.64 (s, 1H), 6.71 (t, 1H), 6.38 (d, 1H), 5.25-5.05 (m, 1H), 4.74-4.69 (m, 1H), 4.26-4.20 (m, 1H), 4.07-4.03 (m, 1H), 3.81 (s, 3H), 3.79-70 (m, 2H), 3.45-3.40 (m, 2H), 3.31-3.22 (m, 2H), 2.81-2.74 (m, 2H), 2.15-2.11 (m, 2H), 1.46 (d, 3H); MS (ESI) m/z = 481.9 (M + H)⁺

Example 29. (S)-N-(2-(3,3-Difluoroazetidin-1-yl)ethyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as a pale yellow solid (8.8 mg) was prepared in the same fashion as Example 21 except that 2-(3,3-difluoroazetidin-1-yl)ethan-1-amine (14.28 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.42 (d, 1H), 8.34 (d, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 6.72 (t, 1H), 6.37 (d, 1H), 4.75-4.69 (m, 1H), 4.27-4.20 (m, 1H), 4.08-4.03 (m, 1H), 3.80 (s, 3H), 3.70 (t, 4H), 3.45 (q, 2H), 2.85 (brs, 2H), 2.15-2.11 (m, 2H), 1.45 (d, 3H); MS (ESI) m/z = 500.0 (M + H)⁺

Example 30. (S)-N,1¹,6-Trimethyl-N-((1-methylazetidin-3-yl)methyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

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

Example 31. (S)-N-(4-(Dimethylamino)butyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as a pale yellow solid (6.5 mg) was prepared in the same fashion as Example 21 except that N ¹, N ¹-dimethylbutane-1,4-diamine (9.14 mg, 0.079 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.67 (d, 1H), 8.34 (d, 1H), 8.28 (s, 1H), 8.20-8.14 (m, 3H), 7.47 (brs, 1H), 6.37 (d, 1H), 4.79-4.74 (m, 1H), 4.27-4.21 (m, 1H), 4.11-4.06 (m, 1H), 3.82 (s, 3H), 3.41 (q, 2H), 2.36 (t, 2H), 2.25 (s, 6H), 2.17-2.14 (m, 2H), 2.07-2.02 (m, 1H), 1.69-1.63 (m, 3H), 1.47 (d, 3H); MS (ESI) m/z = 480.9 (M + H)⁺

Example 32. (S)-N-(3-(Dimethylamino)propyl)-N,1¹,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as a pale yellow solid (19 mg) was prepared in the same fashion as Example 21 except that N ¹,N ¹,N ³-trimethylpropane-1,3-diamine (12.19 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.37 (s, 1H), 8.33 (d, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 6.38 (d, 1H), 6.31 (d, 1H), 4.80-4.74 (m, 1H), 4.27-4.20 (m, 1H), 4.11-4.06 (m, 1H), 3.81 (s, 3H), 3.60-3.52 (m, 2H), 3.13 (s, 3H), 2.31-2.27 (m, 2H), 2.23 (s, 6H), 2.17-2.13 (m, 2H), 1.86-1.81 (m, 2H), 1.42 (d, 3H); MS (ESI) m/z = 480.0 (M + H)⁺

Example 33. (S)-N-(3-(Dimethylamino)-2,2-dimethylpropyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as a pale yellow solid (33 mg) was prepared in the same fashion as Example 21 except that N ¹,N ¹,2,2-tetramethylpropane-1,3-diamine (13.66 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 9.47 (s, 1H), 8.99 (d, 1H), 8.33 (d, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 6.37 (d, 1H), 4.81-4.75 (m, 1H), 4.29-4.23 (m, 1H), 4.10-4.06 (m, 1H), 3.82 (s, 3H), 3.33 (d, 2H), 2.39 (s, 8H), 2.19-2.15 (m, 2H), 1.47 (d, 3H), 1.02 (s, 6H); MS (ESI) m/z = 494.0 (M + H)⁺

Example 34. (S)-1¹,6-Dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

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

Example 35. (S)-1¹,6-Dimethyl-N-(2-morpholinoethyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

