Field of the Invention The present invention relates to substituted furo[3,2-6]pyridines as inhibitors of various protein kinases, regulators or modulators, pharmaceutical compositions containing the compounds, and pharmaceutical use of the compounds and compositions in the treatment of the diseases such as, for example, cancer, inflammation, pain, neurodegenerative diseases or viral infections.

Background Art

Protein kinases are involved in regulation of practically all processes that are central to the growth, development, and homeostasis of eukaryotic cells. In addition, some protein kinases have an important role in oncogenesis and tumor progression and several kinase inhibitors are now approved for the treatment of cancer (D. J. Matthews and M. E. Gerritsen: Targeting protein kinases for cancer therapy, Wiley, 2010).

Examples of kinase inhibitors that are used in modern oncology include: imatinib (treatment of CML); dasatinib (CML with resistance to prior treatment, including imatinib); nilotinib (CML); bosutinib (CML); gefitinib (non-small cell lung cancer); erlotinib (non-small cell lung cancer and pancreatic cancer); lapatinib (breast cancer); sorafenib (metastatic renal cell carcinoma, hepatocellular cancer); vandetanib (metastatic medullary thyroid cancer); vemurafenib (inoperable or metastatic melanoma); crizotinib (non- small cell lung cancer); sunitinib (metastatic renal cell carcinoma, gastrointestinal stromal tumor that is not responding to imatinib, or pancreatic neuroendocrine tumors); pazopanib (renal cell carcinoma and advanced soft tissue sarcoma); regorafenib (metastatic colorectal cancer); cabozantinib (metastatic medullary thyroid cancer); dabrafenib (BRAF V600E mutation-positive advanced melanoma); and trametinib (in combination with dabrafenib for the treatment of BRAF V600E/K-mutant metastatic melanoma).

Various kinases are regarded as good targets for pharmacological inhibition in order to treat proliferative and/or neurodegenerative diseases. Biological and potential therapeutic significance of some selected kinases is briefly summarized below. The regulation of splice site usage provides a versatile mechanism for controlling gene expression and for the generation of proteome diversity, playing an essential role in many biological processes. The importance of alternative splicing is further illustrated by the increasing number of human diseases that have been attributed to mis-splicing events. Appropriate spatial and temporal generation of splicing variants demands that alternative splicing be subjected to extensive regulation, similar to transcriptional control. The CLK (Cdc2-like kinase) family has been implicated in splicing control {Experimental Cell Research 1998, 241, 300.). Pharmacological inhibition of CLKl/Sty results in blockage of SF2/ASF-dependent splicing of beta-globin pre-mRNA in vitro by suppression of CLK- mediated phosphorylation. It also suppresses dissociation of nuclear speckles as well as CLK1 /Sty-dependent alternative splicing in mammalian cells and was shown to rescue the embryonic defects induced by excessive CLK activity in Xenopus {Journal of Biological Chemistry 2004, 279, 24246.).

Alternative mRNA splicing is a mechanism to regulate protein isoform expression and is regulated by alternative splicing factors. The alternative splicing factor 45 (SPF45) is overexpressed in cancer and its overexpression enhances two processes that are important for metastasis, i.e. cell migration and invasion, dependent on biochemical regulation by CLK1 {Nucleic Acids Research 2013, 41, 4949.). CLK1 phosphorylates SPF45 on eight serine residues. CLK1 expression enhances, whereas CLK1 inhibition reduces, SPF45- induced exon 6 exclusion from Fas mRNA. Inhibition of CLK1 increases SPF45 degradation through a proteasome-dependent pathway. In addition, small-molecule inhibitors of specific CLKs can suppress HIV-1 gene expression and replication {Retrovirology 2011, 8, 47.), which could be used in concert with current drug combinations to achieve more efficient treatment of the infection. Inhibition of CLK1 can be applicable in the treatment of Alzmeimer's disease {Current Drug Targets 2014, 15, 539.).

DYRK (dual specifity tyrosine phosphorylation-regulated kinase) family enzymes are essential components of important signaling cascades in the pathophysiology of cancer and Alzheimer's disease and their biological expression levels regulate key signaling processes in these diseases. In particular, DYR 2 is over-expressed in adenocarcinomas of the esophagus and lung {Cancer Research 2003, 63, 4136.) and DYRK1A in glioblastoma where its inhibition compromised tumors' survival and produced a profound decrease in tumor burden {Journal of Clinical Investigation 2013, 123, 2475.). DYRKIB activation that is induced by microtubule damage triggers microtubule stabilization and promotes the mitochondrial translocation of p21Ci l/wafl to suppress apoptosis. Its inhibition caused reduced viability of cancer cells (ACS Chemical Biology 2014, 9, 731.). Correspondingly, it has been understood that inhibition of DYRK kinases alone or in combination with other chemotherapeutic drugs may have tumor suppression effect and the enzymes are therefore appropriate targets for pharmacological inhibition (Bioorganic & Medicinal Chemistry Letters 2013, 23, 6610.; Medicinal Chemistry Research 2014, 23, 1925.).

In addition, DYRK kinases are also over-expressed in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Pick disease (Neurobiology of Disease 2005, 20, 392.; Cellular and Molecular Life Sciences 2009, 66, 3235.).

HIPK2 (homeodomain-interacting protein kinase) is a tumor suppressor and functions as an evolutionary conserved regulator of signaling and gene expression. This kinase regulates a vast array of biological processes that range from the DNA damage response and apoptosis to hypoxia signaling and cell proliferation. Recent studies showed the tight control of HIPK2 by hierarchically occurring posttranslational modifications such as phosphorylation, small ubiquitin-like modifier modification, acetylation, and ubiquitination. Dysregulation of HIPK2 can result in increased proliferation of cell populations as it occurs in cancer or fibrosis. Inappropriate expression, modification, or localization of HIPK2 can be a driver for these proliferative diseases (Journal of Molecular Medicine 2013, 91, 1051.).

FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase (RTK), is a membrane- bound receptor with an intrinsic tyrosine kinase domain. Its activation regulates a number of cellular processes (e.g. phospholipid metabolism, transcription, proliferation, and apoptosis), and through these processes, FLT3 activation plays a critical role in governing normal hematopoiesis and cellular growth Expression of FLT3 has been evaluated in hematologic malignancies. The majority of B-cell acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) blasts (> 90%) express FLT3 at various levels (Clinical Cancer Research 2009, 15, 4263.). Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment (Oncologist 2011, 16, 1162.; PLoS One 2014, 9, e83160/1.; Leukemia Lymphoma 2014, 55, 243.). Tropomyosin-related kinase (TRK) is a family of three RTKs (TRK- A, TRK-B, TRK-C) regulating several signaling pathways that are important for survival and differentiation of neurons. TRK-A regulates proliferation and is important for development and maturation of the nervous system, promotes survival of cells from death. Point mutations, deletions and chromosomal rearrangements cause ligand-independent receptor dimerization and activation of TRK-A. In mutated version of TRK, abnormal function will render cells unable to undergo differentiation in response to ligand in their microenvironment, so they would continue to grow when they should differentiate, and survive when they should die. Activated TRK-A oncogenes have been associated with several human malignancies, e.g., breast, colon, prostate, thyroid carcinomas and AML {Cell Cycle 2005, 4, 8.; Cancer letters 2006, 232, 90.). In addition, inhibition of TRK can be relevant for the treatment of inflammation (PLoS One 2013, 8, e83380.) and pain (Expert Opinion on Therapeutic Patents 2009, 19, 305.).

In summary, there is a need for inhibitors of different protein kinases in order to treat or prevent disease states associated with abnormal regulation of the kinases-mediated biological processes.

Disclosure of the Invention The present invention provides substituted furo[3 ,2 -b] pyridine compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, and their use in the treatment, prevention, inhibition or amelioration of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions.

The present invention provides compounds represented by the structural formula (I):

or a pharmaceutically acceptable salt, solvate or a prodrug thereof, wherein: L ⁵ is selected from the group consisting of a bond, -N(R ^U )-;

L ² is selected from the group consisting of a bond, -0-; L ³ is selected from the group consisting of a bond, -N(R ^] ')-, -0-; L ⁶ is selected from the group consisting of a bond, -0-;

L ⁷ is selected from the group consisting of a bond, -N(R ⁿ )-;

R ⁵ is selected from the group consisting of Ci-C ₆ alkyl; aryl; heteroaryl; biaryl; bi(heteroaryl); cycloalkylaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl; cycloalkylheteroaryl; heterocyclylheteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted;

R ² is selected from the group consisting of H; -CF ₃ ; N¾; -CI; -Br; -F; C]-C ₆ alkyl;

R ³ is selected from the group consisting of H; C C ₆ alkyl; aryl; cycloalkyl; heteroaryl; biaryl; heteroarylaryl; arylheteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted; R ⁶ is selected from the group consisting of H; -CF3; NH ₂ ; -CI; -Br; -F; Ci-Ce alkyl; aryl; heteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted; R ⁷ is selected from the group consisting of H; Q-C6 alkyl; aryl; cycloalkyl; heteroaryl; biaryl; heteroarylaryl; arylheteroaryi; wherein each of the substituent moieties can be unsubstituted or optionally substituted;

R ¹¹ is selected from the group consisting of H, Ci-C ₆ alkyl; provided that the substituent in position 5 (L5-R5) is not oxadiazolyl or methyl- oxadiazolyl.

As used in this disclosure, the following terms, unless otherwise indicated, have the - following meanings:

"alkyl" means an aliphatic hydrocarbon group which may be straight or branched and contains 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms in the chain. Examples of suitable alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl. The alkyl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF ₃ , OCF ₃ , OR ⁹ , SR ⁹ , SOH, S0 ₂ H, S0 ₂ N(H, C1-C4 alkyl) _2} CHO, COO(H, C _r C ₄ alkyl), COH, C(0)N(H ₅ C1-C4 alkyl), 0(CH ₂ ) _p N(CH ₃ ) ₂ and NR ⁹ R ¹⁰ ;

"aryl" means an aromatic monocyclic or polycyclic ring system containing 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Examples of suitable aryls are phenyl, naphthyl. The aryl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF ₃ , OCF ₃ , OR ⁹ , SR ⁹ , SOH, S0 ₂ H, S0 ₂ N(H, C,-C ₄ alkyl) ₂ , CHO, COO(H, d-C ₄ alkyl), COH, C(0)N(H, C C ₄ alkyl), NR ⁹ R ¹⁰ , -(CR ⁹ R ¹⁰ ) _P R ^¾ , 0(CH ₂ ) _p N(CH ₃ ) ₂ and -(CR ⁹ R ¹⁰ ) _p OR ^9a ;

"cycloalkyl" means an aliphatic monocyclic or bicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 7 carbon atoms. Suitable examples include cyclopentyl, cyclohexyl, cycloheptyl, 1-decalinyl, norbornyl, adamantyl. The cycloalkyl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF ₃ , OCF ₃ , OR ⁹ , SR ⁹ , SOH, S0 ₂ H, S0 ₂ N(H, C 1 -C4 alkyl) ₂ , CHO, COO(H, C 1-C4 alkyl), COH, C(0)N(H ₅ d-C ₄ alkyl), NR ⁹ R ¹⁰ , -(CR ⁹ R ¹⁰ ) _p R ^9a ₅ 0(CH ₂ ) _p N(CH ₃ ) ₂ and - (CR ⁹ R ¹⁰ ) _p OR ^9a ;

"heterocyclyl" means an aliphatic monocyclic or bicyclic ring system containing 3 to 10 carbon atoms, preferably 4 to 8 carbon atoms, and at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Suitable examples include piperazinyl and morpholinyl. Preferably, heterocyclyl is not a bicyclic ring system containing only N heteroatoms. The heterocyclyl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF ₃ , OCF ₃ , OR ⁹ , SR ⁹ , SOH, S0 ₂ H, S0 ₂ N(H, C1 -C4 alkyl) ₂ , CHO, COO(H, C _r C ₄ alkyl), COH, C(0)N(H, Ci-C ₄ alkyl), NR ⁹ R ¹⁰ , -(CR ⁹ R ¹⁰ ) _p R ^9a , 0(CH ₂ ) _p N(CH ₃ ) ₂ and -(CR ⁹ R ¹⁰ ) _p OR ^9a ;

"heteroaryl" means an aromatic monocyclic or bicyclic ring system containing 1 to 14 carbon atoms, preferably 3 to 7 carbon atoms, most preferably 3 to 5 carbon atoms, and at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Examples of suitable heteroaryls are pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrrolyl, imidazolyl. Preferably, heteroaryl is not indolyl, indolinolyl or imidazopyridazinyl. The heteroaryl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF ₃ , OCF ₃ , OR ⁹ , SR ⁹ , SOH, S0 ₂ H, S0 ₂ N(H, C _r C ₄ alkyl) ₂ , CHO, COO(H, C1-C4 alkyl), COH, C(0)N(H, C C alkyl), NR ⁹ R ¹⁰ , -(CR ⁹ R ¹⁰ ) _p R ^9a , 0(CH ₂ ) _p N(CH ₃ ) ₂ and - (CR ⁹ R ^I0 ) _p OR ^9a ;

"biaryl" means an aryl-aryl- group in which each of the aryls is independently as previously described. An example is biphenyl;

"bi(heteroaryl)" means an heteroaryl-heteroaryl- group in which each of the heteroaryls is independently as previously described;

"cycloalkylaryl" means a cycloalkyl-aryl- group in which the cyclo alkyl and aryl are as previously described;

"heterocyclylaryl" means a heterocyclyl-aryl- group in which the heterocyclyl and aryl are as previously described; "heteroarylaryl" means a heteroaryl-aryl- group in which the heteroaryl and aryl are as previously described;

"arylheteroaryl" means a aryl-heteroaryl- group in which the aryl and heteroaryl are as previously described;

"cycloalkylheteroaryl" means a cycloalkyl-heteroaryl- group in which the heteroaryl and cycloalkyl are as previously described;

"heterocyclylheteroaryl" means a heterocyclyl-heteroaryl- group in which the heterocyclyl and heteroaryl are as previously described;

wherein

each of aryl, cycloalkyl, heterocyclyl, heteroaryl, biaryl, bi(heteroaryl), cycloalkylaryl, heterocyclylaryl, heteroarylaryl, arylheteroaryl, cycloalkylheteroaryl, and heterocyclylheteroaryl can be bound directly or via a methylene or ethylene spacer;

p is an integer in the range of from 1 to 7, more preferably from 1 to 5, even more preferably 1 to 3;

R ⁹ is H or C 1 -C6 alkyl, unsubstituted or optionally substituted by -OH, -NH ₂ , -N(CH ₃ ) ₂ ; R ^9a is H or C1-C6 alkyl, unsubstituted or optionally substituted by -OH, -NH ₂ , -N(CH ₃ ) ₂ ; R ¹⁰ is H or C1-C6 alkyl, unsubstituted or optionally substituted by -OH, -NH ₂ , -N(C¾) ₂ .

In a preferred embodiment, R is selected from the group consisting of aryl; heteroaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl; heterocyclylheteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F, CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH ₂ , N(CH ₃ ) ₂ , 0(CH2) _P N(CH ₃ ) ₂ . More preferably, R ⁵ is selected from the group consisting of aryl; heteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F, CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH ₂ , N(CH ₃ ) ₂ , 0(CH ₂ ) _p N(CH ₃ ) ₂ . Even more preferably, the heteroaryl in R ⁵ is pyrazolyl.

In a preferred embodiment, any of L 5, L 7 is independently selected from the group consisting of a bond, -NH-.

In another preferred embodiment, any of L ² , L ⁶ is a bond. In yet another preferred embodiment, L ³ is a bond or -0-.

In a preferred embodiment, R is selected from the group consisting of aryl; heteroaryl; biaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F, CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH ₂ , N(C¾) ₂ , 0(CH2) _P N(CH ₃ )2. Even more preferably, the aryl in R ³ is phenyl, naphthyl (e.g., 2-naphthyl) and the biaryl in R ³ is biphenyl (e.g., 3- biphenyl).

In a preferred embodiment, R ⁶ is selected from the group consisting of H; -CI; -Br; -F; - OH; -NH ₂ ; or methyl.

In a preferred embodiment, R ² is selected from the group consisting of H; -CI; -Br; -F; - OH; -N¾; or methyl.

In a preferred embodiment, R ⁷ is selected from the group consisting of H; Cj-Ce alkyl; aryl; heteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F _} CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, N¾, N(CH ₃ ) ₂ , 0(CH ₂ ) _P N(CH ₃ )2.

Preferably, at least one of R and R is not H when the corresponding L (i.e., L or L , respectively) is a bond.

In a preferred embodiment, -L ² -R ² , -L ⁶ -R ⁶ , -L ⁷ -R ⁷ are hydrogens and -L ^3, -R ³ is not hydrogen.

In one preferred embodiment, -L ² -R ² , -L ⁶ -R ⁶ , -L ⁷ -R ⁷ are hydrogens, -L ³ -R ³ is aryl or biaryl (optionally substituted) and -L ^s -R ⁵ is heteroaryl (optionally substituted).

In a preferred embodiment, any of aryl; cycloalkyl; heterocyclyl; heteroaryl; biaryl; bi(heteroaryl); cycloalkylaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl; cycloalkylheteroaryl; heterocyclylheteroaryl is unsubstituted or substituted with at least one substituent selected from the group consisting of NH ₂ , N(CH ₃ )2, OH, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert -butyl. In another preferred embodiment, any of -L ² -R ² , -L ³ -R ³ , -L ⁶ -R ⁶ , -L ⁷ -R ⁷ _, -L ⁵ -R ⁵ can be hydroxy(C C6)alkylamino, amino (C ₁ -C ₆ )alkylamino or dimethylamino(Ci-C ₆ )alkylamino.

Pharmaceutically acceptable salts are salts with acids or bases, or acid addition salts. The acids and bases can be inorganic or organic acids and bases commonly used in the art of formulation, such as hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartarate, gluconate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, primary, secondary and tertiary amides, ammonia. In general, the compounds described in this invention can be prepared through the general routes described below in Schemes 1-6.

Pd-catalyzed coupling of 6-chloro-2-iodopyridin-3-ol with vinyl boronates provides intermediate 1 (as shown in Scheme 1), whose copper-mediated closure provides the furopyridine system in intermediate 2. Subsequent Pd-catalyzed coupling of intermediate 2 with proper C-nucIeophiles leads to compounds 3 with R ⁵ substituent attached via C-C bond.

Scheme 1

1

Cu'

base, 0 ₂

3 2

= e.g., B(OR) ₂ , BF ₃ K, Sn(R) _3i MgX, ZnX Alternatively, intermediate 2 can be subjected to amination to yield amine-containing compounds 4 depicted in Scheme 2.