The title compound as a pale yellow solid (25.5 mg) was prepared in the same fashion as Example 21 except that 2-morpholinoethan-1-amine (13.65 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.50 (d, 1H), 8.35 (d, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.77 (s, 1H), 6.78 (s, 1H), 6.37 (d, 1H), 4.77-4.71 (m, 1H), 4.28-4.22 (m, 1H), 4.09-4.05 (m, 1H), 3.81 (s, 3H), 3.74 (t, 4H), 3.52 (q, 2H), 2.63 (t, 2H), 2.53 (brs, 4H), 2.15 (q, 2H), 1.46 (d, 3H); MS (ESI) m/z = 495.0 (M + H)⁺

Example 36. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)methanone

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

Example 37. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)methanone

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

Example 38. (S)-N-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide

The title compound as a pale yellow solid (2.4 mg) was prepared in the same fashion as Example 21 except that N-(azetidin-3-yl)-N-methylmethanesulfonamide (17.22 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.37-8.33 (m, 2H), 8.15 (d, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.56 (s, 1H), 6.39 (d, 1H), 4.78-4.71 (m, 2H), 4.54-4.38 (m, 4H), 4.29-4.23 (m, 1H), 4.12-4.08 (m, 1H), 3.82 (s, 3H), 3.01 (s, 3H), 2.85 (s, 3H), 2.19-2.14 (m, 2H), 1.47 (s, 3H); MS (ESI) m/z = 528.2 (M + H)⁺

Example 39. (S)-(3-(Difluoromethoxy)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as a pale yellow solid (38 mg) was prepared in the same fashion as Example 21 except that 3-(difluoromethoxy)azetidine hydrochloride (16.73 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.58 (s, 1H), 6.38 (d, 1H), 6.30 (t, 1H), 5.10-5.04 (m, 1H), 4.78-4.73 (m, 1H), 4.58 (q, 2H), 4.34 (brs, 2H), 4.29-4.22 (m, 1H), 4.12-4.07 (m, 1H), 3.82 (s, 3H), 2.20-2.14 (m, 2H), 1.47 (d, 3H); MS (ESI) m/z = 486.9 (M + H)⁺

Example 40. (S)-(6-(Difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as a pale yellow solid (40.7 mg) was prepared in the same fashion as Example 21 except that 6-(difluoromethyl)-2-azaspiro[3.3]heptane hydrochloride (19.26 mg, 0.105 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 8.31 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 6.38 (d, 1H), 5.80 (td, 1H), 4.76 (td, 1H), 4.33-4.22 (brs, 5H), 4.09 (dt, 1H), 3.82 (s, 3H), 2.71-2.60 (m, 1H), 2.43-2.31 (m, 4H), 2.19-2.14 (m, 2H), 1.46 (d, 3H); MS (ESI) m/z = 510.9 (M + H)⁺

Example 41. (S)-1-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-3-methylbutan-2-one

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

Example 42. (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone

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

Example 43. ((S)-1¹,8-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone

The reaction mixture of (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (30 mg, 0.079 mmol) prepared in Reference Example 2, HATU (59.82 mg, 0.157 mmol) and DIPEA (30.5 mg, 0.236 mmol) in DMF (1 mL) was stirred at room temperature for 20 minutes, and then (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (15.71mg, 0.079 mmol)　　was added.　The reaction mixture was stirred at　80　^oC　for　2 hours.　The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex = 0-100%) to yield ((S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (20.4 mg, 0.039 mmol, 49.25 % yield) as an off-white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.36-8.31 (m, 3H), 8.24 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 6.37 (d, 1H), 5.45-5.42 (m, 1H), 4.99-4.92 (m, 1H), 4.46-4.35 (m, 2H), 4.03-3.95 (m, 1H), 3.75 (s, 3H), 3.48-3.31 (m, 4H), 2.99 (s, 3H), 2.27-2.19 (m, 1H), 1.97-1.1.91 (m, 1H), 1.45 (d, 3H), 1.11 (d, 3H); MS (ESI) m/z = 526.9 (M + H)⁺

Example 44. (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (13.1 mg) was prepared in the same fashion as Example 43 except that 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (9.25 mg, 0.039 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.42 (t, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 6.37 (d, 1H), 5.89 (tt, 1H), 5.44-5.37 (m, 1H), 4.48-4.46 (m, 2H), 4.05-3.94 (m, 2H), 3.76 (s, 3H), 3.51-3.45 (m, 1H), 3.04-2.97 (m, 1H), 2.31-2.20 (m, 3H), 1.96-1.90 (m, 1H), 1.11 (d, 3H); MS (ESI) m/z = 484.9 (M + H)⁺

Example 45. (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (13.4 mg) was prepared in the same fashion as Example 43 except that 3-(2,2-difluoropropyl)azetidine hydrochloride (6.75 mg, 0.039 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.42 (t, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 6.37 (d, 1H), 5.45-5.37 (m, 1H), 4.46 (brs, 2H), 4.02-3.94 (m, 3H), 3.76 (s, 3H), 3.51-3.44 (m, 1H), 3.09-3.02 (m, 1H), 2.29-2.19 (m, 3H), 1.96-1.90 (m, 1H), 1.63 (t, 3H), 1.11 (d, 3H); MS (ESI) m/z = 498.9 (M + H)⁺

Example 46. ((2R,3R)-2-Methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The reaction mixture of 1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (20 mg, 0.051 mmol) prepared in Reference Example 3, HATU (38.46 mg, 0.101 mmol) and DIPEA (19.61 mg, 0.152 mmol) in DMF (1 mL) was stirred at room temperature for 20 minutes, and then (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride (10.1mg, 0.051 mmol)　　was added.　The reaction mixture was stirred at　80　^oC　for　2 hours.　The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex = 0-100%) to yield ((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone (18.7 mg, 0.035 mmol, 68.39 % yield) as an off-white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.34-8.28 (m, 3H), 8.15 (s, 1H), 8.02 (s, 1H), 7.85 (brs, 1H), 6.37 (d, 1H), 4.97-4.90 (m, 1H), 4.77 (brs, 1H), 4.45-4.34 (m, 2H), 4.13 (brs, 1H), 3.83 (s, 3H), 3.51 (brs, 1H), 3.40-3.3.27 (m, 3H), 2.97 (s, 3H), 2.85 (brs, 1H), 1.43 (d, 3H), 1.35 (brs, 3H), 1.00 (brs, 3H); MS (ESI) m/z = 540.9 (M + H)⁺

Example 47. (3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (7.8 mg) was prepared in the same fashion as Example 46 except that 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (8.92 mg, 0.038 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.46 (t, 1H), 8.36 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.42 (s, 1H), 6.38 (d, 1H), 5.90 (tt, 1H), 4.77 (brs, 1H), 4.48 (brs, 2H), 4.13 (brs, 1H), 4.05 (brs, 2H), 3.86 (s, 3H), 3.54 (brs, 1H), 3.05-2.98 (m, 1H), 2.91 (brs, 1H), 2.31-2.20 (m, 2H), 1.37 (brs, 3H), 1.01 (brs, 3H); MS (ESI) m/z = 498.9 (M + H)⁺

Example 48. (3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

The title compound as an off-white solid (6.9 mg) was prepared in the same fashion as Example 46 except that 3-(2,2-difluoropropyl)azetidine hydrochloride (6.51 mg, 0.038 mmol) was used instead of (2R,3R)-2-methyl-3-(methylsulfonylmethyl)azetidine hydrochloride. ¹H-NMR (CDCl₃, 400 MHz) δ 8.46 (t, 1H), 8.36 (d, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.43 (s, 1H), 6.38 (d, 1H), 4.78 (brs, 1H), 4.47 (brs, 2H), 4.14 (brs, 1H), 4.03 (brs, 2H), 3.86 (s, 3H), 3.53 (brs, 1H), 3.10-3.03 (m, 1H), 2.90 (brs, 1H), 2.30-2.20 (m, 2H), 1.64 (t, 3H), 1.37 (brs, 3H), 1.01 (brs, 3H); MS (ESI) m/z = 512.9 (M + H)⁺

Example 49. (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(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)methanone

Step 1. Methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)amino)nicotinate

The title compound as an off-white solid (927 mg) was prepared in the same fashion as step 1 in Reference Example 1 except that methyl-4,6-dichloronicotinate (1000 mg, 4.854 mmol) prepared in step1 was used instead of ethyl-4,6-dichloronicotinate. MS (ESI) m/z = 258.9 (M + H)+

Step 2. Methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate

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

Step 3. Methyl (S)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

The title compound as an off-white solid (927 mg) was prepared in the same fashion as step 3 in Reference Example 1 except that methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate (290 mg, 0.65 mmol) prepared in step 2 was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate. MS (ESI) m/z = 410.0 (M + H)+