Scheme 2

Also, 5-chlorofuro[3,2- ]pyridine can be converted into iodide 5, which can be brominated to yield intermediate 6 (Scheme 3). Sequential chemoselective Pd-catalyzed couplings provide target compounds 3 where R and R are diferent aryls or heteroaryls (Scheme 3).

Scheme 3

Reaction of 6-chloro-2-iodopyridin-3-ol with trimethylsilyl acetylene gives the furopyridine intermediate 8, which can be subjected to a Pd-catalyzed coupling (e.g. Suzuki reaction) and subsequent N-oxidation followed by the treatment with POCl ₃ to yield chlorinated intermediate 10, as illustrated in Scheme 4. Scheme 4

The TMS group in 10 can be removed by KF in methanol to yield intermediate 11, which can be subjected to Pd-catalyzed C-C bond formation or animation (indicated in Scheme 5) to yield compounds 12 and 13, respectively.

Scheme 5

As depicted in Scheme 6, 6-chloro-2-iodopyridin-3-oI can be allylated to give intermediate 14, which can be cyclized to furopyridine intermediate 15, which upon Pd-catalyzed C-C bond formation or animation yields compounds 16 and 17, respectively. Scheme 6

Compounds 16 can be further elaborated (shown in Scheme 7) by N-oxidation-chlorination sequence to yield chlorinated intermediate 18, which can be subjected to Pd-catalyzed C-C bond formation or amination to yield compounds 19 and 20, respectively.

Scheme 7

In addition, iodination of 5-bromopyridin-3-ol provides intermediate 21, which can be converted into compound 22. Subsequent Pd-catalyzed coupling followed by N-oxidation and regioselective chlorination yield chloride 24 (Scheme 8). Scheme 8

Another Pd-catalyzed coupling on intermediate 24, followed by the by N-oxidation- chlorination sequence and another Pd-catalyzed coupling provide intermediate 26. Removal of the TMS group, followed by final Pd-catalyzed coupling provide target compounds 27 with substituents at positions 7- and 5, respectively (Scheme 9).

Scheme 9

The compounds of formula (I) can be useful as protein kinase inhibitors and can be useful in the treatment and prevention of proliferative diseases, e.g. cancer, inflammation and arthritis, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases, and fungal diseases. In one preferred embodiment, the protein kinase is not GSK3. In another preferred embodiment, the protein kinase is selected from CLK2, CLK4, HIPK1, HIPK2, HIPK3, FLT3, TRKA and DYRK2.

The present invention thus provides the compounds of formula (I) for use as medicaments. More specifically, it provides the compounds of formula (I) for use in the treatment and prevention of conditions selected from proliferative diseases, neurodegenerative diseases, cardiovascular diseases, pain, viral diseases, and fungal diseases.

The present invention also provides a method for treatment, inhibition, amelioration or prevention of a condition selected from proliferative diseases, neurodegenerative diseases, cardiovascular diseases, pain, viral diseases, and fungal diseases, in a patient suffering from such condition, comprising the step of administering at least one compound of formula (I) to said patient.

The present invention further includes pharmaceutical compositions comprising at least one compound of formula (I) and at least one pharmaceutically acceptable auxiliary compound. The auxiliary compounds may include, e.g., carriers, diluents, fillers, preservatives, stabilisers, binders, wetting agents, emulsifiers, buffers, etc. Suitable auxiliary compounds are well known to those skilled in the art of formulation. The pharmaceutical compositions are prepared by known methods, e.g., mixing, dissolving etc.

Examples of carrying out the Invention

Preparative Example 1 To a solution of (PhO) ₃ P (2.09 g; 6.75 mmol) in anhydrous CH ₂ C1 ₂ (10 mL) was added Br ₂ (0.380 mL; 7.38 mmol) dropwise under Ar atmosphere at -60 °C. Then triethylamine (1.10 mL; 7.89 mmol) and a solution of 2-acetonaphthone (1.03 g; 6.05 mmol) in anhydrous CH2CI2 (5 mL) were added. The resulting reaction mixture was stirred under Ar for 18 h, while warming to 25 °C, and then heated to reflux for additional 2 h. Then, the CH2CI2 and excess of triethylamine and Br ₂ were evaporated and the residue was purified by column chromatography on silica gel (eluent: hexane/CH ₂ Cl2 - 2:1). The product was obtained as a pale orange solid (0.947 g; 67 %).

^! H NMR (500 MHz, CDC1 ₃ ) δ 8.07 (d, J = 1.55 Hz, 1H); 7.87-7.77 (m, 3H); 7.69-7.66 (m, 1H); 7.52-7.46 (m, 2H); 6.25 (d, J= 2.10 Hz, 1H); 5.87 (d, J- 2.10 Hz, 1H).

¹³ C NMR (126 MHz, CDCI3) δ 135.9, 133.7, 133.2, 131.3, 128.8, 128.1, 127.8, 127.1, 126.9, 124.4, 118.2.

HRMS (APCI): calcd. for Ci ₂ H ₁₀ Br [M+H] ⁺ = 232.9960; found [M+H] ⁺ = 232.9958.

Preparative Example 2 A

A mixture of vinyl bromide from Preparative Example 1 (0.947 g; 4.06 mmol), bis(pinacolato)diboron (1.140 g; 4.49 mmol), PPh ₃ (0.066 g; 0.25 mmol), potassium phenolate (0.809 g; 6.12 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.089 g; 0.13 mmol) in anhydrous toluene (20 mL) was stirred under N ₂ at 50 °C for 24 h. The crude mixture was then cooled to 25 °C, poured into water (100 mL) and extracted with EtOAc (3x80 mL). The organic extracts were washed with brine (80 mL), dried over Na ₂ S0 _4j filtered, and the solvent was evaporated. The obtained oil was purified by column chromatography on silica gel (eluent: hexane/CH ₂ Cl ₂ - 2:1) to yield the product as a pale orange solid (0.460 g; 40 %).

1H NMR (500 MHz, CDC1 ₃ ) S 7.94 (s, lH); 7.84-7.75 (m, 3H); 7.61 (dd, J- 1.50 Hz, 8.54 Hz, 1H); 7.46-7.38 (m, 2H); 6.20 (d, J = 2.29 Hz, 1H); 6.14 (d, J= 2.73 Hz, 1H); 1.35 (s, 12H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 139.1, 133.8, 132.9, 131.4, 128.5, 127.8, 127.7, 126.4, 126.0, 125.8, 84.1, 25.1.

HRMS (APCI): calcd. for Ci ₈ H ₂₂ B0 ₂ [M+H]* = 281.1711; found [M+H] ⁺ = 281.1708.

Preparative Example 2B

A heatgun-dried round bottom flask containing Ni(dppp)Cl ₂ (0.251 g; 0.46 mmol) was flushed with N ₂ , anhydrous THF (24 mL) was added, followed by dropwise addition of DIBAL-H (1.0 M solution in heptane; 20 mL; 20 mmol) at 25 °C. The mixture was cooled to 0 °C and 4-ethynylanisole (2.0 mL; 15.4 mmol) was added slowly over 5 min. The resulting black solution was allowed to warm to 25 °C and stirred for additional 2 h. Then, 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (7.6 mL; 46.4 mmol) was added dropwise at 0 °C and the resulting reaction mixture was stirred under N ₂ at 80 °C for 15 h. The reaction was then quenched by dropwise addition of water (50 mL) at 0 °C, allowed to warm to 25 °C and stirred for additional 1 h. The mixture was poured into saturated aqueous solution of potassium sodium tartarate (200 mL) and extracted with Et ₂ 0 (3x150 mL). The extracts were washed with brine (200 mL), dried over MgS0 ₄ , filtered and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 10:1) to yield the product as a pale yellow solid (3.22 g; 80 %).

1H NMR (500 MHz, CDC1 ₃ ) 6 7.45-7.41 (m, 2H); 6.87-6.82 (m, 2H); 5.99 (d, J= 2.65 Hz, 1H); 5.94 (d, J= 2.82 Hz, 1H); 3.79 (s, 3H); 1.31 (s, 12H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 159.1, 134.2, 129.2, 128.5, 113.9, 84.0, 77.5, 77.2, 77.0, 55.5, 25.0.

HRMS (APCI): calcd. for C ₁₅ H ₂₂ B0 ₃ [M+H] ⁺ = 260.1693; found [M+H] ⁺ = 260.1696.

Preparative Example 2C By essentially same procedure set forth in Preparative Example 2B, using l-(tert-butyl)-4- ethynylbenzene, the compound given below was prepared.

White solid.

^! H NMR (500 MHz, CDC1 ₃ ) δ 7.44 (d, J= 8.5 Hz, 2H), 7.35 (d, J= 8.5 Hz, 2H), 6.08 (d, J = 2.8 Hz, 1H), 6.02 (d, J= 3.0 Hz, 1H), 1.36 - 1.30 (m, 21H).

¹³ C MR (126 MHz, CDC1 ₃ ) <S 150.0, 138.5, 130.2, 126.9, 125.2, 83.8, 34.6, 31.5, 25.0. HRMS (APCI): calcd. for C ₁₈ H ₂₇ B0 ₂ [M+Hf = 286.2213; found [M+H] ⁺ = 286.2213.

Preparative Example 3

To a stirred solution of 2-chloro-5-hydroxypyridine (6.0 g, 46.3 mmol) in H ₂ 0 (80 mL) were added Na ₂ C0 ₃ (10.3 g, 97.3 mmol) and I ₂ (11.8 g, 46.3 mmol). The resulting mixture was stirred at 25 °C under N ₂ for 2 h. Then it was neutralized by HC1 (1M, aprox. 50 mL) to pH=7 and extracted with EtOAc (3x110 mL). The organic extracts were washed with brine (150 mL), dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The product was obtained as a pale yellow solid (11.1 g, 94 %).

1H NMR (500 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H); 7.30 (d, J = 8.40 Hz, 1H); 7.18 (d, J = 8.40 Hz, 1H).

^I3 C NMR (126 MHz, DMSO-d ₆ ) S 153.9, 138.1, 124.0, 123.9, 107.7.

HRMS (APCI): calcd. for C ₅ H ₄ C1IN0 [M+H] ⁺ = 255.9021; found [M+H] ⁺ = 255.9018.

Preparative Example 4A

To a mixture of vinyl boronate from Preparative Example 2A (0.460 g; 1.64 mmol), pyridinol from Preparative Example 3 (0.349 g; 1.37 mmol), K3PO4 (1.196 g; 5.64 mmol) and PdCl ₂ .dppf (0.063 g; 0.068 mmol) were added under N ₂ 1 ,2-dimethoxyethane (8 mL) and water (2 mL). The resulting reaction mixture was refluxed for 15 h. Then it was cooled to 25 °C, poured into brine (80 mL) and extracted with CH ₂ CI ₂ (3x60 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ CI ₂ ) to yield the product as a pale yellow solid (0.105 g; 27 %).

^] H NMR (500 MHz, CDC1 ₃ ) δ 7.85-7.75 (m, 3H); 7.72 (d, J = 1.33 Hz, 1H) 7.52 (dd, J = 1.86 Hz, 8.57 Hz, 1H); 7.50-7.45 (m, 2H); 7..26-7.22 (m, 2H); 6.06 (s, 1H); 5.79 (s, 1H); 5.07 (s, 1H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 149.6, 145.6, 143.8, 142.3, 134.9, 133.7, 133.6, 129.1 , 128.7, 127.9, 127.4, 127.0, 126.9, 126.8, 125.0, 124.5, 120.9.

Preparative Example 4B

By essentially same procedure set forth in Preparative Example 4A, using 1 phenylvinylboronic acid pinacol ester instead of vinyl boronate from Preparative Exampl 2A, the compound given below was prepared.

1H NMR (500 MHz, CDCI ₃ ) δ 7.39-7.31 (m, 5H); 7.23-7.18 (m, 2H); 5.93 (d, J

1H); 5.71 (d, J= 0.68 Hz, 1H); 5.00 (brs, 1H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 149.5, 145.5, 143.8, 142.2, 137.6, 129.3, 129.3, 127.3, 127.2, 125.0, 120.1.

HRMS (APCI): calcd. for C ₁₃ H _U C1N0 [M+H] ⁺ = 232.0524; found [M+H] ⁺ = 232.0525. Preparative Example 4C

By essentially same procedure set forth in Preparative Example 4A, using the vinyl boronate from Preparative Example 2B, the compound given below was prepared.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.30-7.25 (m, 2H); 7.23-7.17 (m, 2H); 6.89-6.85 (m, 2H); 5.83 (d, J= 0.65 Hz, 1H); 5.59 (d, J= 0.52 Hz, 1H); 5.10 (brs, 1H); 3.80 (s, 3H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 160.6, 149.5, 145.8, 143.1, 142.1, 129.8, 128.6, 127.2, 124.9, 118.3, 114.7, 55.6.

HRMS (APCI): calcd. for Ci ₄ H ₁₃ ClN0 ₂ [M+H] ⁺ = 262.0629; found [M+H] ⁺ - 262.0631.

Preparative Example

The product from Preparative Example 3 (1.16 g, 4.53 mmol), the product from Preparative Example 2C (1.18 g, 4.12 mmol), K ₃ P0 ₄ (3.5 g, 16.5 mmol), DMF (5.5 mL) and PdC fdppf) (150 mg, 0.206 mmol) were placed into a 50 mL round bottom flask and the mixture was stirred under N ₂ at 80 °C for 14 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (CH ₂ Cl ₂ /hexane; 4:1). The product was obtained as a white solid (492 mg, 41 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.42 - 7.37 (m, 2H), 7.32 - 7.28 (m, 2H), 7.24 - 7.20 (m, 2H), 5.92 (d, J= 0.8 Hz, 1H), 5.69 (d, J= 0.7 Hz, 1H), 5.04 (s, 1H), 1.32 (s, 9H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 152.5, 149.4, 145.5, 143.4, 142.0, 134.3, 127.1, 126.8, 126.2, 124.7, 119.3, 34.8, 31.4.

HRMS (APCI): calcd. for Ci ₇ H ₁₈ ClNO [M+H] ⁺ = 288.1150; found [M+H] ⁺ = 288.1148.

Preparative Example 4E

2-(3,3-dimethylbut-l-en-2-yl)-4,4,5,5-tetramethyl-l,3,2-d ioxaborolane (400 mg, ί.90 mmol), DMF (7 mL), ₃ P0 ₄ (1.2 g, 5.72 mmol), the product from Preparative Example 3 (584 mg, 2.28 mmol) and PdCl ₂ (dppf) (69 mg, 95 μηιοΐ) were placed into a 25 mL round bottom flask. The mixture was stirred under N ₂ at 80 °C for 9 h. Then, additional PdC-2(dppf) (47 mg, 64 μιηοΐ) was added and the mixture was stirred at 90 °C for additional 45 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (from EtOAc/hexane; 1 :20 to EtOAc). The product was obtained as a white solid (40 mg, 10 %) of limited stability.

^! H NMR (300 MHz, CDC1 ₃ ) δ 7.22 (d, J= 8.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.62 (s, 1H), 5.35 (s, 1H), 5.15 (s, 1H), 1.20 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 153.4, 148.6, 147.7, 140.8, 125.8, 123.8, 116.0, 37.2, 29.6. HRMS (APCI): calcd. for C _u Hi ₄ ClNO [M+H] ⁺ = 212.0837; found [M+H] ⁺ = 212.0835.

Preparative Example 5A

A mixture of the product from Preparative Example 4 A (0.105 g; 0.37 mmol), copper(I) acetate (0.029 g; 0.24 mmol), 8-hydroxyquinoline (0.037 g; 0.25 mmol) and K ₂ C0 ₃ (0.067 g; 0.48 mmol) in anhydrous N.N-dimethylacetamide (1.5 mL) was stirred under 0 ₂ at 140 °C for 18 h. Then the reaction mixture was concentrated under reduce pressure, the residual oil was poured into water (50 mL) and extracted with EtOAc (3x30 mL). The organic extracts were washed with brine (40 mL), dried over MgS0 _4; filtered and the solvent was evaporated. The resulting residue was purified by column chromatography on silica gel (eluent: hexane/CH ₂ Cl ₂ - 1 : 1) to yield the product as a pale solid product (0.037 g; 36 %).

^! H NM (500 MHz, CDC1 ₃ ) δ 8.67 (s, 1H); 8.23 (s, 1H); 8.01-7.93 (m, 2H); 7.90 (d, J = 8.53 Hz, 1H); 7.85-7.82 (m, 1H); 7.75 (d, J= 8.60 Hz, 1H); 7.53-7.45 (m, 2H); 7.29 (d, J= 8.59 Hz, 1H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 148.0, 147.3, 146.4, 146.0, 133.9, 133.2, 128.7, 128.7, 127.9, 127.3, 126.5, 126.4, 126.4, 124.9, 121.7, 121.3, 119.9.

HRMS (APCI): calcd. for Ci ₇ H ₁₀ ClNO [M+H] ⁺ = 280.0524; found [M+H] ⁺ = 280.0526.

Preparative Example 5B

By essentially same procedure set forth in Preparative Example 5 A, using product from Preparative Example 4B, the compound given below was prepared.

1H NMR (500 MHz, CDC1 ₃ ) δ 8.12 (s, 1H); 8.04-7.99 (m, 2H); 7.73 (d, J = 8.61 Hz, 1H); 7.49-7.43 (m, 2H); 7.37-7.32 (m, 1H); 7.27 (d, J= 8.60 Hz, 1H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 147.9, 147.3, 146.1, 145.9, 129.9, 129.1, 128.2, 127.3, 121.8, 121.3, 119.8.

HRMS (APCI): calcd. for C _[3 H ₉ C1N0 [M+H] ^÷ = 230.0367; found [M+H = 230.0365.

Preparative Example 5C

By essentially same procedure set forth in Preparative Example 5A, using the product from Preparative Example 4C, the compound given below was prepared.

1H NMR (500 MHz, CDC1 ₃ ) δ 8.05 (s, 1H); 7.97-7.93 (m, 2H); 7.71 (d, J = 8.59 Hz, 1H); 2.25 (d, J= 8.59 Hz, 1H); 7.01-6.97 (m, 2H); 3.84 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 159.7, 147.9, 147.1, 146.0, 145.2, 128.5, 122.4, 121.5, 121.2, 119.6, 114.6, 55.6.

HRMS (APCI): calcd. for C ₁₄ H _n ClN0 ₂ [M+H] ⁺ = 260.0473; found [M+H] ⁺ = 260.0469.

Preparative Example 5D

The product from Preparative Example 4D (470 mg, 1.63 mmol), Cu(OAc) ₂ (148 mg, 0.816 mmol), quinolin-8-oI (118 mg, 0.816 mmol), K ₂ C0 ₃ (248 mg, 1.79 mmol) were placed into a 50 mL round bottom flask. The flask was filled with 0 ₂ . Then, N, N- dimethylacetamide (4 mL) was added and the mixture was stirred at 140 °C for 75 min. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (CH ₂ Cl ₂ /hexane; 1 : 1). The product was obtained as an orange solid (378 mg, 74 %).