Step 4. (S)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

The title compound as an off-white solid (42 mg) was prepared in the same fashion as step 4 in Reference Example 1 except that methyl (S)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (55 mg, 0.134 mmol) prepared in step 3 was used instead of ethyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate. MS (ESI) m/z = 396.0 (M + H)+

Step 5. (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(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)methanone

The reaction mixture of (S)-1¹,1^3,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (20 mg, 0.051 mmol) prepared in step 4, HATU (38.46 mg, 0.101 mmol) and N,N-Diisopropylethylamine (19.61 mg, 0.152 mmol) in DMF (1 mL) was stirred at rt for 20 min, and then 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate (11.89 mg, 0.051 mmol)　　was added.　The reaction mixture was stirred at　80　^oC　for　2 hours.　The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex=0-100%) to yield (S)-(3-(2,2-difluoroethyl)azetidin-1-yl)(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)methanone (10 mg, 0.02 mmol, 39.66 %) as an off-white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.38 (d, 1H), 8.24 (s, 1H), 8.23 (d, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 6.36 (d, 1H), 5.89 (tt, 1H), 4.76 (t, 1H), 4.48 (brs, 2H), 4.26-4.20 (m, 1H), 4.03-3.99 (m, 3H), 3.75 (s, 3H), 3.04-2.97 (m, 1H), 2.59 (s, 3H), 2.31-2.18 (m, 3H), 2.12-2.09 (m, 1H), 1.45 (d, 3H); MS (ESI) m/z = 499.0 (M + H)+

Example 50. (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(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)methanone

The title compound as an off-white solid (12.9 mg) was prepared in the same fashion as Example 49 except that 3-(2,2-difluoropropyl)azetidine hydrochloride (8.68mg, 0.051 mmol) was used instead of 3-(2,2-difluoroethyl)azetidine 2,2,2-trifluoroacetate. ¹H-NMR (CDCl₃, 400 MHz) δ 8.38 (d, 1H), 8.25 (d, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.77-7.70 (m, 1H), 6.36 (d, 1H), 4.77 (t, 1H), 4.47 (brs, 2H), 4.25-4.20 (m, 1H), 4.03-3.99 (m, 3H), 3.75 (s, 3H), 3.09-3.02 (m, 1H), 2.59 (s, 3H), 2.30-2.18 (m, 3H), 2.12-2.07 (m, 1H), 1.63 (t, 3H), 1.45 (d, 3H); MS (ESI) m/z = 513.0 (M + H)⁺

Example 51. (S)-(3-(Difluoromethoxy)azetidin-1-yl)(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)methanone

Step 1. (6-Chloro-4-fluoropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone

The reaction mixture of 4,6-dichloronicotinic acid (150 mg, 0.0781 mmol), HATU (594.12 mg, 1.562 mmol) and DIPEA (0.41 mL, 2.344 mmol) in DMF (1.57 mL) was stirred at room temperature for 20 minutes, and then 3-(difluoromethoxy)azetidine hydrochloride (124.66 mg, 0.781 mmol)　　was added.　The reaction mixture was stirred at　80　^oC　for　2 hours.　The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (EA/n-Hex = 0-60%) to yield (6-Chloro-4-fluoropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone (58 mg, 0.195 mmol, 24.99 % yield) as yellow liquid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.39 (s, 1H), 7.45 (s, 1H), 6.27 (t, 1H), 5.10-5.04 (m, 1H), 4.55-4.51 (m, 1H), 4.28-4.23 (m, 2H), 4.12-4.09 (m, 1H).

Step 2. (S)-(6-Chloro-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone

The title compound as an off-white solid (39 mg) was prepared in the same fashion as step 1 in Reference Example 1 except that (6-Chloro-4-fluoropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone (56 mg, 0.188 mmol) prepared in step 1 was used instead of 4,6-dichloronicotinate. MS (ESI) m/z = 349.9 (M + H)⁺

Step 3. (S)-(4-((4-((4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone

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

Step 4. (S)-(3-(Difluoromethoxy)azetidin-1-yl)(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)methanone