^] H NMR (500 MHz, CDC1 ₃ ) S 8.11 (s, 1H), 7.94 (d ₅ J = 8.5 Hz, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.51 (d, J= 8.5 Hz, 2H), 7.28 (d, J= 8.6 Hz, 1H), 1.36 (s, 9H).

I ³ C NMR (126 MHz, CDC1 ₃ ) δ 151.2, 147.8, 147.1, 146.0, 145.7, 127.0, 126.8, 126.0, 121.7, 121.1, 1 19.6, 34.8, 31.5.

HRMS (APCI): calcd. for C ₁₇ H _I6 C1N0 [M+H] ⁺ = 286.0993; found [M+H] ⁺ = 286.0991.

Preparative Example 5E

By essentially same procedure set forth in Preparative Example 5D ₅ using the product from Preparative Example 4E, the compound given below was prepared.

White solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.63 (d, J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.17 (d, J= 8.6 Hz, 1H), 1.48 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 147.7, 147.0, 145.8, 144.3, 131.0, 120.6, 118.8, 31.0, 29.6. HRMS (APCI): calcd. for [M+H] ⁺ = 210.0680; found [M+H] ⁺ = 210.0682.

Preparative Example 6A

To a mixture of the product from Preparative Example 5B (0.052 g; 0.23 mmol), 1- methylpyrazole-4-boronic acid pinacol ester (0.059 g; 0.28 mmol), K ₃ P0 ₄ (0.227 g; 1.07 mmol) and PdCl ₂ (dppf) (0.011 g; 0.015 mmol) were added under N ₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). The resulting reaction mixture was refluxed for 18 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were dried over a ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ /EtOAc - 2:1) to yield the product as a pale orange solid (0.051 g; 81 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.17-8.13 (m, 2H); 8.09 (s, 1H); 7.99 (d, J = 5.58 Hz, 2H); 7.72 (d, J = 8.61 Hz, 1H); 7.50-7.7.44 (m, 2H); 7.42 (d, J = 8.60 Hz; 1H); 7.37-7.32 (m, 1H); 3.96 (s, 3H).

¹³ C NMR (126 MHz, CDCI ₃ ) S 148.9, 147.7, 145.9, 145.2, 137.7, 131.0, 129.1, 128.9, 127.8, 127.3, 124.4, 121.7, 119.2, 115.8, 39.4.

HRMS (APCI): calcd. for Ci ₇ H _i4 N ₃ 0 [M+H = 276.1131; found [M+H] ⁺ = 276.1 128.

Preparative Example 6B

To a mixture of the product from Preparative Example 5B (0.311 g; 1.36 mmol), phenylboronic acid pinacol ester (0.225 g; 1.85 mmol), K ₃ P0 ₄ (1.20 g; 5.64 mmol) and PdCl ₂ .dppf (0.062 g; 0.084 mmol) were added under N ₂ 1,2-dimethoxyethane (8 mL) and water (2 mL). The reaction mixture was refluxed under N ₂ for 19 h. Then it was cooled to 25 °C, diluted with EtOAc (40 mL), poured into brine (50 mL) and extracted with EtOAc (3x40 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane EtOAc - 5: 1) to yield the product as a pale yellow wax (0.262 g; 71 %).

Ή NMR (500 MHz, CDC1 ₃ ) S 8.26-8.19 (m, 2H); 8.17-8.10 (m, 3H); 7.83 (d, J= 8.66 Hz, 1H); 7.73 (d, J= 8.67 Hz, 1H); 7.54-7.46 (m, 4H); 7.45-7.33 (m, 2H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) S 154.3, 148.3, 146.1, 145.4, 140.0, 130.9, 129.0, 128.9, 128.8, 127.9, 127.4, 127.3, 122.0, 119.2, 116.8.

HRMS (APCI): calcd. for Ci ₉ H _[4 NO [M+H] ⁺ = 272.1070; found [M+H] ⁺ = 272.1074. Preparative Example 6C

To a mixture of the product from Preparative Example 5B (0.078 g; 0.34 mmol), 1-Boc- pyrazole-4-boronic acid pinacol ester (0.122 g; 0.42 mmol), K ₃ P0 (0.282 g; 1.33 mmol) and palladium catalyst PdCl ₂ .dppf (0.018 g; 0.024 mmol) were added under N ₂ 1 ,2-dimethoxyethane (2 mL) and water (0.5 mL). The reaction mixture was refluxed under N ₂ for 15 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3 ^χ 15 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 2:1) to yield the product as a pale yellow solid (0.047 g; 38 %).

Ή NMR (300 MHz, CDC1 ₃ ) δ 8.27 (s, 1H); 8.18-8.11 (m, 3H); 7.78 (d, J= 8.59 Hz, 1H); 7.53-7.44 (m, 3H); 7.40-7.32 (m, 1H); 1.68 (s, 9H).

Preparative Example 6D

To a mixture of the product from Preparative Example 5B (0.088 g; 0.38 mmol), 3- pyridineboronic acid pinacol ester (0.098 g; 0.48 mmol), ₃ P0 (0.336 g; 1.58 mmol) and palladium catalyst PdCl ₂ .dppf (0.019 g; 0.026 mmol) were added under N ₂ 1 ,2-dimethoxyethane (2 mL) and water (0.5 mL). The reaction mixture was refluxed under N ₂ for 19 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3x15 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ /MeOH - 15:1) to yield the product as a pale brown solid (0.087 g; 83 %).

1H NM (500 MHz, CDC1 ₃ ) δ 9 A3 (brs, 1H); 8.73 (brs, 1H); 8.44 (d, J - 7.88 Hz, 1H); 8.23-8.15 (m, 3H); 7.87 (d, J= 8.57 Hz, 1H); 7.74 (d, J= 8.61 Hz, 1H); 7.53-7.34 (m, 4H). 1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 151.5, 149.6, 148.7, 148.6, 146.6, 145.8, 1358,; 134.8, 130.6, 129.1, 128.1, 127.3, 124.2, 122.0, 119.5, 1 16.7.

HRMS (APCI): calcd. for C ₁₈ H ₁₃ N ₂ 0 [M+H] ⁺ = 273.1022; found [M+H] ⁺ = 273.1022.

To a mixture of Preparative Example 5 A (0.053 g; 0.19 rnmol), 1 -rnethylpyrazole-4- boronic acid pinacol ester (0.048 g; 0.23 rnmol), K ₃ P0 ₄ (0.177 g; 0.83 rnmol) and PdCl ₂ .dppf (0.010 g; 0.014 rnmol) were added under N ₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). The reaction mixture was refluxed for 19 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: EtOAc/MeOH - 20: 1) to yield the product as a pale yellow solid (0.049 g; 79 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.86 (s, 1H); 8.21 (s, 1H); 8.11-7.99 (m, 3H); 7.97-7.89 (m, 2H); 7.85 (d, J= 7.82 Hz, 1H); 7.76 (d, J= 8.26 Hz, 1H); 7.54-7.42 (m, 3H); 3.99 (s, 3H). I ³ C NMR (126 MHz, CDC1 ₃ ) δ 148.9, 147.8, 145.9, 145.6, 137.8, 133.9, 133.1, 129.2, 128.6, 128.5, 128.3, 128.0, 126.5, 126.2, 125.1, 124.4, 121.6, 119.4, 1 16.0, 39.5.

HRMS (APCI): calcd. for C _2! H ₁₆ N ₃ 0 [M+H] ⁺ = 326.1288; found [M+H] ⁺ = 326.1284.

Preparative example 7B

Tert-butyl 4-(4,4,5 , 5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2 -yl)- 1 H-pyrazole- 1 -carboxylate (77 mg, 0.26 mmol), the product from Preparative Example 5 A (61 mg, 0.22 mmol), K ₃ P0 ₄ (180 mg, 0.85 mmol), 1,2-dimethoxyethane (2 mL), ¾0 (0.5 mL) and PdCl ₂ (dppf) (1.8 mg, 0.008 mmol) were added into a 25 mL round bottom flask. The mixture was refluxed under N ₂ for 18 h, then saturated aqueous solution of NH ₄ C1 (15 mL) was added, the mixture was extracted with EtOAc (10 mL) and then with CH ₂ C1 ₂ (2x20 mL). The organic extracts were dried over Na ₂ S0 _4j filtered, and the solvents were evaporated. The residue was loaded on silica gel and purified by column chromatography (EtOAc/hexane; 5:4) to afford the product as a light yellow solid (47 mg, 69 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.94 (s, 1H), 8.32 - 8.20 (m, 3H), 8.11 (d, J = 8.6 Hz, 1H), 8.00 - 7.91 (m, 2H), 7.87 (d, J= 7.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.56 - 7.47 (m, 3H).

]H NMR (300 MHz, DMSO-d6) <5 13.04 (b, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.52 - 8.20 (m, 3H), 8.14 - 7.99 (m, 3H), 7.99 - 7.90 (m, 1H) _S 7.78 (d, J = 8.7 Hz, 1H), 7.63 - 7.49 (m, 2H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 148.6, 147.8, 146.0, 145.5, 133.8, 133.0, 128.5, 128.4, 128.2, 127.9, 126.4, 126.1, 124.9, 121.5, 119.2, 116.1.

HRMS (APCI): calcd. for C ₂₀ H _i3 N ₃ O [M+H] ⁺ = 312.1131; found [M+H] ⁺ - 312.1129.

Preparative example 7C

l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyra2ole (41 mg, 0,17 mmol), the product from Preparative Example 5 A (40 mg, 0.14 mmol), K ₃ P0 ₄ (91 mg, 0.43 mmol), 1 ,2-dimethoxyethane (2 mL) _s H ₂ 0 (0.5 mL) and PdCl ₂ (dppf) (3.1 mg, 4.3 μπιοΐ) were added into a 25 mL round bottom flask and the mixture was refluxed under N ₂ for 2 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (EtOAc/hexane; 1 :1) to yield the product as a light yellow wax (40 mg, 79 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.91 (s, 1H), 8.23 (s, 1H), 8.13 - 8.07 (m, 3H), 7.98 - 7.92 (m, 2H), 7.87 (d, J- 8.0 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.55 - 7.47 (m, 3H), 4.60 (sep, J= 13.4, 6.7 Hz, 1H), 1.62 (s, 3H), 1.60 (s, 3H).

f ³ C NMR (126 MHz, CDC1 ₃ ) δ 149.1, 147.6, 145.9, 145.3, 137.3, 133.8, 133.0, 128.4, 128.4, 128.3, 127.8, 126.3, 126.0, 125.4, 125.0, 123.6, 121.5, 119.2, 115.8, 54.2, 23.1. HRMS (APCI): calcd. for C ₂₃ H ₁₉ N ₃ 0 [M+H] ⁺ = 354.1601 ; found [M+H] ⁺ = 354.1596.

Preparative example 7D

Tert-butyl 3 ,5 -dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole- 1 - carboxylate (55 mg, 0.17 mmol), the product from Preparative Example 5A (40 mg, 0.14 mmol), K ₃ P0 ₄ (91 mg, 0.43 mmol), 1 ,2-dimethoxyethane (2 mL), H ₂ 0 (0.5 mL) and PdCl ₂ (dppf) (3.1 mg, 4.3 μπΐοΐ) were added into a 25 mL round bottom flask and the mixture was refluxed under N ₂ for 24 h. Then, additional tert-butyl 3,5-dimethyl-4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yI)-lH-pyrazole-l-carboxylate (30 mg, 0.09 mmol) and PdCl ₂ (dppf) (4 mg, 5.4 μιηοΐ) were added and the mixture was refluxed under N ₂ for additional 24 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (EtOAc MeOH; 30:1) and then re- chromatographed (EtOAc/hexane; 1 :1). So obtained material was purified by preparative TLC (EtOAc/hexane; 1 :1) and then by another preparative TLC (CH ₂ Cl ₂ /MeOH; 15:1). The product was obtained as a colorless wax (7.2 mg, 29 % yield).

1H NMR (300 MHz, CDC1 ₃ ) S 8.99 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 8.6, 1.6 Hz, 1H), 7.99 - 7.79 (m, 4H), 7.57 - 7.43 (m, 2H), 7.39 (d, J= 8.6 Hz, 1H), 2.62 (s, 6H).

I ³ C NMR (126 MHz, CDC1 ₃ ) S 150.4, 147.0, 145.8, 145.3, 144.7, 143.4, 133.8, 132.9, 128.4, 128.3, 128.2, 127.8, 126.4, 126.3, 126.0, 124.7, 121.6, 1 18.9, 118.8, 118.1, 12.9, 12.3.

HRMS (APCI): calcd. for C ₂₂ Hi ₇ N ₃ 0 [M+H] ⁺ = 340.1444; found [M+H] ⁺ = 340.1441.

Preparative example 7E

(l,3,5-trimethyl-lH-pyrazol-4-yl)boronic acid (33 mg, 0.21 mmol), the product from Preparative Example 5A (50 mg, 0.18 mmol), K3PO4 (133 mg, 0.63 mmol), 1,2- dimethoxyethane (2.4 mL), H ₂ 0 (0.6 mL) and PdChtdppf) (6.5 mg, 8.9 μηιοΐ) were added into a 10 mL round bottom flask and the mixture was refluxed under N ₂ for 18 h. Additional PdCl ₂ (dppf) (4 mg, 5.4 μπιοΐ) and K ₃ P0 ₄ (118 mg, 0.56 mmol) were added and the mixture was refluxed for additional 12 h. Then, another portion of PdCbidppf) (4 mg, 5.4 μτηοΐ) was added and the mixture was refluxed for additional 10 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (EtOAc/hexane; from 1 :1 to 2:1) and then by preparative TLC (CH ₂ Cl ₂ /MeOH; 15:1) to yield the product as a colorless wax (5 mg, 8 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.99 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 8.5, 1.7 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.88 - 7.82 (m, 2H), 7.54 - 7.44 (m, 2H), 7.35 (d, J - 8.6 Hz, 1H), 3.85 (s, 3H), 2.59 (s, 3H), 2.51 (s, 3H).

i ³ C NMR (126 MHz, CDCI3) S 150.7, 147.0, 145.9, 145.8, 145.3, 138.1, 133.9, 132.9, 128.4, 128.3, 128.2, 127.8, 126.4, 126.3, 126.0, 124.7, 121.6, 119.2, 118.9, 118.8, 36.1, 13.7, 11.2. HRMS (APCI): calcd. for C23H19N3O [M+H] ⁺ = 354.1601 ; found M+H] ⁺ = 354.1599.

A mixture of 5-thiazole boronic acid MIDA ester (69 mg, 0.29 mmol), the product from Preparative Example 5A (62 mg, 0.22 mmol), K ₃ P0 ₄ (165 mg, 0.78 mmol), 1,2- dimethoxyethane (2 mL), H ₂ 0 (0.5 mL) and PdCl ₂ (dppf) (8.1 mg, 11 μηιοΐ) was stirred at 60 °C under N ₂ for 2 h and then at 80 °C for 7 h. Additional PdCl ₂ (dppf) (4 mg, 5.4 μιηοΐ), the mixture was refluxed for 27 h, then additional PdCI ₂ (PPti3) ₂ (4 mg, 5.7 μπιοΐ) was added and the mixture was refluxed for additional 24 h. Then, additional Pd(PPh.3) ₄ (5 mg, 4.3 μπιοΐ) and 5-thiazole boronic acid MIDA ester (20 mg, 0.083 mmol) were added and the mixture was refluxed for additional 24 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (EtOAc/hexane; from 1 :2 to 1 :1) and then by preparative TLC (EtOAc/hexane; 1 :1). The product was obtained as a light yellow solid (7 mg, 10%).

1H NM (300 MHz, CDC1 ₃ ) δ 8.98 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.30 (s, 1H), 8.07 (dd, J = 8.6, 1.7 Hz, 1H), 8.03 - 7.84 (m, 4H), 7.74 (d, J = 8.6 Hz, 1H), 7.58 - 7.48 (m, 2H).

^I3 C NMR (126 MHz, CDCI3) δ 154.4, 148.4, 147.0, 146.3, 146.1, 141.4, 139.7, 133.8, 133.0, 128.6, 128.5, 127.8, 127.7, 126.5, 126.5, 126.3, 124.6, 121.4, 119.5, 116.0.

HRMS (APCI): calcd. for C ₂₀ Hi ₂ N ₂ OS [M+H] ⁺ = 329.0743; found [M+Hf = 329.0747.

Preparative Example 8A

To a freshly prepared solution of (S)-l-[(J? )-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- fert-butylphosphine (0.013 g; 0.023 mmol) and Pd(OAc) ₂ (0.007 g; 0.030 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) were added the product from Preparative Example 5B (0.053 g; 0.23 mmol), i-BuOK (0.036 g; 0.32 mmol) and 3-methoxy-4-(4- methylpiperazin-l-yl)aniline (0.064 g; 0.29 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 16 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3*10 mL). The organic extracts were dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: C¾Ci2/7N NH ₃ in MeOH - 30:1) to yield the product as a dark orange semi - solid (0.079 g; 83 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.05-8.02 (m, 2H); 7.99 (s, 1H); 7.59 (d, J = 8.93 Hz, 1H); 7.44-7.39 (m, 2H); 7.33-7.27 (m, 2H); 6.91-6.81 (m, 2H); 6.70 (d, J = 8.94 Hz, 1H); 6.49 (brs, 1H); 3.80 (s, 3H); 3.10 (s, 4H); 2.68 (s, 4H); 2.38 (s, 3H).

^,3 C NMR (126 MHz, CDCI3) 6 154.0, 153.1, 144.6, 143.7, 137.3, 136.6, 131.3, 128.9,

127.6, 127.2, 121.5, 121.0, 118.9, 112.3, 106.5, 104.8, 55.8, 55.6, 50.9, 46.2.

HRMS (APCI): calcd. for C ₂₅ H ₂₇ N ₄ 0 ₂ [M+H] ⁺ = 415.2129; found [M+H] ⁺ = 415.2129.

Preparative Example 8B

To a freshly prepared solution of (5)-l-[(.¾/.)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- tert-butylphosphine (0.007 g; 0.012 mmol) and Pd(OAc) ₂ (0.004 g; 0.018 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) were added the product from Preparative Example 5B (0.067 g; 0.29 mmol), t-BuOK (0.041 g; 0.43 mmol) and (0.062 g; 0.35 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 14 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were dried over MgS0 , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (ehient: C¾Cl ₂ /MeOH - 50:1) to yield the product as an orange solid (0.062 g; 58 %). 1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H); 8.59 (s, 1H); 8.25-8.20 (m, 2H); 7.84 (d, J = 9.01 Hz, 1H); 7.72-7.66 (m, 2H); 7.54-7.47 (m, 2H); 7.38-7.31 (m, 1H); 6.98-6.91 (m, 2H); 6.79 (d, J= 9.04 Hz, 1H); 3.78-3.72 (m, 4H); 3.08-3.03 (m, 4H).

l ³ C NMR (126 MHz, DMSO-d6) δ 153.6, 145.3, 145.0, 143.0, 141.6, 134.6, 131.0, 128.5, 127.0, 126.2, 121.0, 119.7, 118.9, 115.8, 107.7, 66.1, 49.4.

HRMS (APCI): calcd. for C23H22N3O2 [M+H] ⁺ = 372.1707; found [M+H] ⁺ = 372.1704.

To a freshly prepared solution of (jS)-l-[(i?p)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- ier/-butylphosphine (0.008 g; 0.014 mmol) and Pd(OAc) ₂ (0.010 g; 0.042 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from Preparative Example 5B (0.061 g; 0.26 mmol), t-BuOK (0.038 g; 0.40 mmol) and 4-(4-methyl-l- piperazinyl)aniline (0.057 g; 0.30 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 19 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3x15 mL). The organic extracts were dried over MgS0 ₄ , filtered and the solvent was evaporated. The resulting residue was purified by column chromatography on silica gel (eluent: CH ₂ CL/ N NH ₃ in MeOH— 15:1) to yield the product as a pale brown solid (0.069 g; 68 %). Ή NMR (500 MHz, CDC1 ₃ ) δ 8.08-8.04 (m, 2H); 7.99 (s, 1H); 7.56 (d, J = 8.96 Hz, 1H); 7.46-7.41 (m, 2H); 7.37-7.28 (m, 3H); 6.93 (d, J= 5.55 Hz, 2H); 6.66 (d, J= 8.61 Hz, 1H); 6.41 (brs, 1H); 3.18 (brs, 4H); 2.63-2.57 (m, 4H); 2.36 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 147.8, 144.5, 143.8, 134.0, 131.3, 128.9, 127.5, 127.2, 122.8, 122.7, 121.3, 120.9, 117.5, 105.4, 55.4, 50.0, 46.3.

HRMS (APCI): calcd. for C ₂₄ H ₂₅ N ₄ 0 [M+H] ⁺ = 385.2023; found [M+H] ⁺ = 385.2030.

Preparative Example

To a freshly prepared solution of (S)-l-[(i? _/ >)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- tert-butylphosphine (0.009 g; 0.016 mmol) and Pd(OAc) ₂ (0.015 g; 0.068 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from Preparative Example 5B (0.054 g; 0.23 mmol), i-BuOK (0.033 g; 0.34 mmol) and 4-aminopyridine (0.024 g; 0.26 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 14 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ /7N NH ₃ in MeOH - 10:1) to yield the product as a pale yellow solid (0.034 g; 50 %).

1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H); 8.71 (s, 1H); 8.35 (d, J = 5.44 Hz, 2H); 8.19 (d, J = 7.31, 2H); 8.02 (d, J = 8.93 Hz, 1H); 7.77 (d, J= 5.66 Hz, 2H); 7.58-7.50 (m, 3H); 7.41-7.35 (m, 1H); 6.98 (d, J= 8.94 Hz, 1H).

1 ³ C NMR (126 MHz, DMSO-d6) δ 152.0, 149.7, 147.8, 145.9, 143.8, 141.8, 130.5, 128.6, 127.3, 126.3, 121.5, 120.0, 111.3, 109.2.

HRMS (APCI): calcd. for Ci _S H _I4 N ₃ 0 [M+H] ⁺ = 288.1131; found [M+H] ⁺ = 288.1131.

Preparative Example 8E

To a freshly prepared solution of (5)-l-[( _J R _/ >)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- iert-butylphosphine (0.011 g; 0.020 mmol) and palladium catalyst Pd(OAc) ₂ (0.008 g; 0.033 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from Preparative Example 5B (0.053 g; 0.23 mmol), t-BuOK (0.032 g; 0.34 mmol) and aniline (0.025 mL; 0.27 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 15 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3> 10 mL). The organic extracts were dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 5:1) to yield the product as a brownish semi - solid

(0.050 g; 76 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.08-8.04 (m, 2H); 8.02 (s, 1H); 7.64 (d, J = 8.96 Hz, 1H); 7.49-7.43 (m, 4H); 7.37-7.29 (m, 3H); 7.07-7.00 (m, 1H); 6.81 (d, J= 8.96 Hz, 1H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) S 153.4, 144.8, 144.7, 141.2, 130.9, 129.4, 129.0, 127.8, 127.2, 122.7, 121.3, Π9.9, 106.5.

HRMS (APCI): calcd. for C ₁₉ H ₁₅ N ₂ 0 [M+H] ⁺ = 287.1179; found [M+H] ⁺ = 287.1180.

Preparative Example 8F

To a solution of the product from Preparative Example 5B (0.045 g; 0.20 mmol), (R)- BINAP (0.017 g; 0.027 mmol), Pd ₂ (dba) ₃ (0.014 g; 0.015 mmol) and f-BuOK (0.033 g; 0.29 mmol) in anhydrous toluene (2 mL) was added jV,N-dimethylethylenediarn.ine (0.022 mL; 0.20 mmol) and the resulting mixture was stirred under N ₂ at 80 °C for 20 h. Then it was cooled to 25 °C, diluted with EtOAc (lOmL), poured into water (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were washed with brine (15 mL), dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by preparative TLC (eluent: CH ₂ C1 ₂ /7N NH ₃ in MeOH - 17:1) to yield the product as an orange wax (0.024 g; 43 %).

1H NMR (500 MHz, CDC1 ₃ ) S 8.13-8.08 (m, 2H); 7.96 (s, 1H); 7.51 (d, J = 8.93 Hz, 1H);

7.45-7.39 (m, 2H); 7.32-7.26 (m, 1H); 6.39 (d, J = 8.93 Hz, 1H); 5.04-4.95 (m, 1H); 3.50

(dd, J= 5.71 Hz, 11.41 Hz, 2H); 2.60 (t, J= 6.06 Hz, 2H); 2.29 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 156.9, 143.9, 143.8, 143.5, 131.7, 128.8, 127.3, 127.0,

121.1, 120.7, 105.4, 58.6, 45.6, 40.1.

HRMS (APCI): calcd. for Ci ₇ H ₂₀ N ₃ O [M+H] ⁺ = 282.1601 ; found [M+H] ⁺ = 282.1600.

Preparative Example 8G e

To a freshly prepared solution of (.S)-l-[(-¾p)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- tert-butylphosphine (0.01 1 g; 0.023 mmol) and Pd(OAc) ₂ (0.007 g; 0.030 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) were added the product from Preparative Example 5C (0.054 g; 0.22 mmol), t-BuONa (0.030 g; 0.31 mmol) and 3-methoxy-4-(4- methylpiperazin-l-yl)aniline (0.056 g; 0.25 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 18 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted with EtOAc (3x 10 mL). The organic extracts were dried over MgS0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ /7N N¾ in MeOH - 17:1) to yield the product as a pale orange foam (0.041 g; 42 %).

Ή NMR (500 MHz, CDCI3) δ 7.99-7.95 (m, 2H); 7.91 (s, 1H); 7.56 (d, J = 8.92 Hz, 1H); 7.27-7.22 (m, 1H); 6.91-6.81 (m, 2H); 6.68 (d, J = 8.93 Hz, 1H); 6.50 (brs, 1H); 3.83 (s, 3H); 3.80 (s, 3H); 3.08 (brs, 4H); 2.64 (brs, 4H); 2.36 (s, 3H). ^I3 C NMR (126 MHz, CDC1 ₃ ) S 159.2, 153.9, 153.1, 144.4, 143.7, 137.3, 136.6, 128.4, 123.8, 121.1, 120.9, 1 18.8, 114.3, 112.3, 106.3, 104.8, 55.7, 55.6, 55.5, 51.1, 46.3.

HRMS (APCI): calcd. for C26H29N4O3 [M+H] ⁺ = 445.2234; found [M+H] ⁺ = 445.2235.

Preparative Example 9

To a stirred solution of the product from Preparative Example 6C (0.049 g; 0.14 mmol) in ethanol (2 mL) was added aqueous solution of HCl (3M; 0.9 mL; 2.7 mmol) and the resulting mixture was stirred under N ₂ at 60 °C for 8 h. Then, the ethanol and HCl were evaporated and the oily residue was mixed with CH ₂ C1 ₂ (2 mL), MeOH (lmL) and Na ₂ C0 ₃ (200 mg) and the mixture was stirred at 25 °C. After 20 min., the solvents were evaporated and the solid residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ /7N NH ₃ in MeOH - 10:1) to yield the product as a pale yellow solid (0.026 g; 75 %).

1H NMR (500 MHz, CD ₃ OD) <5 836 (s, 1H); 8.31-8.08 (m, 4H); 7.85 (d, J= 8.64 Hz, 1H); 7.63 (d, J- 8.64 Hz, 1H); 7.49-7.44 (m, 2H); 7.36-7.31 (m, 1H).

¹³ C NMR (126 MHz, CD ₃ OD) S 150.2, 149.0, 147.1, 146.8, 138.6, 132.2, 129.7, 128.6, 128.1, 122.5, 120.3, 117.2.

HRMS (APCI): calcd. for C ₁₆ H ₁₂ N30 [M+H] ⁺ = 262.0975; found [M+Hf = 262.0976.

Preparative Example 10

The product from Preparative Example 3 (4.5 g; 17.62 mmol) was placed into a 250 mL round bottom flask. TEA (32 mL) and 1,4-dioxane (32 mL) were added and the mixture was purged with N ₂ . Ethynylf imethylsilane (2.25 g; 22.9 mmol), Cul (0,168 g; 0,881 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.247 mg, 0.352 mmol) were added and the mixture was stirred at 45 °C under N ₂ for 2.5 h. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc; from 15:1 to 10:1) to yield the product as an orange solid (2.90 g; 73 % yield).

1H NMR (500 MHz, CDC1 ₃ ) 6 7.67 (dd, J= 0.85 Hz, 8.56 Hz, 1H); 7.17 (d, J = 8.56 Hz, 1H); 7.03 (d, J= 0.84 Hz, 1H); 0.35 (m, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 170.8, 149.9, 148.5, 146.7, 120.7, 119.1, 116.8, -1.9.

HRMS (APCI): calcd. for C _{] 0} H, ₃ ClNOSi [M+H] ⁺ = 226.0449; found [M+H] ⁺ = 226.0446.

Preparative Example 11

To a solution of the product from Preparative Example 10 (1.013 g; 4.49 mmol) in methanol (20 mL) was added KF (0.803 g; 13.82 mmol) and the resulting mixture was stirred under N ₂ at 60 °C for 15 h. Then it was cooled to 25 °C, poured into aqueous solution of HC1 (0.1M; 100 mL) and extracted with EtOAc (3x60 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/ EtOAc - 10:1) to yield the product as a pale yellow solid (0.579 g; 84 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.84 (d, J = 2.28 Hz, 1H); 7.70 (dd, J = 0.84 Hz, 8.60 Hz, 1H); 7.21 (d, J= 8.60 Hz, 1H); 6.90 (dd, J= 0.84 Hz, 2.26 Hz, 1H).

, ³ C MR (126 MHz, CDC1 ₃ ) S 150.3, 147.6, 147.2, 146.9, 121.1, 119.5, 108.1.

HRMS (APCI): calcd. for C ₇ H ₅ C1N0 [M+H] ⁺ = 154.0054; found [M+H] ⁺ = 154.0055.

Preparative Example 12A

To a mixture of the product from Preparative Example 11 (0.201 g; 0.89 mmol), 1-Boc- pyrazole-4-boronic acid pinacol ester (0.0.317 g; 1.07 mmol), ₃ P0 ₄ (0.781 g; 3.68 mmol) and PdCl ₂ .dppf (0.039 g; 0.053 mmol) were added under N ₂ 1,2-dimethoxyethane (4 mL) and water (1 mL). The reaction mixture was refluxed for 19 h. Then it was cooled to 25 °C, diluted with EtOAc (20 mL), poured into brine (30 mL) and extracted with EtOAc (3 20 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl2/MeOH - 1 : 1). So obtained solid was further purified by preparative TLC (eluent: CH ₂ CI ₂ /MeOH - 15:1) to yield the pale yellow crystalline product (0.080 g; 49 ).

1H NMR (500 MHz, CD ₃ OD) δ 8.17 (s, 2H); 8.04 (d, J - 2.28 Hz, 1H); 7.89 (dd, J= 0.83 Hz, 8.64 Hz, 1H); 7.62 (d, J= 8.65 Hz, 1H); 6.96 (dd, J= 0.85 Hz, 2.26 Hz, 1H); 4.86 (brs, 1H).

¹³ C NMR (126 MHz, CD ₃ OD) δ 151.4, 150.1, 148.2, 148.1, 133.4, 123.8, 120.9, 117.7, 108.2.

HRMS (APCI): calcd. for CioH ₈ N ₃ 0 [M+H] ⁺ = 186.0662; found [M+H] ⁺ = 186.0659.

Preparative Example 12B

To a mixture of the product from Preparative Example 11 (0.052 g; 0.34 mmol), 1- methylpyrazole-4-boronic acid pinacol ester (0.092 g; 0.44 mmol), ¾Ρ0 ₄ (0.308 g; 1.45 mmol) and PdCl ₂ .dppf (0.017 g; 0.023 mmol) were added under N ₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). The reaction mixture was refluxed for 14 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3x15 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ /Me0H - 10:1) to yield the product as a brown solid (0.045 g; 66 %).

!H NMR (500 MHz, CDC1 ₃ ) δ 7.94 (s, 2H); 7.80 (d, J= 2.21 Hz, 1H); 7.72 (d, J= 8.53 Hz, 1H); 7.39 (d, J= 8.59 Hz, 1H); 6.95 (d, J= 1.64 Hz, 1H); 3.94 (s, 3H). ^iJ C NMR (126 MHz, CDC1 ₃ ) δ 149.3, 149.0, 147.5, 146.7, 137.7, 128.9, 124.1, 119.2, 116.0, 108.3, 39.4.

H MS (APCI): calcd. for C _u Hi ₀ N ₃ O [M+H] ⁺ = 200.0818; found [M+H] ⁺ = 200.0817.

Preparative Example 13

To a mixture of the product from Preparative Example 10 (1.62 g; 7.16 mmol), phenylboronic acid (1.13 g; 9.26 mmol), triethylamine (10 mL; 71.8 mmol) and PdCl ₂ .dppf (0.160 g; 0.22 mmol) were added under N ₂ 1 ,2-dimethoxyethane (12 mL) and water (3 mL). The reaction mixture was refluxed under N ₂ for 20 h. Then it was cooled to 25 °C, diluted with EtOAc (70 mL), poured into brine (90 mL) and extracted with EtOAc (3x70 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 15:1) to yield the product as a pale yellow solid (1.61 g; 84 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.01-7.96 (m, 2H); 7.78 (dd _s J = 0.93 Hz, 8.61 Hz, IH); 7.61 (d, J = 8.62 Hz, IH); 7.49-7.43 (m, 2H); 7.41-7.35 (m, IH); 7.20 (d, J= 0.81 Hz, IH); 0.39-0.39 (m, 9H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 169.5, 154.3, 150.3, 148.6, 140.3, 128.9, 128.6, 127.5, 118.7, 117.6, 1 16.9, -1.8.

HRMS (APCI): calcd. for Ci ₆ Hi ₈ NOSi [M+H] ⁺ - 268.1152; found [M+H] ⁺ = 268.1153.

Preparative Example 14

To a stirred solution of the product from Preparative Example 13 (1.61 g, 6.02 mmol) in anhydrous CH ₂ C1 ₂ (20 ml) was added MCPBA (1.88 g, 10.9 mmol) and the resulting mixture was stirred under N ₂ at 25 °C for 72 h. Then it was poured into saturated aqueous solution of NaHC0 ₃ (110 mL) and extracted with CH2CI2 (3x60 mL). The organic extracts were washed with brine (50 mL), dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ /MeOH - 12: 1 ) to yield the product as a pale yellow solid (1.60 g; 94 %).

1H NMR (500 MHz, CDCI ₃ ) δ 7.86-7.80 (m, 2H); 7.50-7.39 (m, 5H); 7.30 (d, J= 8.58 Hz, 1H); 0.38-0.36 (m, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 169.0, 153.2, 144.7, 139.6, 133.1, 129.8, 129.4, 128.5, 122.2, 112.0, 110.4, -1.9.

HRMS (APCI): calcd. for Ci ₆ H ₁₇ N0 ₂ Si [2M+H] ⁺ = 567.213; found [2M+H] ⁺ = 567.2134.

Preparative Example 15

To a stirred solution of the product from Preparative Example 14 (0.575 g, 2.03 mmol) in CHCI3 (10 ml) was added POCl ₃ (3.4 mL; 36.5 mmol) and the resulting mixture was refluxed under N ₂ for 1 h. Then, the CHCI3 and POCI3 were evaporated under reduced pressure. The dark oily residue was diluted with CH2CI2 (50 mL), poured into saturated aqueous solution of NaHC0 ₃ (200 mL) and extracted with CH ₂ C1 ₂ (3 x70 mL). The organic extracts were washed with water (50 mL), brine (80 mL), dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/CH ₂ CI ₂ - 1:1) to yield the product as a colorless wax (0.339 g; 55 %). Ή NMR (500 MHz, CDCI ₃ ) δ 7.99-7.94 (m, 2H); 7.63 (s, 1H); 7.49-7.44 (m, 2H); 7.42- 7.37 (m, 1H); 7.20 (s, 1H); 0.41-0.38 (m, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 170.6, 155.4, 149.8, 146.8, 139.3, 129.1, 129.0, 127.4, 126.5, 118.1, 117.3, -1.8.

HRMS (APCI): calcd. for Ci ₆ H _!6 ClNOSi [M+H] ⁺ = 302.0762; found [M+H] ⁺ = 302.0764.

Preparative Example 16

To a solution of the product from Preparative Example 15 (1.11 g; 3.68 mmol) in methanol (10 mL) was added KF (0.646 g; 11.1 mmol) and the resulting mixture was stirred under N ₂ at 60 °C for 20 h. Then it was cooled to 25 °C, poured into aqueous solution of HCl (0.1M; 40 mL) and extracted with EtOAc (3x30 mL). The organic extracts were washed with brine (30 mL), dried over Na ₂ S0 _4j filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: C¾C1 ₂ / MeOH - 20: 1) to yield the product as a white solid (0.796 g; 94 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.99-7.95 (m, 2H); 7.90 (d, J = 2.18 Hz, 1H); 7.68 (s, 1H); 7.51-7.44 (m, 2H); 7.43-7.39 (m, 1H); 7.09 (d, J= 2.15 Hz, 1H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 155.8, 150.2, 148.8, 144.0, 138.8, 129.4, 129.1, 127.5, 127.0, 117.6, 109.2.