The title compound as an off-white solid (14.6 mg) was prepared in the same fashion as step 3 in Reference Example 1 except that (S)-(4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)(3-(difluoromethoxy)azetidin-1-yl)methanone (40 mg, 0.074 mmol) prepared in step 3 was used instead of (S)-ethyl 4-((4-((4-(4-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloronicotinate. ¹H-NMR (CDCl₃, 400 MHz) δ 8.39 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 6.36 (d, 1H), 6.30 (t, 1H), 5.09-5.04 (m, 1H), 4.76 (t, 1H), 4.61-4.54 (m, 2H), 4.34 (brs, 2H), 4.26-4.21 (m, 1H), 4.04-4.00 (m, 1H), 3.75 (s, 3H), 2.60 (s, 3H), 2.26-2.03 (m, 2H), 1.45 (d, 3H); MS (ESI) m/z = 500.9 (M + H)⁺

Example 52. (S)-N-(2,2-Difluoroethyl)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

Step 1. 4-Amino-6-chloro-N-(2,2-difluoroethyl)nicotinamide

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

Step 2. (S)-6-Chloro-N-(2,2-difluoroethyl)-4-((4-hydroxybutan-2-yl)amino)nicotinamide

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

Step 3. (S)-4-((4-((4-(4-Aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)amino)-6-chloro-N-(2,2-difluoroethyl)nicotinamide

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

Step 4. (S)-N-(2,2-Difluoroethyl)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide

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

Example 53. (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

Step 1. (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol

To the solution of (3R)-butane-1,3-diol (10.0 g, 110.96 mmol) and imidazole (9.8 g, 144.25 mmol) in DCM (100 mL) was added tert-butyldimethylchlorosilane (18.4 g, 122.06 mmol) at 0^oC and the reaction mixture was stirred overnight while being slowly warmed to room temperature. The reaction mixture was diluted in DCM and washed by sat. brine. The organic layer was collected, dried over MgSO₄, and then concentrated. The crude product was then purified by column chromatography (EA/n-Hex=0-40%) to yield (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol

(21.25 g, 103.97 mmol, 93.7% yield) as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) δ 4.07-4.03 (m, 1H), 3.93-3.89 (m, 1H), 3.87-3.83 (m, 1H), 3.39 (s, OH), 1.68-1.66 (m, 2H), 1.22 (d, 3H), 0.93 (s, 9H), 0.11 (s, 6H)

Step 2. methyl (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-chloronicotinate

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

Step 3. methyl (S)-6-chloro-4-((4-hydroxybutan-2-yl)oxy)nicotinate

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

Step 4. methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)oxy)-6-chloronicotinate

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

Step 5. methyl (S)-1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate

To a solution of methyl (S)-4-((4-((4-(4-aminopyrimidin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)butan-2-yl)oxy)-6-chloronicotinate (587 mg, 1.31 mmol) prepared in Step 4 in 1,4-dioxane (6 mL) were added tris(dibenzylideneacetone)dipalladium(0) (241 mg, 0.26 mmol), XPhos (250 mg, 0.53 mmol) and cesium carbonate (1.3 g, 3.94 mmol). The reaction mixture was stirred at 120 ℃ for 2 hours. The reaction mixture was diluted in DCM, filtered through celite, and then concentrated. The crude residue was purified by silica gel column chromatography (EA/n-Hex=40-100%) and triturated by EA/isopropyl ether to yield methyl (S)-1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (168 mg, 0.41 mmol, 31.2% yield) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.77 (s, 1H), 8.70 (s, 1H), 8.44 (d, 1H), 7.51 (s, 1H), 6.41 (d, 1H), 5.18-5.20 (m, 1H), 4.77 (t, 1H), 4.08-4.06 (m, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 2.61 (s, 3H), 2.40-2.30 (m, 2H), 1.58 (d, 3H); MS (ESI) m/z = 411.2 (M + H)⁺

Step 6. (S)-1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid

To a solution of methyl (S)-1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate (55 mg, 0.13 mmol) prepared in Step 5 in THF (2 mL), water (0.5 mL) and methanol (0.5 mL) was added 3N NaOH (447.8 uL, 1.34 mmol). The reaction mixture was stirred at 60 ℃ for 4 hours. The reaction mixture was cooled, concentrated, dissolved in water and acidified by 9N HCl to pH1-2 and stirred for 30 minutes. The resulting solid was filtered and dried in vacuo to yield (S)-1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (35 mg, 0.09 mmol, 72.7% yield) as a pale yellow solid. ¹H-NMR (DMSO-d ₆, 400 MHz) δ 10.5 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.40 (d, 1H), 6.84 (d, 1H), 5.01-4.99 (m, 1H), 4.52 (m, 1H), 4.27-4.25 (m, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 2.25-2.24 (m, 2H), 1.46 (d, 3H); MS (ESI) m/z = 397.2 (M + H)⁺