HRMS (APCI): calcd. for C13H9CINO [M+H] ⁺ = 230.0367; found [M+H] ⁺ = 230.0365.

Preparative Example 17A

To a solution of the product from Preparative Example 16 (0.103 g; 0.45 mmol), (R)- BINAP (0.016 g; 0.026 mmol), Pd(dba) ₂ (0.017 g; 0.030 mmol) and t-BuOK (0.078 g; 0.69 mmol) in anhydrous toluene (3 mL) was added 3-picolylamine (0.050 mL; 0.49 mmol) and the resulting mixture was stirred under N ₂ at 80 °C for 17 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into water (25 mL) and extracted with EtOAc (3 ^χ 10 mL). The organic extracts were washed with brine (15 mL), dried over MgS0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / MeOH - 10:1) to yield the product as an orange foam (0.056 g; 42 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.62 (d, J= 59.05 Hz, 2H); 7.84 (d, J= 7.29 Hz, 2H); 7.75- 7.66 (m, 2H); 7.44-7.25 (m, 4H); 6.96 (d, J = 2.02 Hz, 1H); 6.81 (s, 1H); 5.09 (brs, 1H); 4.63 (d, J= 5.71 Hz, 2H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 156.5, 149.5, 149.3, 147.5, 146.7, 140.8, 139.4, 136.8, 135.2, 133.7, 128.8, 128.6, 127.5, 124.0, 109.1, 99.6, 45.0.

HRMS (APCI): calcd. for C _]9 H ₁₆ N ₃ 0 [M+H] ^÷ - 302.1288; found [M+H] ⁺ = 302.1285.

Preparative Example 17B

To a solution of the product from Preparative Example 16 (0.207 g; 0.90 mmol), (R)- BINAP (0.035 g; 0.056 mmol), Pd(dba) ₂ (0.050 g; 0.087 mmol) and t-BuOK (0.146 g; L30 mmol) in anhydrous toluene (3 mL) was added benzylamine (0.120 mL; 1.10 mmol) and the resulting mixture was stirred under N ₂ at 80 °C for 17 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into water (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were washed with brine (15 mL), dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / MeOH - 15:1). So obtained solid was further purified by preparative TLC (eluent: CH ₂ Cl ₂ /MeOH - 20:1) to yield the product as a brownish foam (0.233 g; 86 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.90-7.85 (m, 2H); 7.69 (d, J = 2.19 Hz, 1H); 7.44-7.28 (m, 8H); 6.95 (d, J= 2.19 Hz, 1H); 6.85 (s, 1H); 4.96 (t, J= 5.13 Hz, 1H); 4.59 (d, J= 5.63 Hz, 2H). ^1J C NMR (126 MHz, CDC1 ₃ ) δ 156.6, 147.2, 146.7, 141.2, 139.7, 138.1, 136.9, 129.1, 128.7, 128.4, 128.0, 127.7, 127.6, 109.2, 99.5, 47.4.

HRMS (APCI): calcd. for C ₂₀ Hi ₇ N ₂ O [M+H] ⁺ = 301.1335; found [M+H] ⁺ = 301.1335.

Preparative Example 17C

To a freshly prepared solution of xantphos (0.012 g; 0.021 mmol) and Pd ₃ (dba) ₂ (0.022 g; 0.024 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) were added the product from Preparative Example 16 (0.049 g; 0.22 mmol), f-BuO (0.052 g; 0.46 mmol) and 4- morpholinoaniline (0.048 g; 0.27 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 16 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3x15 mL). The organic extracts were dried over MgS0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: Ο¾Ο ₂ /Μβ0Η - 1 :1). So obtained oil was farther purified by preparative TLC (eluent: CHbCLVMeOH - 20:1) to yield the product as a brownish solid (0.018 g; 22 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.86-7.83 (m, 2H); 7.74 (d, J= 2.20 Hz, 1H); 7.42-7.37 (m, 2H); 7.36-7.31 (m, 1H); 7.26-7.21 (m, 2H); 7.15 (s, 1H); 6.99 (d, J = 2.20 Hz, 1H); 6.97- 6.93 (m, 2H); 6.34 (brs, 1H); 3.90-3.85 (m, 4H); 3.20-3.14 (m, 4H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 156.3, 149.1, 147.5, 147.2, 140.9, 137.9, 137.0 131.4, 128.7, 128.5, 127.6, 124.7, 116.9, 109.2, 100.3, 67.1, 49.8.

HRMS (APCI): calcd. for C ₂₃ H ₂₂ N ₃ 02 [M+H] ⁺ = 372.1707; found [M+H] ⁺ = 372.1707.

Preparative Examples 17D-17I By essentially same procedure set forth in Preparative Example 17C, using proper amines instead of 4-morpholinoaniline, the compounds given below were prepared.

Pre arative Example 17D

Brown semi - solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.87-7.83 (m _} 2H); 7.74 (d, J = 2.21 Hz,; 1H); 7.42-7.37 (m, 2H); 7.35-7.31 (m, 1H); 7.25 (s, 1H); 6.98 (d, J= 2.20 Hz, 1H); 6.95 (d, J= 8.36 Hz, 1H); 6.87 (dd, J= 2.33 Hz, 8.36 Hz, 1H); 6.83 (d, J= 2.33 Hz, 1H); 6.38 (brs, 1H); 3.84 (s, 3H); 3.20-3.02 (m, 4H); 2.69-2.58 (m, 4H); 2.36 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 156.4, 153.3, 147.6, 147.4, 140.9, 138.8, 137.4, 137.0, 134.4, 128.7, 128.5, 127.5, 119.2, 115.3, 109.3, 107.1, 100.6, 55.9, 55.6, 50.9, 46.3.

HRMS (APCI): calcd. for C ₂₅ H ₂₇ N ₄ 0 ₂ [M+H] ⁺ = 415.2129; found [M+H] ⁺ = 415.2130.

Preparative Example 17E

Orange solid.

⁵ H NMR (500 MHz, DMSO-d ₆ ) δ 8.36 (d, J = 2.26 Hz, 1H); 8.01-7,97 (m, 2H); 7.93 (s, 1H); 7.61-7.50 (m, 3H); 7.48-7.43 (m, 1H); 7.38 (s, 1H); 7.21 (d, J= 2.25 Hz, 1H); 2.33 (s, 3H). ⁱ³ C NMR (126 MHz, DMSO-d ₆ ) δ 168.5, 153.3, 150.6, 146.5, 143.5, 138.8, 130.8, 128.7, 128.7, 126.6, 121.5, 110.7, 108.0, 53.7, 20.0.

HRMS (APCI): calcd. for d ₇ Hi ₄ N ₃ OS [M+H] ⁺ = 308.0852; found [M+H] ⁺ = 308.0850.

Preparative Example 17F

Pale yellow solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.89-7.86 (m, 2H); 7.76 (d, J = 2.21 Hz, 1H); 7.44-7.29 (m, 8H); 7.18-7.14 (m, 1H); 7.00 (d, J= 2.22 Hz, 1H); 6.48 (brs, 1H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 156.4, 147.7, 147.6, 140.9, 139.5, 137.2, 136.4, 129.9, 128.8, 128.5, 127.5, 124.5, 121.8, 109.3, 101.0.

HRMS (APCI): calcd. for Ci ₉ H, ₅ N ₂ 0 [M+H] ⁺ = 287.1179; found [M+H] ⁺ = 287.1178.

Preparative Example 17G

Orange semi - solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.95-7.90 (m, 2H); 7.69 (d, J= 2.17 Hz, 1H); 7.46-7.40 (m, 2H); 7.38-7.33 (m, 1H); 6.94 (d, J = 2.17 Hz, 1H); 6.81 (s, 1H); 5.36-5.23 (m, 1H); 3.43 (dd _s J= 5.19 Hz, 11.56 Hz, 2H); 2.69-2.62 (m, 2H); 2.30 (s, 6H). ¹³ C NMR (126 MHz, CDC1 ₃ ) S 156.4, 147.1, 146.6, 141.3, 140.1, 137.0, 128.7, 128.4, 127.6, 109.0, 99.5, 57.8, 45.3, 40.2.

HRMS (APCI): calcd. for Ci ₇ H ₂ oN ₃ 0 [M+H] ⁺ = 282.1601; found [M+H] ⁺ = 282.1602.

Preparative Example 17H

Pale yellow solid foam.

1H NMR (500 MHz, CDC1 ₃ ) δ 8.41 (s, 1H); 8.03-7.98 (m, 2H); 7.76 (d, J = 2.21 Hz, 1H); 7.46-7.42 (m, 2H); 7.39-7.35 (m, 1H); 7.15 (brs, 1H); 7.02 (d, J = 2.21 Hz, 1H); 1.57 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 156.5, 152.0, 148.1, 147.3, 140.3, 136.9, 131.4, 128.8, 128.8, 127.7, 109.4, 105.5, 82.4, 28.5.

HRMS (APCI): calcd. for Ci ₈ Hi ₉ N ₂ 0 ₃ [M+H] ⁺ = 311.1390; found [M+H] ⁺ = 311.1394.

Preparative Example 171

Orange wax.

1H NMR (500 MHz, CDC1 ₃ ) δ 7.93-7.89 (m, 2H); 7.73 (d, J = 2.22 Hz, 1H); 7.47-7.41 (m, 2H), 7.40-7.35 (m, 1H); 6.99 (d, J= 1.60 Hz, 1H); 6.92 (s, 1H); 3.67-3.60 (m, 8H); 1.48 (s, 9H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 156.3, 154.9, 147.2, 142.3, 138.0, 128.8, 128.7, 127.6, 108.9, 102.9, 80.4, 48.1, 28.7.

HRMS (APCI): calcd. for C ₂₂ H ₂₆ N ₃ 0 ₃ [M+H] ⁺ = 380.1969; found [M+H] ⁺ = 380.1970.

Preparative Example 18A

To a stirred solution of the product from Preparative Example 17H (0.031 g; 0.10 mmol) in ethanol (2 mL) was added aqueous solution of HCl (3M; 0.7 mL; 2.1 mmol) and the resulting mixture was stirred under N ₂ at 60 °C for 18 h. Then the ethanol and HCl were evaporated and the oily residue was treated with CH2CI2 (2 mL), MeOH (lmL) and Na ₂ C0 ₃ (200 mg) and the mixture was stirred at 25 °C. After 20 min., the solvents were evaporated and the solid residue was purified by preparative TLC (eluent: CH ₂ Cl2 7N NH ₃ in MeOH - 50:1) to yield the product as a white solid (0.019 g; 88 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.92-7.87 (m, 2H); 7.72 (d, J= 2.20 Hz, 1H); 7.45-7.40 (m, 2H); 7.38-7.33 (m, 1H); 6.95 (d, J= 2.20 Hz, 1H); 6.92 (s, 1H); 4.49 (brs, 2H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) S 156.1, 147.8, 147.5, 140.6, 138.5, 137.0, 128.8, 128.5, 127.5, 109.0, 103.2.

HRMS (APCI): calcd. for Ci ₃ H, ]N ₂ 0 [M+H]* = 21 1.0866; found [M+H] ⁺ = 211.0866.

Preparative Example 18B

By essentially same procedure set forth in Preparative Example 18A, using the product from Preparative Example 171, the compound given below was prepared.

Pale yellow semi - solid.

^] H NMR (500 MHz, CDC1 ₃ ) δ 7.93-7.89 (m, 2H); 7.71 (d, J= 2.21 Hz, 1H); 7.46-7.40 (m, 2H); 7.38-7.34 (m, 1H); 6.96 (d, J = 2.22 Hz, 1H); 6.92 (s, 1H); 3.65-3.60 (m, 4H); 3.13- 3.04 (m, 4H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 156.4, 148.4, 146.9, 142.7, 141.0, 138.2, 128.8, 128.5, 127.6, 108.9, 102.8, 49.2, 46.0.

HRMS (APCI): calcd. for Ci ₇ H ₁₈ N ₃ 0 [M+H = 280.1444; found [M+H] ⁺ - 280.1443.

Preparative Example 19 A

To a freshly prepared solution of (iS)-l-[(i.p)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- tert-butylphosphine (0.012 g; 0.022 mmol) and Pd(OAc) ₂ (0.008 g; 0.037 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from Preparative Example 16 (0.049 g; 0.21 mmol), f-BuOK (0.038 g; 0.34 mmol) and 4-ammo-N,N-dimethyl- benzenesulfonamide (0.051 g; 0.25 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 16 h. Then it was diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3x15 mL). The organic extracts were dried over MgS0 _4s filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ /MeOH - 15:1). So obtained oil was further purified by preparative TLC (eluent: CH ₂ Ci2 MeOH - 20:1) to yield the yellow semi - solid product (0.036 g; 43 %).

Ή NMR (500 MHz, CDC1 ₃ ) <S 7.90-7.86 (m, 2H); 7.78-7.71 (m, 3H); 7.49 (s, 1H); 7.45- 7.32 (m, 5H); 7.03 (brs, 1H); 7.00 (d, J= 2.15 Hz, 1H); 2.72 (s, 6H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 156.4, 148.3, 148.3, 144.5, 140.3, 137.6, 134.1, 129.8, 129.2, 128.9, 128.9, 127.5, 118.8, 109.2, 103.2, 38.2.

HRMS (APCI): calcd. for C ₂ iH ₂ oN ₃ 0 ₃ S [M+H] ⁺ = 394.1220; found [M+H] ⁺ = 394.1217.

Preparative Example 19B

By essentially same procedure set forth in Preparative Example 19A, using cyclohexylamine instead of 4-amino-N,7V-dimethyl-benzenesulfonamide, the compound given below was prepared.

Yellow wax.

1H NMR (500 MHz, CDC1 ₃ ) δ 7.92-7.87 (m, 2H); 7.66 (d, J = 2.17 Hz, 1H); 7.45-7.39 (m, 2H); 7.38-7.32 (m, 1H); 6.96 (d, J = 2.17 Hz, 1H); 6.81 (s, 1H); 4.70 (brs, 1H); 3.65-3.52 (m, 1H); 2.16-2.05 (m, 2H); 1.84-1.75 (m, 2H); 1.71-1.62 (m, 1H); 1.48-1.36 (m, 2H); 1.35-1.19 (m, 4H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 156.0, 147.1, 146.0, 140.8, 139.4, 136.7, 128.7, 128.5, 127.6, 108.8, 99.5, 51.5, 33.4, 25.8, 25.0.

HRMS (APCI): calcd. for C _i9 H _2i N ₂ 0 [M+H] ⁺ = 293.1648; found [M+H] ⁺ = 293.1647.

Preparative Example 19C

Degassed 1,2-dimethoxyethane (2.5 mL) was added under N ₂ into a 10 mL round bottom flask containing Pd ₂ (dba) ₃ (15.9 mg, 0.017 mmol) and SPhos (7.1 mg ₅ 0.017 mmol). After 5 min, the product from Preparative Example 16 (40 mg, 0.17 mmol), 5-methylisoxazoI-3- amine (20 mg, 0.212 mmol) and Cs ₂ CC>3 (125 mg, 0.383 mmol) were added. The mixture was stirred at 80 °C under N ₂ for 24 h, then the temperature was elevated to 120 °C and the mixture was stirred for additional 24 h. ¾0 (15 mL) was added and the mixture was extracted with EtOAc (3x25 mL). The organic phase was dried over Na ₂ S04, filtered, and then the solvent was evaporated. The residue was purified by column chromatography (CH ₂ Cl ₂ EtOAc; 2:1) and then by preparative TLC (CH ₂ Cl ₂ /EtOAc; 2:1). The product was obtained as a colorless wax (14 mg, 30 % yield).

Ή NMR (300 Hz, CDC1 ₃ ) S 8.21 (s, 1H), 8.03 (d, J= 7.9 Hz, 2H), 7.77 (d, J = 1.7 Hz, 1H), 7.54 - 7.34 (m, 3H), 7.09 - 6.96 (m _s 2H), 5.92 (s, 1H), 2.42 (s, 3H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) 6 169.4, 159.5, 156.4, 147.6, 146.7, 140.0, 136.4, 132.8, 128.5, 128.4, 127.3, 109.0, 104.3, 94.8, 12.4.

HRMS (APCI): calcd. for Ci 7Hi ₃ N ₃ 0 ₂ [M+H] ⁺ = 292.1081 ; found [M+H] ⁺ = 292.1082.

Preparative Example 1 D

By essentially same procedure set forth in Preparative Example 19C, using isoxazol-3- amine instead of 5-methylisoxazoI-3 -amine, the compound given below was prepared.

Colorless wax.

Ή NMR (500 MHz, CDCI ₃ ) δ 8.30 (d, J= 1.7 Hz, 1H), 8.28 (s, 1H), 8.07 - 8.01 (m, 2H), 7.78 (d, J= 2.2 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 7.14 (s, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.28 (d, J = 1.7 Hz, 1H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) <? 158.2, 157.6, 155.8, 146.8, 146.1, 139.3, 135.6, 131.8, 127.7, 127.7, 126.6, 108.3, 103.7, 97.0.

HRMS (APCI): calcd. for Ci«HnN ₃ 0 ₂ [M+H] ⁺ = 278.0924; found [M+H = 278.0926.

Preparative Example 19E

By essentially same procedure set forth in Preparative Example 19C, using pyridin-3- amine instead of 5-methylisoxazol-3-amine, the compound given below was prepared.

Colorless wax.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.65 (s, 1H) _; 8.42 (d, J= 4.2 Hz, 1H), 7.93 - 7.84 (m, 2H) ₃ 7.78 (d, J = 2.2 Hz, 1H), 7.71 - 7.62 (m, 1H), 7.46 - 7.31 (m, 5H), 7.02 (d, J = 2.2 Hz, 1H), 6.66 (s, 1H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 156.4, 148.0, 147.9, 145.3, 143.5, 140.4, 137.1, 136.4, 135.5, 128.7, 128.6, 128.2, 127.4, 124.1, 109.2, 101.1.

HRMS (APCI): calcd. for C ₁₈ Hi ₃ N ₃ 0 [M+H] ⁺ = 288.1131; found [M+H] ⁺ = 288.1132.

Preparative Example 19E By essentially same procedure set forth in Preparative Example 19C, using 1 -methyl- 1H- pyrazol-4-amine instead of 5-methyIisoxazol-3-amine, the compound given below was prepared.

Yellow wax.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.89 - 7.84 (m, 2H), 7.75 (d, J = 2.2 Hz, 1H), 7.55 (s, 1H), 7.46 - 7.39 (m, 3H), 7.38 - 7.34 (m, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.98 (s, 1H), 6.00 (s, 1H), 3.94 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 156.4, 147.5, 146.9, 140.8, 138.8, 136.6, 136.1, 128.6, 128.4, 127.4, 125.9, 121.4, 109.0, 100.0, 39.7.

HRMS (APCI): calcd. for C _I7 Hi ₄ N ₄ 0 [M+H] ⁺ = 291.1240; found [M+H] ⁺ = 291.1237.

Preparative Example 20

To a mixture of the product from Preparative Example 3 (4.34 g; 17.0 mmol) and K ₂ C0 ₃ (7.07 g; 51.1 mmol) in N,N-dimethylformamide (30 mL) was added under N ₂ crotyl bromide (2.6 mL; 25.3 mmol). The resulting reaction mixture was stirred under N ₂ at 60 °C for 2 h. Then the solvent was evaporated and the residue was suspended between H ₂ 0 (120 mL) and CH ₂ C1 ₂ (90 mL). The water phase was extracted with CH ₂ C1 ₂ (3x100 mL). The organic extracts were washed with brine (100 mL), dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 1 :1). So obtained pale yellow solid was washed with cold pentane (3 x 25 mL) to yield the white crystalline product (4.24 g; 81 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.19-7.11 (m, 1H); 6.93 (d, J= 8.46 Hz, 1H); 5.93-5.83 (m, 1H); 5.71-5.61 (m, 1H); 4.52 (d, J= 5.49 Hz, 2H); 1.75 (d, J= 6.42 Hz, 3H).

^I3 C NMR (126 MHz, CDCI3) S 154.4, 141.6, 131.7, 124.7, 123.7, 121.3, 110.0, 70.8, 18.1. HRMS (APCI): calcd. for C ₉ Hi ₀ ClINO [M+H] ⁺ = 309.9490; found [M+H] ⁺ = 309.9488. Preparative Example 21

The mixture of the product from Preparative Example 20 (4.24 g; 13.7 mmol), K2CO3 (4.75 g; 34.4 mmol), HCOONa (0.934 g; 13.7 mmol); tetrabutylammonium chloride (4.21 g; 15.1 mmol) and Pd(OAc) ₂ (0.185 g; 0.82 mmol) in N,N-dimemylformamide (30 mL) was stirred under N ₂ at 80 °C for 3 h. Then the solvent was evaporated and the residue was suspended between ¾0 (180 mL) and CH2CI2 (100 mL). The aqueous phase was extracted with CH2CI2 (3x100 mL). The organic extracts were washed with brine (100 mL), dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 30:1) to yield the product as a pale yellow solid (0.774 g; 31 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.66-7.62 (m, 2H); 7.19 (d, J= 8.55 Hz, 1H); 2.76 (dq, J = 1.23 Hz, 7.51 Hz, 2H); 1.33 (t, J= 7.52 Hz, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 147.8, 147.4, 146.6, 146.2, 123.6, 120.9, 119.2, 16.0, 13.5. HRMS (APCI): calcd. for C ₉ H ₉ CINO [M+H] ⁺ = 182.0367; found [M+Hf = 182.0365.

Preparative Example 22

To a freshly prepared solution of (iS)-l-[(i?p)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- tert-butylphosphine (0.022 g; 0.039 mmol) and Pd(OAc) ₂ (0.009 g; 0.039 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from Preparative Example 21 (0.087 g; 0.48 mmol), i-BuONa (0.064 g; 0.66 mmol) and N,N- dimethylethylenediamine (0.063 mL; 0.57 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 15 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3 ^x 15 mL). The organic extracts were dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2CI2/7N NH ₃ in MeOH - 15:1) to yield the product as an orange oil (0.081 g; 73 %).

1H NMR (500 MHz, CDC1 ₃ ) S 7.46-7.41 (m, 2H); 6.32 (d, J= 8.87 Hz, 1H); 5.00-4.89 (m, 1H); 3.42 (dd, J= 5.69 Hz, 11.45 Hz, 2H); 2.68 (dq, J= 1.14 Hz, 7.51 Hz, 2H ); 2.58 (t, J = 6.06 Hz, 2H); 2.28 (s, 6H); 1.31 (t, J = 7. 1 Hz, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 156.7, 145.3, 143.7, 143.2, 123.0, 120.4, 104.5, 58.6, 45.5, 40.2, 16.2, 13.5.

HRMS (APCI): calcd. for C, ₃ H ₂ oN ₃ 0 [M+H] ⁺ = 234.1601 ; found [M+H] ⁺ = 234.1601.

Preparative Example 23

To a mixture of the product from Preparative Example 21 (0.053 g; 0.29 mmol), 1- methylpyrazole-4-boronic acid pinacol ester (0.074 g; 0.36 mmol), K ₃ P0 ₄ (0.262 g; 1.23 mmol) and PdCl ₂ .dppf (0.013 g; 0.017 mmol) were added under N ₂ 1 ,2-dimethoxyethane (2 mL) and water (0.5 mL). The reaction mixture was refluxed for 19 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3^15 mL). The organic extracts were dried over Na2S0 , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl2 MeOH - 10:1) to yield the product as a brown semi - solid (0.055 g; 83 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.04-7.91 (m, 2H); 7.64 (d, J- 8.49 Hz, 1H); 7.58 (s, 1H); 7.36 (d, J= 8.51 Hz, 1H); 3.94 (s, 3H); 2.81 (q, J= 7.35 Hz, 2H); 1.37 (t, J= 7.49 Hz, 3H). ^I3 C NMR (126 MHz, CDCI3) δ 148.1, 147.5, 147.1, 145.1, 137.7, 129.0, 124.3, 123.7, 118.9, 115.7, 39.3, 16.2, 13.5.

HRMS (APCI): calcd. for Ci ₃ H ₁₄ N ₃ 0 [M+H] ⁺ = 228.1131 ; found [M+H] ⁺ = 228.1133.

Preparative Example 24

To a mixture of the product from Preparative Example 21 (1.43 g; 7.85 mmol), phenylboronic acid (1.24 g; 10.2 mmol), K ₃ P0 ₄ (6.86 g; 32.3 mmol) and PdCl ₂ .dppf (0.530 g; 0.72 mmol) were added under N ₂ 1 ,2-dimethoxyethane (50 mL) and water (10 mL). The reaction mixture was refluxed under N ₂ for 18 h. Then it was cooled to 25 °C, diluted with EtOAc (70 mL), poured into brine (100 mL) and extracted with EtOAc (3> 70 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 15:1) to yield the product as a pale yellow solid (1.59 g; 91 %).

Ή NM (500 MHz, CDC1 ₃ ) δ 8.04 (d, J - 7.51 Hz, 2H); 7.73 (d, J = 8.54 Hz, 1H); 7.63 (d, J= 8. 1 Hz, 2H); 7.51-7.43 (m, 2H); 7.42-7.35 (m, 1H); 2.86 (q _} J= 7.48 Hz, 2H); 1.41 (t, J= 7.37 Hz, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 153.8, 147.9, 147.7, 145.2, 140.4, 128.9, 128.6, 127.4, 124.1, 118.7, 116.6, 16.2, 13.6.

HRMS (APCI): calcd. for Ci ₅ Hi ₄ NO [M+H] ⁺ = 224.107; found [M+H] ⁺ = 224.1068.

Preparative Example 25

To a stirred solution of the product from Preparative Example 24 (1.59 g, 7.12 mmol) in anhydrous CH ₂ CI ₂ (20 ml) was added MCPBA (2.22 g, 12.9 mmol) and the resulting mixture was stirred under N ₂ at 25 °C for 72 h. Then it was poured into saturated aqueous solution of NaHC0 ₃ (150 mL) and extracted with CH ₂ CI ₂ (3x80 mL). The organic extracts were washed with brine (80 mL), dried over Na ₂ S0 _; filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ EtOAc - 5:1) to yield the product as a pale yellow solid (0.545 g; 32 %). ^! H NMR (500 MHz, CDC1 ₃ ) δ 7.83-7.76 (m, 2H); 7.50-7.35 (m, 5H); 7.27 (d, J= 8.60 Hz, 1H); 3.07 (q, J= 7.37 Hz, 2H); 1.34 (t, J= 7.41, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 151.0, 145.4, 144.0, 137.7, 133.1, 129.9, 129.3, 128.4, 122.2, 1 10.4, 18.1, 14.9.

HRMS (APCI): calcd. for Ci ₅ H ₁₄ N0 ₂ [M+H] ⁺ = 240.1019; found [M+H] ⁺ = 240.1017.

Preparative Example 26

To a stirred solution of the product from Preparative Example 25 (0.713 g, 2.98 mmol) in CHCI ₃ (15 ml) was added POCl ₃ (6 mL, 64.4 mmol) and the resulting mixture was refluxed under N ₂ for 1 hr. Then, the CHCI ₃ and POCI ₃ were evaporated under reduced pressure. The dark oily residue was diluted with CH ₂ C1 ₂ (50 mL), poured into saturated aqueous solution of NaHC0 ₃ (200 mL) and extracted with CH ₂ C1 ₂ (3*50 mL). The organic extracts were washed with water (50 mL), with brine (80 mL), dried over Na ₂ S0 , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/CH ₂ Cl ₂ - 2:1) to yield the product as a white solid (0.282 g; 37 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.07-7.98 (m, 2H); 7.69-7.64 (m _s 2H); 7.52-7.36 (m, 3H); 2.84 (dd, J= 6.89 Hz, 14.36 Hz, 2H); 1.45-1.39 (m, 3H).

^!3 C NMR (126 MHz, CDC1 ₃ ) S 155.0, 149.1, 145.8, 144.2, 139.3, 129.1, 129.0, 127.4, 126.3, 124.8, 117.1, 16.3, 13.5.

HRMS (APCI)-. calcd. for Ci _S Hi ₃ ClNO [M+H] ⁺ = 258.0680; found [M+H] ⁺ = 258.0678.

Preparative Example 27A

To a solution of the product from Preparative Example 26 (0.202 g; 0.78 mmol), (R)- BINAP (0.032 g; 0.052 mmol), Pd ₂ (dba) ₃ (0.044 g; 0.048 mmol) and t-BuOK (0.146 g; 1.30 mmol) in anhydrous toluene (4 mL) was added benzylamine (0.100 mL; 0.92 mmol) and the resulting mixture was stirred under N ₂ at 80 °C for 17 h. Then it was cooled to 25 °C, diluted with EtOAc (10 mL), poured into water (25 mL) and extracted with EtOAc (3x10 mL). The organic extracts were washed with brine (15 mL), dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2CI2/ MeOH - 20:1) to yield a brownish solid (0.168 g; 65 %).

^! H NMR (500 MHz, CDC1 ₃ ) δ 7.94-7.89 (m, 2H); 7.49-7.46 (m, 1H); 7.43-7.27 (m, 8H); 6.85 (s, 1H); 4.89 (brs, 1H); 4.58 (d, J- 5.67 Hz, 2H); 2.83 (dd, J= 1.08 Hz, 7.49 Hz, 2H); 1.38 (t, J= 7.51 Hz, 3H).

) ³ C NMR (126 MHz, CDC1 ₃ ) δ 155.7, 146.6, 143.1, 141.4, 139.6, 138.3, 137.2, 129.1, 128.7, 128.3, 128.0, 127.7, 127.6, 124.6, 99.3, 47.4, 16.4, 13.6.

HRMS (APCI): calcd. for C22H21N2O [M+H] ⁺ = 329.1648; found [M+H] ⁺ = 329.1650.

Preparative Example 27B

By essentially same procedure set forth in Preparative Example 27A, using N,N- dimethylethylenediamine instead of benzylamine, the compound given below was prepared.

Yellow wax.

1H NMR (500 MHz, CDC1 ₃ ) δ 7.99-7.95 (m, 2H); 7.48-7.46 (m, 1H); 7.45-7.40 (m, 2H); 7.37-7.32 (m, 1H); 6.81 (s, 1H); 5.19-5.11 (m, 1H); 3.41 (dd, J= 5.16 Hz, 1 1.70 Hz, 2H); 2.82 (qd, J = 1.20 Hz, 7.50 Hz, 2H); 2.66-2.59 (m, 2H); 2.28 (s, 6H); 1.38 (t, J = 7.51 Hz, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 155.6, 146.7, 142.9, 141.6, 139.9, 137.3, 128.7, 128.2, 127.6, 124.5, 99.3, 57.9, 45.4, 40.3, 16.4, 13.6.

HRMS (APCI): calcd. for Ci ₉ H ₂₄ N ₃ 0 [M+H] ⁺ = 310.1914; found [M+H] ⁺ = 310.1915.

Preparative Example 28

To a stirred solution of the product from Preparative Example 27A (0.052 g, 0.16 mmol) in hot EtOH (2 ml) were added Pd(OH) ₂ (37 mg) and ammonium formate (0.059 g; 0.94 mmol) and the resulting mixture was refluxed under N ₂ for 42 h. Then it was cooled to 25 °C, filtereded, and the solvent was evaporated. The residue was purified by preparative TLC (eluent: CH2CI2/NH3 in MeOH - 50:1) to yield the product as a white solid (0.012 g; 32 %).

1H NMR (500 MHz, CDC1 ₃ ) S 7.96 (d, J = 7.43 Hz, 2H); 7.50 (s, 1H); 7.46-7.39 (m, 2H); 7.38-7.31 (m, 1H); 6.92 (s, 1H); 4.36 (brs, 2H); 2.82 (q, J= 7.26 Hz, 2H); 1.38 (t, J= 7.45 Hz, 3H). ^U C NMR (126 MHz, CDC1 ₃ ) δ 155.3, 147.7, 143.6, 140.9, 138.1, 137.4, 128.7, 128.3, 127.4, 124.5, 103.0, 16.4, 13.6.

HRMS (APCI): calcd. for C _!5 Hi ₅ N ₂ 0 [M+H] ⁺ = 239.1179; found [M+H] ⁺ = 239.1179.

Preparative Example 29

To a freshly prepared solution of xantphos (0.022 g; 0.038 mmol) and Pd ₃ (dba) ₂ (0.042 g; 0.046 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from

Preparative Example 26 (0.104 g; 0.40 mmol), r-BuOK (0.097 g; 0.86 mmol) and aniline

(0.048 mL; 0.53 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 16 h.

Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3 15 mL). The organic extracts were dried over MgS0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc - 15:1) to yield the product as a pale solid (0.064 g; 51

%).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.96-7.91 (m, 2H); 7.56-7.53 (m, 1H); 7.45-7.27 (m, 8H); 7.17-7.12 (m, 1H); 6.40 (brs, 1H); 2.86 (qd, J = 1.15 Hz, 7.50 Hz, 2H); 1.41 (t, J = 7.51 Hz, 3H).

^I3 C NMR (126 MHz, CDC1 ₃ ) δ 155.5, 147.7, 143.5, 141.1, 139.8, 137.6, 136.1, 129.9, 128.7, 128.4, 127.6, 124.8, 124.2, 121.5, 100.9, 16.4, 13.6.

HRMS (APCI): calcd. for C ₂ iH] ₉ N ₂ 0 [M+H] ⁺ = 315.1492; found [M+H] ⁺ = 315.1492.

Preparative Example 30

To a freshly prepared solution of xantphos (0.023 g; 0.039 mmol) and Pd ₃ (dba)2 (0.036 g; 0.039 mmol) in anhydrous 1 ,2-dimethoxyethane (2 mL) were added the product from Preparative Example 26 (0.104 g; 0.40 mmol), t-BuOK (0.158 g; 1.40 mmol) and 5-amino- 3-methyl-isothiazole hydrochloride (0.115 g; 0.76 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 22 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3*15 mL). The organic extracts were dried over MgS0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ MeOH - 20:1). So obtained oil was further purified by preparative TLC (eluent: CH ₂ Cl ₂ / eOH - 30:1) to yield the product as a pale orange solid (0.053 g; 39 %).

1H NM (500 MHz, DMSO-d6) δ 8.15-8.12 (m, 1H); 8.03-7.98 (m, 2H); 7.94-7.88 (m, 1H); 7.56-7.50 (m, 3H); 7.47-7.43 (m, 1H); 7.37 (s, 1H); 2.77 (qd, J = 1.05 Hz, 7.48 Hz, 2H); 2.32 (s, 3H); 1.35 (t, J= 7.51 Hz, 3H).

¹³ C NMR (126 MHz, DMSO-d6) δ 168.4, 152.7, 146.4, 146.0, 143.9, 138.9, 130.6, 128.7, 128.6, 126.6, 122.8, 121.5, 110.6, 53.9, 20.0, 15.5, 13.3.

HRMS (APCI); calcd. for Ci ₉ H _i8 N ₃ OS [M+H] ⁺ = 336.1165; found [M+H] ⁺ = 336.1164.

Preparative Example 31A

To a freshly prepared solution (5)-l-[(i- )-2-(dicyclohexylphosphino)ferrocenyl]ethyldi- tert-butylphosphine (0.011 g; 0.021 mmol) and Pd(OAc) ₂ (0.006 g; 0.028 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) were added the product from Preparative Example 26 (0.109 g; 0.42 mmol), t-BuONa (0.060 g; 0.62 mmol) and 3-picolylamine (0.045 mL; 0.44 mmol) and the resulting mixture was stirred under N ₂ at 100 °C for 17 h. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3x 15 mL). The organic extracts were dried over MgS0 _4s filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl ₂ /MeOH - 10:1). So obtained oil was further purified by preparative TLC (eluent: CH ₂ C1 ₂ NH ₃ in MeOH - 30:1) to yield the product as a pale yellow solid (0.081 g; 58 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.67 (s, 1H); 8.55 (d, J= 4.20 Hz, 1H); 7.92-7.86 (m, 2H); 7.73-7.68 (m, 1H); 7.48 (s, 1H); 7.43-7.37 (m, 2H); 7.36-7.31 (m, 1H); 7.29-7.25 (m, 1H); 6.81 (s, 1H); 5.01-4.90 (m, 1H); 4.62 (d, J = 5.83 Hz, 2H); 2.82 (qd, J = 0.84 Hz, 7.45, 2H); 1.38 (t, J = 7.51 Hz, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 155.7, 149.5, 149.3, 146.9, 143.3, 141.1, 139.2, 137.1,

135.2, 133.9, 128.7, 128.4, 127.5, 124.6, 123.9, 99.4, 45.0, 16.4, 13.6.

HRMS (APCI): calcd. for C21H20N3O [M+H] ⁺ = 330.1601 ; found [M+H] ⁺ = 330.1598. Preparative Examples 31B-31D

By essentially same procedure set forth in Preparative Example 31 A, using proper amines instead of 3-picolylamine, the compounds given below were prepared.

Preparative Example 31B

Pale yellow solid.