Step 7. (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone

To a solution of (S)-1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylic acid (35 mg, 0.09 mmol) prepared in Step 6 in DMF (1 mL) was added HATU (67 mg, 0.18 mmol) and N,N-diisopropylethylamine (46.3 uL, 0.27 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then 3-(2,2-difluoropropyl)azetidine hydrochloride (15 mg, 0.09 mmol) was added. The reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was cooled, diluted in DCM, washed by water, dried over MgSO₄, and then concentrated. The crude product was purified by column chromatography (MeOH/EA=0-10%) and stirred in EA/n-Hex for 1 hour to give (S)-(3-(2,2-difluoropropyl)azetidin-1-yl)(1¹,1³,6-trimethyl-1¹ H-5,9-dioxa-3-aza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone (18.8 mg,0.04 mmol, 41.3% yield) as an off-white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.73 (s, 1H), 8.43 (d, 1H), 8.21 (d, 1H), 7.74 (s, 1H), 6.44 (d, 1H), 5.22-5.20 (m, 1H), 4.76 (t, 1H), 4.40-4.38 (m, 1H), 4.23-4.17 (m, 1H), 4.08-4.05 (m, 1H), 3.91-3.90 (m, 2H), 3.77 (s, 3H), 3.00-2.95 (m, 1H), 2.61 (s, 3H), 2.29-2.21 (m, 4H), 1.67-1.57 (m, 6H); MS (ESI) m/z = 514.2 (M + H)⁺

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 (Optiplate^TM 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 and 4 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

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 (Optiplate^TM 384, white, PerkinEImer; 6007290).

Table 5

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

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R₁is hydrogen or C_1-3alkyl,

R₂is selected from the group consisting of

C_1-6alkoxy;

C_3-6cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of OH and halogen;

3-7 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, C_1-6alkyl substituted with one or more halogens, C_1-6alkoxy, C_1-6alkoxy substituted with one or more halogens, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C_1-6alkylcarbonylmethyl, and mono or di-C_1-6alkylaminolmethyl; and

-NR₃R₄, wherein R₃ and R₄ are, independently each other, hydrogen, C_1-6alkyl optionally substituted with one or more halogens, mono or di-(C_1-6alkyl)amino-C_1-6alkyl, or 3-7 membered heterocyclyl-C_1-3alkyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-6alkyl, and

L is a linear or branched C_3-6alkylene.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁is hydrogen or methyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁is methyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R₂is C_1-6alkoxy; C_3-6cycloalkyl; 3-7 membered heterocyclyl optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, C_1-6alkyl substituted with one or more halogens, C_1-6alkoxy substituted with one or more halogens, methanesulfonylmethyl, N-methyl-methanesulfonylamino, dimethylaminosulfonylmethyl, C_1-6alkylcarbonylmethyl, and mono or di-C_1-6alkylaminolmethyl; or -NR₃R₄.
The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the 3-7 membered heterocyclyl is selected from the group consisiting of pyrrolidine, azetidine, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.3]hexane, 2,6-diazaspiro[3.4]octane, and 2,7-diazaspiro[3.5]nonane.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R₃ and R₄ are, independently each other, hydrogen, C_1-6alkyl, halo-C_1-6alkyl, or di-(C_1-6alkyl)amino-C_1-6alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R₃ is hydrogen or C_1-6alkyl and R₄ is 3-7 membered heterocyclyl-C_1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-6alkyl.
The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the 3-7 membered heterocyclyl-C_1-3alkyl is selected from the group consisting of azetidinyl-C_1-3alkyl, piperazinyl-C_1-3alkyl, morpholinyl-C_1-3alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is n-propylene, 1-methylpropylene, 3-methylpropylene, 2,2-dimethylpropylene, or n-butylene.
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)-Cyclopropyl(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(2) Cyclopropyl(1¹-methyl-1¹ H-10-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclodecaphane-4⁵-yl)methanone;

(3) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(4) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(5) (S)-1-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-N,N-dimethylmethanesulfonamide;

(6) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(7) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone;

(8) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

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

(10) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2,2,2-trifluoroethyl)azetidin-1-yl)methanone;

(11) Cyclopropyl(1¹-methyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(12) Methyl (S)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate;

(13) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(pyrrolidin-1-yl)methanone;

(14) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(15) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone;

(16) (S)-N,N,1¹,6-Tetramethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(17) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-hydroxypyrrolidin-1-yl)methanone;

(18) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone;

(19) Methyl (S)-1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate;

(20) Methyl 1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxylate;

(21) ((S)-1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(22) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methanone;

(23) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-fluoro-2-azaspiro[3.3]heptan-2-yl)methanone;

(24) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(25) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(26) (S)-(3-(2,2-Difluoroethyl)-3-methylazetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(27) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-(2-fluoropropan-2-yl)azetidin-1-yl)methanone;

(28) (S)-N-(2-(3-Fluoroazetidin-1-yl)ethyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(29) (S)-N-(2-(3,3-Difluoroazetidin-1-yl)ethyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(30) (S)-N,1¹,6-Trimethyl-N-((1-methylazetidin-3-yl)methyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(31) (S)-N-(4-(Dimethylamino)butyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(32) (S)-N-(3-(Dimethylamino)propyl)-N,1¹,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(33) (S)-N-(3-(Dimethylamino)-2,2-dimethylpropyl)-1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(34) (S)-1¹,6-Dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(35) (S)-1¹,6-Dimethyl-N-(2-morpholinoethyl)-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide;

(36) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)methanone;

(37) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)methanone;

(38) (S)-N-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-N-methylmethanesulfonamide;

(39) (S)-(3-(Difluoromethoxy)azetidin-1-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(40) (S)-(6-(Difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)(1¹,6-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(41) (S)-1-(1-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carbonyl)azetidin-3-yl)-3-methylbutan-2-one;

(42) (S)-(1¹,6-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone;

(43) ((S)-1¹,8-Dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)((2R,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)methanone;

(44) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(45) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,8-dimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(46) ((2R,3R)-2-Methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(47) (3-(2,2-Difluoroethyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(48) (3-(2,2-Difluoropropyl)azetidin-1-yl)(1¹,7,7-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-yl)methanone;

(49) (S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(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)methanone;

(50) (S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(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)methanone;

(51) (S)-(3-(Difluoromethoxy)azetidin-1-yl)(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)methanone; and

(52) (S)-N-(2,2-Difluoroethyl)-1¹,1³,6-trimethyl-1¹ H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4⁵-carboxamide.
(S)-(3-(2,2-Difluoroethyl)azetidin-1-yl)(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)methanone or a pharmaceutically acceptable salt thereof.
(S)-(3-(2,2-Difluoropropyl)azetidin-1-yl)(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)methanone or a pharmaceutically acceptable salt thereof.
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 12, or a pharmaceutically acceptable salt thereof.
The method of claim 13, wherein the protein kinase-mediated disease is cancer or immune disease.
The method of claim 14, 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.
The method of claim 14, wherein the cancer is lung cancer.
The method of claim 14, wherein the cancer is non-small cell lung cancer.
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 12, or a pharmaceutically acceptable salt thereof.
The method according to claim 18, 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.
The method according to claim 18, wherein the at least one mutant is at least one double mutant selected from the group consisting of EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/C797X (X=G, N), EGFR Del19/L792X (X=F, H, P, R, V, Y), EGFR Del19/L718X (X=Q, V), EGFR L858R/T790M, EGFR L858R/C797S, EGFR L858R/C797X (X=G, N), EGFR L858R/L792X (X=F, H, P, R, V, Y) and EGFR L858R/L718X (X=Q, V).
The method according to claim 18, wherein the at least one mutant is at least one double mutant selected from the group consisting of EGFR Del19/C797S and EGFR L858R/C797S.
The method according to claim 18, 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).
The method according to claim 18, wherein the at least one mutant is at least one triple mutant selected from the group consisting of EGFR Del19/T790M/C797S and EGFR L858R/T790M/C797S.
A pharmaceutical composition for treating a protein kinase-mediated disease, comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof as active ingredients.
The composition of claim 24, the protein kinase-mediated disease is cancer or immune disease.
The composition of claim 25, 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.
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 12, or a pharmaceutically acceptable salt thereof as active ingredients.