1H NMR (500 MHz, CDC1 ₃ ) δ 7.97-7.91 (m, 2H); 7.78-7.73 (m, 2H); 7.59-7.55 (m, 1H); 7.50 (s, 1H); 7.46-7.32 (m, 5H); 6.90 (brs, 1H); 2.86 (qd, J= 0.86 Hz, 7.44 Hz, 2H); 2.76- 2.70 (m, 6H); 1.40 (t, J = 7.51 Hz, 3H).

1 ³ C NMR (126 MHz, CDCI ₃ ) 6 155.3, 148.1, 144.6, 144.3, 140.1, 138.0, 133.9, 129.9, 129.3, 128.9, 127.6, 126.6, 124.7, 1 18.7, 103.1, 38.2, 16.4, 13.6.

HRMS (APCI): calcd. for C ₂ 3H _{24 3} 03S [M+H] ⁺ = 422.1533; found [M+H] ⁺ = 422.1534.

Preparative Example 31C

Brown solid.

1H NMR (500 MHz, CDC1 ₃ ) δ 7.92-7.86 (m, 2H); 7.55-7.52 (m, 1H); 7.42-7.30 (m, 4H); 7.23-7.20 (m, 1H); 7.17-7.13 (m, 1H); 6.98-6.92 (m, 2H); 6.31 (brs, 1H); 3.90-3.84 (m, 4H); 3.20-3.14 (m _s 4H); 2.87 (q, J= 7.42 Hz, 2H); 1.39 (t, J= 7.50 Hz, 3H).

i ³ C NMR (126 MHz, CDCI3) δ 155.3, 149.0, 143.5, 137.3, 131.6, 128.7, 128.5, 127.7, 124.6, 124.6, 124.5, 123.8, 117.0, 1 16.4, 100.3, 67.1, 49.8, 16.5, 13.6.

HRMS (APCI): calcd. for C25H26N3O2 [M+Hf = 400.2020; found [M+H] ⁺ = 400.2019.

Preparative Example 31D

Brown solid foam.

lR NMR (500 MHz, CDC1 ₃ ) δ 7.98-7.93 (m, 2H); 7.53-7.50 (m, IH); 7.46-7.40 (m, 2H); 7.39-7.33 (m, IH); 6.92 (s, IH); 3.66-3.56 (m, 8H); 2.84 (q, J= 7.39 Hz, 2H); 1.48 (s, 9H); 1.38 (t, J= 7.51 Hz, 3H).

¹³ C NMR (126 MHz, CDCI ₃ ) S 155.4, 154.9, 143.0, 142.2, 138.4, 128.8, 128.5, 127.6, 124.2, 102.8, 80.4, 48.1, 28.6, 16.3, 13.6.

HRMS (APCI): calcd. for C24H30N3O3 [M+H] ⁺ = 408.2282; found [M+H] ⁺ = 408.2281.

Preparative Example 32

To a stirred solution of the product from Preparative Example 3 ID (0.088 g; 0.22 mmol) in ethanol (2 mL) was added aqueous HCl (3 M; 1.4 mL; 4.2 mmol) and the resulting mixture was stirred under N ₂ at 60 °C for 17 h. Then, the ethanol and HCl were evaporated and the oily residue was mixed with CH ₂ C1 ₂ (2 mL), MeOH (lmL) and Na ₂ C0 ₃ (200 mg) and the mixture was stirred at 25 °C. After 20 min., the solvents were evaporated and the solid residue was purified by column chromatography on silica gel (eluent: CH2CI2/7N N¾ in MeOH - 15: 1) to yield the product as a pale solid (0.048 g; 72 %).

^[ H NMR (500 MHz, CDC1 ₃ ) δ 7.99-7.94 (m, 2H); 7.51-7.48 (m, IH); 7.46-7.40 (m, 2H); 7.38-7.32 (m, IH); 6.93 (s, IH); 3.63-3.56 (m, 4H); 3.11-3.04 (m, 4H); 2.82 (qd, J = 1.22 Hz, 7.50 Hz, 2H); 2.04 (brs, IH); 1.37 (t, J= 7.51 Hz, 3H).

i ³ C NMR (126 MHz, CDC1 ₃ ) δ 155.4, 148.4, 142.7, 142.6, 141.3, 138.5, 128.7, 128.3, 127.5, 124.2, 102.5, 49.3, 46.1, 16.3, 13.6.

HRMS (APCI): calcd. for C _!9 H ₂ 2N ₃ 0 [M+H] ⁺ = 308.1757; found [M+H] ⁺ = 308.1755.

Preparative Example 33

To a mixture of the product from Preparative Example 26 (0.047 g; 0.18 mmol), 1- methylpyrazole-4-boronic acid pinacol ester (0.045 g; 0.22 mmol), K ₃ P0 ₄ (0.163 g; 0.77 mmol) and PdCI ₂ (dppf) (0.009 g; 0.013 mmol) were added under N ₂ 1 ,2-dimethoxyethane (2 mL) and water (0.5 mL). The reaction mixture was refluxed for 15 hrs. Then it was cooled to 25 °C, diluted with EtOAc (15 mL), poured into brine (20 mL) and extracted with EtOAc (3x 15 mL). The organic extracts were dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eiuent: Ci^CLVEtOAc - 10:1). So obtained oil was further purified by preparative TLC (eiuent: CH ₂ C1 ₂ ) to yield the product as a white solid (0.024 g; 43 %).

Ή N R (500 MHz, CDC1 ₃ ) S 8.14 (d, J = 3.08 Hz, 2H); 8.07-8.02 (m, 2H); 7.73 (s, 1H); 7.67-7.64 (m, 1H); 7.50.7.44 (m, 2H); 7.41-7.36 (m, 1H); 3.99 (s, 3H); 2.87 (qd, J = 1.10 Hz, 7.49 Hz, 2H); 1.41 (t, J= 7.52 Hz, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 154.4, 148.2, 144.7, 144.2, 140.4, 138.4, 130.5, 128.9, 128.6, 127.5, 124.3, 124.2, 1 16.1 , 1 12.5, 39.5, 16.3, 13.6.

HRMS (APCI): calcd. for C ₁₉ H ₁₈ N ₃ 0 [M+H] ⁺ = 304.1444; found [M+H] ⁺ = 304.1444.

Preparative Example 34A

Into a 10 mL flask were placed 1,2-dimethoxyethane (3 mL), Pd(OAc)2 (1.8 mg, 0.008 mmol) and CyPF(t-Bu) (4.4 mg, 0.008 mmol) and the mixture was stirred at 25 °C under N2 for 5 min. Then, the product from Preparative Example 5A (55 mg, 0.20 mmol), N ^! ,N ^! - dimethylpropane- 1,3 -diamine (24 mg, 0.24 mmol) and t-BuONa (28 mg, 0.30 mmol) were added and the mixture was refluxed for 22 h. Brine (30 mL) was added and the mixture was extracted with EtOAc (30+20+20 mL). The organic phase was dried over Na ₂ S0 ₄ , filtered, and the solvent was evaporated. The residue was purified by preparative TLC on silica gel (CH ₂ Cl ₂ /7 M solution of N¾ in MeOH; 30:1). The product was obtained as a green solid (24 mg, 35 %).

!H NM (500 MHz, CDC1 ₃ ) δ 8.09 (s, 1H), 8.04 (dd, J= 8.5, 1.7 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.52 - 7.43 (m, 2H), 6.42 (d, J = 8.9 Hz, 1H), 3.56 (t, J= 6.6 Hz, 2H), 2.53 (t, J= 6.9 Hz, 2H), 2.31 (s, 6H), 1.94 (p, J= 6.8 Hz, 2H).

¹³ C NMR (126 MHz, CDCI3) S 156.9, 144.02, 143.7, 143.4, 133.8, 132.6, 128.9, 128.3, 128.1 , 127.7, 126.1 , 125.8, 125.7, 124.8, 120.7, 120.6, 105.0, 58.0, 45.4, 41.5, 27.0.

HRMS (ESI): calcd. for C22H23N3O [M+H] ⁺ - 346.1914; found [M+H] ⁺ - 346.1912.

Preparative Example 34B By essentially same procedure set forth in Preparative Example 34A, using 2- methoxyethanamine instead of N^N ¹ -dimethylpropane- 1,3 -diamine, the compound given below was prepared.

Dark red solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.84 (s, 1H), 8.10 (s, 1H), 8.04 (dd, J = 8.5, 1.7 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.87 - 7.81 (m, 1H), 7.59 (d, J = 8.9 Hz, lH), 7.53 - 7.44 (m, 2H), 6.46 (d, J= 8.9 Hz, 1H), 3.72 (s, 4H), 3.43 (s, 3H). ¹³ C NMR (126 MHz, CDC1 ₃ ) 6 156.5, 144.3, 143.9, 133.9, 132.8, 128.8, 128.4, 128.2,

127.8, 126.2, 125.9, 125.8, 124.9, 121.0, 120.8, 105.6, 71.6, 58.9, 42.4.

HRMS (APCI): calcd. for C ₂ oH ₁₈ N ₂ 0 ₂ [M+H] ⁺ = 319.1441 ; found [M+H] ⁺ = 319.1437.

Preparative Example 35

5-bromopyridin-3~ol (1.1 g, 6.3 mmol), iodine (1.6 g, 6.3 mmol), Na ₂ C03 (1.4 g, 13.2 g) and ¾0 (21 mL) were placed into a 100 mL round bottom flask. The mixture was stirred under N ₂ at 25 °C for 3 h. The mixture was neutralized with 1 M aqueous solution of HCl and extracted with EtOAc (60+40+40 mL). The organic phase was washed with brine (50 mL), dried over MgS0 ₄ and filtered. The product was obtained as a brown solid (1.89 g; 100 %).

]H NMR (300 MHz, CDC1 ₃ ) S 8.08 (d, J= 2.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 5.39 (s, 1H).

Preparative Example 36

The product from Preparative Example 35 (1.88 g, 6.27 mmol), 1 ,4-dioxane (12 mL) and TEA (12 mL) were placed into a 100 mL round bottom flask. The mixture was purged with N ₂ , then ethynyltrimethylsilane (1.15 mL, 8.15 mmol), PdCl ₂ (PPh ₃ ) ₂ (132 mg, 0.188 mmol) and Cul (71 mg, 0.376 mmol) were added. The mixture was stirred under N ₂ at 45 °C for 3 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :15). The product was obtained as an orange solid (1.04 g, 61 %).

Ή NMR (500 MHz, CDCI ₃ ) δ 8.58 (d, J

(d, J= 1.0 Hz, 1H), 0.37 (s, 9H). ^I3 C NMR (126 MHz, CDCI3) δ 170.2, 150.9, 147.1, 146.8, 121.1, 1 17.1, 115.2, -1.9.

HRMS (APCI): calcd. for Ci ₀ H ₁₂ BrNOSi [M+H] ⁺ = 269.9944; found [M+H] ⁺ = 269.9954.

Preparative Example 37

The product from Preparative Example 36 (47 mg, 0.174 mmol), phenylboronic acid (28 mg, 0.226 mmol), 1 ,2-dimethoxyethane (8 mL), TEA (1 mL) and H ₂ 0 (2 mL) were placed into a 25 mL round bottom flask and the mixture was purged with N ₂ . Then, PdCl ₂ (dppf) (3.8 mg, 5.2 μηιοΐ) was added and the mixture was refluxed under N ₂ for 75 min. After addition of brine (25 mL), the mixture was extracted with EtOAc (3x20 mL). The organic phase was dried over MgS04, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 : 10). The product was obtained as a white solid (39 mg, 84 ¾).

1H NMR (300 MHz, CDC1 ₃ ) S 8.78 (d, J - 1.8 Hz, 1H), 7.93 (d, J = 0.7 Hz, 1H), 7.69 ~ 7.59 (m, 2H), 7.55 - 7.35 (m, 3H), 7.17 (d, J = 0.8 Hz, 1H), 0.40 (s, 9H).

1 ³ C NMR (126 MHz, CDCI3) S 169.6, 151.2, 147.5, 145.1, 138.5, 132.9, 129.7, 129.2, 127.9, 127.6, 1 17.1, 116.4, 1 15.5, -1.8.

HRMS (APCI): calcd. for C ₁₆ H ₁₇ NOSi [M+H] ⁺ = 268.1 152; found [M+H] ⁺ = 268.1160.

Preparative Example 38

The product from Preparative Example 36 (47 mg, 0.174 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3 _? 2-dioxaborolan-2-yI)-lH-pyrazole (47 mg, 0.226 mmol), 1,2- dimethoxyethane (8 mL), TEA (1 mL) and H ₂ 0 (2 mL) were placed into a 25 mL round bottom flask and the mixture was purged with N ₂ . Then, PdCl2(dppf) (3.8 mg, 5.2 μπιοΐ) was added and the mixture was refluxed under N ₂ for 70 min. After addition of brine (25 mL), the mixture was extracted with EtOAc (3x20 mL). The organic phase was dried over MgS0 ₄ , filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (CH2Cl ₂ MeOH; 20:1). The product was obtained as a yellow wax (51 mg, 99 %).

1H NMR (500 MHz, CDCI ₃ ) δ 8.67 (d, J= 1.7 Hz, 1H), 7.79 (m, 2H), 7.68 (s, 1H), 7.12 (d, J= 1.0 Hz, 1H), 3.97 (s, 3H), 0.37 (s, 9H).

i ³ C NMR (126 MHz, CDC1 ₃ ) δ 168.9, 151.3, 146.7, 143.8, 137.1, 127.3, 124.6, 120.5, 117.2, 114.6, 39.3, -1.9.

HRMS (APCI): calcd. for C14H17N3OS1 [M+H] ⁺ = 272.1214; found [M+H] ⁺ = 272.1219.

Preparative Example 39

5-chloropyridin-3-ol (5.12 g, 39.7 mmol), iodine (10.1 g, 39.7 mmol), Na ₂ C0 ₃ (8.83 g, 83.3 mmol) and H ₂ 0 (80 mL) were placed into a 500 mL round bottom flask and the mixture was stirred under N ₂ at 25 °C for 3.5 h. The mixture was neutralized with 1 M aqueous solution of HCl (ca. 120 mL) and extracted with EtOAc (120+70+70 mL). The organic phase was washed with brine (80 mL), dried over MgS0 ₄ and filtered. The product was obtained as a brown solid (10.13 g; 100 %).

Ή NMR (300 MHz, DMSO) <5 11.38 (s, 1H), 7.95 (d, J= 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H).

Preparative Example 40

The product from Preparative Example 39 (8.34 g, 32.7 mmol), ethynyltrimethylsilane (6.0 mL, 42.5 mmol), PdCl ₂ (PPh ₃ ) ₂ (688 mg, 0.98 mmol), Cul (373 mg, 1.96 mmol), 1,4- dioxane (25 mL) and TEA (25 mL) were placed into a 250 mL round bottom flask. The mixture was stirred under N ₂ at 45 °C for 2.5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :15). The product was obtained as an orange solid (4.37 g, 59 %).

5 ^! H NM (500 MHz, CDC1 ₃ ) δ 8.52 (dd, J = 1.9, 1.4 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.16 - 7.12 (m, 1H), 0.40 (d, J= 1.0 Hz, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 170.3, 150.5, 146.9, 144.9, 127.2, 118.3, 117.1 , -1.9.

HRMS (APCI): calcd. for Ci ₀ Hi ₂ ClNOSi [M+H] ⁺ = 226.0449; found [M+H] ⁺ = 226.0458. t o Preparative Example 41

The product from Preparative Example 37 (1.60 g, 5.98 mmol), C¾C1 ₂ (12 mL) and 15 wCPBA (1.86 g, 10.8 mmol) were placed into a 100 mL round bottom flask and the mixture was stirred under N ₂ at 25 °C for 3 h. The mixture was neutralized with saturated aqueous solution of NaHC0 ₃ (30 mL) and extracted with CH ₂ C1 ₂ (3x25 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtO Ac/acetone; 9:1). The product was 20 obtained as a white solid (1.38 g, 82 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.46 (d, J = 1.1 Hz, 1H), 7.62 (m, 1H), 7.57 (m, 2H), 7.49 (m, 2H), 7.45 (m, 1H), 7.41 (d, J= 0.9 Hz, 1H), 0.39 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 169.6, 154.5, 137.7, 136.3, 135.3, 133.4, 129.5, 129.0, 127.4, 111.1, 109.3, -2.0.

25 HRMS (APCI): calcd. for Ci6Hi ₇ 0 ₂ Si [M+H] ⁺ = 284.1101 ; found [M+H] ⁺ = 284.1099.

Preparative Example 42

The product from Preparative Example 41 (1.35 g, 4.75 mmol), chloroform (10 mL) and POCI ₃ (7.96 mL, 8.54 mmol) were placed into a 100 mL round bottom flask and the mixture was refluxed under N ₂ for 1 h. The solvent and POCI3 were evaporated and the residue was mixed with saturated aqueous solution of NaHC0 ₃ (50 mL) and extracted with CH2CI2 (50+25+25 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/CH ₂ Cl ₂ ; 1 :20). The product was obtained as a white solid (0.824 g, 57 %). Ή NMR (500 MHz, CDCI3) δ 8.49 (s, 1H), 7.55 - 7.42 (m, 5H), 7.20 (s, 1H), 0.42 (s, 9H). ^I3 C NMR (126 MHz, CDCI3) δ 170.4, 148.3, 147.9, 147.6, 135.6, 132.0, 130.1, 128.5, 128.3, 124.3, 117.7, -1.8.

HRMS (APCI): calcd for C _]6 H ₁₆ ClNOSi [M+H] ⁺ = 302.0762; found [M+H] ⁺ = 302.0765. The structural integrity of this compound was also confirmed by X-ray crystallography.

Preparative Example 43

Pd(OAc) ₂ (16.7 mg, 74 μιηοΐ), SPhos (40 mg, 99 μπιοΐ) and 1-butanol (5 mL) were placed into a 25 mL flask and stirred for 5 min. The product from Preparative Example 42 (750 mg, 2.48 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaboroIan-2-yl)-lH-pyrazole (724 mg, 3.48 mmol), TEA (10.4 mL, 74 mmol) and ¾0 (1 mL) were added and the mixture was refluxed for 15 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/CHaC^; 1:10). The product was obtained as a pale yellow solid (427 mg, 50 %). Ή NMR (500 MHz, CDC1 ₃ ) δ 8.41 (s, 1H), 7.58 (s, 1H), 7.47 - 7.41 (m, 3H), 7.38 - 7.32 (m, 2H), 7.27 (s, 1H), 7.20 (s, 1H), 3.84 (s, 3H), 0.42 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 168.5, 148.0, 147.8, 147.6, 140.9, 139.1 , 131.4, 130.3, 130.1, 128.9, 128.0, 122.5, 1 17.5, 1 14.3, 39.2, -1.7.

HRMS (APCI): calcd. for C ₂ oH ₂ iN ₃ OSi [M+H] ⁺ - 348.1527; found [M+H] ⁺ = 348.1529.

Preparative Example 44

The product from Preparative Example 43 (420 mg, 1.21 mmol), CH ₂ CI ₂ (5 mL) and tfzCPBA (375 mg, 2.18 mmol) were placed into a 25 mL round bottom flask and the mixture was stirred under N2 at 25 °C for 1 h. The mixture was mixed with saturated aqueous solution of NaHC0 ₃ (40 mL), brine (30 mL) was added and the mixture was extracted with CH ₂ C1 ₂ (50+25+25 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/acetone; 2:1). The product was obtained as a light yellow semi-solid (357 mg, 81 %).

1H NMR (500 MHz, CDCI3) δ 8.13 (s, 1H), 7.49 (s, 1H), 7.47 - 7.42 (m, 4H), 7.34 - 7.28 (m, 2H), 7.15 (s, 1H), 3.82 (s, 3H) _; 0.42 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 168.8, 151.0, 140.1, 137.5, 136.8, 135.5, 132.2, 130.6, 129.7, 129.1, 128.8, 1 16.2, 113.5, 111.4, 39.2, -1.9.

HRMS (APCI): calcd. for C ₂ oH ₂₁ N ₃ 0 ₂ Si [M+H] ⁺ = 364.1476; found [M+H] ⁺ = 364.1478.

Preparative Example 45

The product from Preparative Example 44 (351 mg, 0.966 mmol) and POCl ₃ (4 mL) were placed into a 25 mL round bottom flask and the mixture was stirred under N2 at 100 °C for 25 min. The POCI ₃ was evaporated, the residue was mixed with saturated aqueous solution of NaHC0 ₃ (25 mL) and extracted with CH ₂ C1 ₂ (20+15+15 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1:1). The product was obtained as a white solid (316 mg, 86 %).

1H NMR (500 MHz, CDCI ₃ ) δ 7.53 - 7.47 (m, 4H), 7.28 - 7.26 (m, 1H), 7.26 - 7.25 (m, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 3.78 (s, 3H), 0.42 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 169.6, 147.4, 147.3, 146.9, 140.9, 138.5, 131.6, 130.3, 129.2, 128.5, 127.8, 126.0, 116.9, 114.5, 39.2, -1.8.

HRMS (APCI): calcd. for C ₂ oH ₂ oClN ₃ OSi [M+H] ⁺ = 382.1137; found [M+H] ⁺ = 382.1141.

Preparative Example 46 The product from Preparative Example 45 (285 mg, 0.746 mmol), KF (130 mg, 2.24 mmol) and MeOH (16 mL) were placed into a 50 mL round bottom flask and the mixture was stirred under N ₂ at 62 °C for 43 h.. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :1). The product was obtained as a white solid (213 mg, 92 %).

1H NMR (500 MHz, CDCI ₃ ) δ 7.93 (d, J = 2.3 Hz, 1H), 7.52 - 7.47 (m, 3H), 7.31 - 7.26 (m, 3H), 7.21 (s, 1H), 7.00 (d, J= 2.3 Hz, 1H), 3.80 (s, 3H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 149.4, 148.0, 146.0, 144.4, 140.7, 138.2, 131.9, 130.3, 129.2, 128.6, 128.3, 126.6, 114.0, 108.3, 39.2.

HRMS (APCI): calcd. for [M+H] ⁺ = 310.0742; found [M+H] ⁺ - 310.0750. Preparative Example 47

The product from Preparative Example 38 (2.36 g, 8.7 mmol), CH2CI2 (15 mL) and wCPBA (2.1 g, 15.7 mmol) were placed into a 100 mL round bottom flask and the mixture was stirred under N2 at 25 °C for 45 h. Then, additional MiCBPA (0.62 g, 3.6 mmol) was added and the mixture was stirred for additional 4 h. The mixture was mixed with saturated aqueous solution of NaHC0 ₃ (20 mL), brine (30 mL) was added, and the mixture was extracted with CH ₂ Cl2 (3x70 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH; from 20:1 to 5:1). The product was obtained as a light yellow solid (1.67 g, 66 %).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.36 (d, J= 0.9 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.36 (d, 1H), 3.98 (s, 3H), 0.38 (s, 9H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 168.9, 154.6, 137.1, 131.9, 127.6, 126.8, 118.6, 111.1, 107.4, 39.5, -2.0.

HRMS (APCI): calcd. for Ci ₄ H _!7 N ₃ 0 ₂ Si [2M+H] ⁺ = 575.2253; found [2M+H] ⁺ = 575.2255.

Preparative Example 48 The product from Preparative Example 47 (1.67 g, 5,81 mmol), chloroform (12 mL) and POCl ₃ (9.75 mL, 105 mmol) were placed into a 100 mL round bottom flask and the mixture was refluxed under N ₂ for 45 min. The solvent and POCI ₃ were evaporated and the residue was mixed with saturated aqueous solution of NaHC0 ₃ (40 mL) and extracted with CH2CI2 (50+30+30 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (CH ₂ Ci2/MeOH; 14:1). The product was obtained as a white solid (1.15 g, 65 %).

Ή NMR (500 MHz, CDC1 ₃ ) S 8.58 (s, 1H), 7.87 (s, J= 0.6 Hz, 1H), 7.83 (s, 1H), 7.15 (s, 1H), 4.00 (s, 3H), 0.40 (s, 9H).

1 ³ C NMR (126 MHz, CDCI ₃ ) δ 169.9, 148.2, 147.3, 146.4, 139.0, 129.8, 123.5, 123.2, 117.7, 116.5, 39.3, -1.9.

HRMS (APCI): calcd. for C ₁₄ H _I6 N ₃ OSi [M+H] ⁺ = 306.0824; found [M+H] ⁺ = 306.0825.

Preparative Example 49

Pd(OAc) ₂ (25 mg, 113 μπιοί), SPhos (62 mg, 150 μηΐοΐ) and 1-butanol (8 mL) were placed into a 50 mL flask and stirred for 5 min. The product from Preparative Example 48 (1.15 g, 3.76 mmol), phenylboronic acid (688 mg, 5.64 mmol), TEA (15.7 mL, 113 mmol) and H ₂ 0 (1.6 mL) were added and the mixture was refluxed under N ₂ for 90 min. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH; from 20:1 to 15:1). The product was obtained as a light grey solid (1.32 g, 100 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.64 (s, 1H), 7.45 - 7.39 (m, 5H), 7.25 (d, J = 0.6 Hz, 1H), 7.17 (s, 1H), 7.04 (s ₅ 1H), 3.81 (s, 3H), 0.32 (s, 9H).

^I3 C NMR (126 MHz, CDCI3) S 169.0, 149.3, 147.1, 146.8, 139.1, 133.5, 130.1, 130.1, 129.2, 128.5, 128.5, 122.8, 118.7, 117.3, 39.0, -1.8.

HRMS (APCI): calcd. for C ₂ oH ₂₁ N ₃ OSi [M+H = 348.1527; found [M+H] ⁺ = 348.1530. Preparative Example 50

The product from Preparative Example 49 (1.3 g, 3.74 mmol), CH ₂ C1 ₂ (10 mL) and mCPBA (1.16 g, 6.73 mmol) were placed into a 50 mL round bottom flask and the mixture was stirred under N ₂ at 25 °C for 135 min. The mixture was mixed with saturated aqueous solution of NaHC0 ₃ (40 mL) and then extracted with CH ₂ C1 ₂ (50+40+40 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc MeOH; from 10: 1 to 7:1). The product was obtained as a white semi-solid (1.13 g, 83 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.33 (s, lH), 7.47 - 7.40 (m, 4H), 7.40 - 7.33 (m, 2H), 7.21 (s, 1H), 7.00 (s, 1H), 3.81 (s, 3H), 0.31 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 169.2, 152.6, 138.9, 136.9, 134.2, 132.4, 130.2, 129.5, 128.8, 128.7, 125.3, 123.3, 116.9, 11 1.2, 39.2, -2.0.

HRMS (APCI): calcd. for C ₂ oH ₂₁ N ₃ 0 ₂ Si [M+H] ⁺ = 364.1476; found [M+H] ⁺ = 364.1479.

Preparative Example 51

The product from Preparative Example 50 (1.13 g, 3.11 mmol) and POCI3 (6 mL) were placed into a 50 mL round bottom flask and the mixture was stirred under N ₂ at 100 °C for 20 min. The POCI3 was evaporated, the residue was mixed with saturated aqueous solution of NaHC0 ₃ (100 mL) and extracted with CH ₂ C1 ₂ (60+40+40 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :2). The product was obtained as a white solid (1.02 g, 86 %).

Ή NMR (300 MHz, CDC1 ₃ ) δ 7.38 - 7.32 (m, 3H) _; 7.31 - 7.26 (m, 3H), 7.14 (s, 1H), 7.10 (s, 1H), 3.83 (s, 3H), 0.32 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 170.8, 148.5, 147.6, 146.6, 141.0, 134.6, 133.4, 131.2, 130.2, 128.5, 128.2, 121.5, 116.7, 116.5, 39.0, -1.9.

HRMS (APCI): calcd. for C ₂ oH ₂ oClN ₃ OSi [M+Hf = 382.1137; found [M+H] ⁺ = 382.1141.

Preparative Example 52

By essentially same procedure set forth in Preparative Example 46, using the product from Preparative Example 51 , the compound given below was prepared.

White solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.83 (d, J = 2.3 Hz, 1H), 7.38 - 7.35 (m, 3H), 7.29 - 7.26 (m, 3H), 7.17 (s, 1H), 6.98 (d, J= 2.3 Hz, 1H), 3.83 (s, 3H).

^I3 C NMR (126 MHz, CDC1 ₃ ) δ 150.3, 148.0, 145.6, 140.9, 135.2, 133.0, 131.1, 130.0, 128.8, 128.4, 122.2, 116.2, 108.1, 39.1.

HRMS (APCI): calcd. for Ci ₇ Hi ₂ ClN ₃ 0 [M+H] ⁺ = 310.0742; found [M+H] ⁺ = 310.0746.

Preparative Example 53

The product from Preparative Example 52 (30 mg, 0.969 mmol), 1 ,2-dimethoxyethane (2 mL), K3PO4 (61.7 mg, 0.291 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (26.1 mg, 0.145 mmol) and PdCl ₂ (dppf) (4.3 mg, 5.8 μπιοΐ) were placed into a 25 mL round bottom flask. The mixture was refluxed under N ₂ for 25 h, then additional PdCl ₂ (dppf) (5 mg, 6 μηιοΐ) and H ₂ 0 (0.4 mL) were added and the mixture was refluxed for additional 14 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :1). The product was obtained as a colorless wax (17 mg, 43 %). 1H NMR (500 MHz, CDC1 ₃ ) δ 8.00 - 7.94 (m, 2H), 7.85 (d, J = 1.7 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.39 - 7.35 (m, 3H), 7.32 - 7.27 (m, 2H), 7.08 (s, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 3.91 (s, 3H), 3.65 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 171.2, 167.1, 155.4, 149.9, 146.5, 146.2, 145.8, 140.7, 133.3, 133.1, 130.9, 130.1, 129.9, 129.3, 129.1, 128.5, 128.4, 121.9, 117.5, 108.6, 52.2, 38.9.

HRMS (APCI): calcd. for C25H19N3O3 [M+H] ⁺ - 410.1499; found [M+H] ⁺ = 410.1492.

Preparative Example 54

The product from Preparative Example 5D (40 mg, 0.14 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxyla te (49 mg, 0.168 mmol), K ₃ P0 ₄ (104 mg, 0.49 mmol), 1,2-dimethoxyethane (2.4 mL), H ₂ 0 (0.6 mL) and PdCl ₂ (dppf) (6.2 mg, 8.4 μπιοΐ) were placed into a 10 mL round bottom flask and the mixture was refluxed under N ₂ for 22 h. Then, additional PdCl ₂ (dppf) (8 mg, 10.9 μιηοΐ) was added and the mixture was refluxed for additional 4 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 : 1). The product was obtained as a white solid (18.5 mg, 42 %). 1H NMR (500 MHz, DMSO-d6) S 13.04 (s, 1H), 8.74 (s, 1H), 8.52 - 8.10 (m, 4H), 8.05 (d, J= 8.6 Hz, 1H), 7.73 (d, J= 8.7 Hz, 1H), 7.54 (d, J= 8.2 Hz, 2H), 1.35 (s, 9H).

i ³ C NMR (126 MHz, DMSO-d6) δ 149.8, 148.8, 146.7, 146.1, 144.8, 128.7, 127.7, 126.3, 125.4, 122.4, 1 19.9, 119.5, 115.9, 34.3, 31.1.

HRMS (APCI): calcd. for C20H19N3O [M+H] ⁺ = 318.1601 ; found [M+H] ⁺ = 318.1599.

Preparative Example 55

The product from Preparative Example 5E (11 mg, 52.5 μηιοΐ), degassed 1,2- dimethoxyethane (2 mL) and H ₂ 0 (0,5 mL) were placed into a 5 mL round bottom flask. Then, K ₃ PO4 (39 mg, 0.184 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole-l-carboxylate (18.5 mg, 63 μmol) and PdCbtdppf) (2 mg, 2.6 μιηοΐ) were added and the mixture was stirred under N ₂ at 60 °C for 16 h. Then, additional PdCl ₂ (dppf) (2 mg, 2.6 μπιοΐ), the mixture was refluxed for additional 5 h, another portion of PdCl ₂ (dppf) (2 mg, 2.6 μηιοΐ) and the mixture was refluxed for additional 4 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :1). The product was obtained as a yellow wax (2 mg, 15 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.24 (b, J = 47.6 Hz, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J= 8.1 Hz, 1H), 1.52 (s, 9H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 147.7, 143.5, 131.1, 118.7, 115.2, 31.2, 29.8.

HRMS (APCI): calcd. for C ₁₄ Hi ₅ N ₃ 0 [M+H] ⁺ = 242.1288; found [M+H] ⁺ - 242.1292.

Preparative Example 56

The product from Preparative Example 11 (1.78 g, 11.6 mmol) and degassed 1,4-dioxane (62 mL) were placed into a 250 mL round bottom flask, then AcCl (0.825 mL, 11.6 mmol) was added and the mixture was stirred under N ₂ at 25 °C. After 3 min, Nal (17.4 g, 116 mmol) was added, the flask was wrapped with aluminum foil and the mixture was stirred at 106 °C for 70 h. Additional portions of AcCl were added at these times: 15 h, (0.70 mL, 9.8 mmol); 24 h, (0.80 mL, 11.2 mmol); 40 h (0.80 mL, 11.2 mmol); 48 h (0.825 mL, 11.6 mmol; 64 h (0.825 mL, 11.6 mmol). The solvent was evaporated, the residue was mixed with saturated solution of NaHC0 ₃ (50 mL) and with Na ₂ S ₂ 0 ₃ (5 g), and extracted with CH ₂ CI ₂ (3x90 mL). The organic phase was dried over MgS0 ₄ and filtered. The mixture was concentrated to the volume of 75 mL and hexane (25 mL) was added. To the solution, upon cooling in ice bath, HC1 (15 mL, 1 M solution in Et ₂ 0) was added. The precipitate was collected by filtration. To the solid, TEA (1.9 mL, 14 mmol) and CH ₂ C1 ₂ (20 mL) were added, the mixture was cooled in ice bath, H ₂ 0 (60 mL) was added, and the mixture was extracted with CH ₂ C1 ₂ (3x60 mL). The organic phase was dried over MgS0 ₄ , filtered, and the solvent was evaporated. The product was obtained as a white solid (1.90 g, 67 %). 1H NMR (500 MHz, CDC1 ₃ ) δ 7.81 (d, J= 2.3 Hz, 1H), 7.60 (d, J= 8.5 Hz, 1H), 7.47 (dd, J= 8.5, 0.9 Hz, 1H), 6.96 (dd, J= 2.3, 0.9 Hz, 1H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 149.7, 149.5, 147.5, 129.5, 120.4, 112.0, 108.0.

HRMS (APCI): calcd. for C ₇ H4INO [M+H] ⁺ = 245.9410; found [M+H] ⁺ = 245.9407.

Preparative Example 57

The product from Preparative Example 56 (1.86 g, 7.60 mmol) and CC1 (20 mL) were placed into a 100 mL round bottom flask and the mixture was cooled to -18 °C. Then, bromine (6.49 mL, 114 mmol) was added slowly. The mixture was stirred under N ₂ while allowed to warm up to 25 °C for 90 min. The mixture was poured into a mixture of water (100 mL), ice (50 mL) and Na ₂ S205 (30 g). The resulting mixture was extracted with CH2CI2 (2x100 mL) and EtOAc (100 mL). The organic phase was washed with brine (100 mL), dried over MgS0 ₄ , filtered, and the solvent was evaporated. Toluene (24 mL) and DBU (3.4 mL, 22.8 mmol) were added to the residue and the mixture was stirred under N ₂ at 80 °C for 45 min. The solvent was evaporated and the residue was and purified by column chromatography on silica gel (EtOAc/hexane; from 1 :7 to 1 :5). The product was obtained as a white solid (1.77 g, 72 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.85 (s, 1H), 7.69 (d, J= 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H).

i ³ C NMR (126 MHz, CDC1 ₃ ) δ 147.4, 147.2, 146.8, 131.1, 120.9, 113.0, 98.9.

HRMS (APCI): calcd. for C ₇ H ₃ BrINO [M+H] ⁺ = 323.8515; found [M+H] ⁺ = 323.8512.

Preparative Example 58

A mixture of the product from Preparative Example 57 (167 mg, 0.515 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l _! 3,2-dioxaborolan-2-yl)-lH-pyrazole (113 mg, 0.54 mmol), K3PO4 (383 mg, 1.80 mmol), and PdCl ₂ (dppf) (18.8 mg, 26 μηιοΐ) in 1,2-dimethoxyethane (2 mL) and H ₂ 0 (0.5 mL) was stirred under N ₂ at 25 °C for 2.5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane/EtOAc; 2:3). The product was obtained as an orange solid (80 mg; 56 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.73 (d, J- 8.6 Hz, 1H), 7.46 (d, J= 8.6 Hz, 1H), 3.96 (s, 3H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) S 149.9, 146.6, 146.3, 144.6, 137.6, 129.3, 123.6, 119.6, 116.9, 99.6, 39.3.

HRMS (APCI): calcd. for CnH ₈ BrN ₃ 0 [M+H] ⁺ = 277.9924; found [M+H] ⁺ = 277.9920.

Preparative Example 59

By essentially same procedure set forth in Preparative Example 58, using tert-butyl 4- (4,4,5,5-tetramethyI-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l- carboxylate instead of 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-py razole, the compound given below was prepared.

White solid.

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.65 (s, 1H), 8.27 (s, 1H), 7.90 (s, 1H), 7.79 (d, J= 8.6 Hz, 1H), 7.54 (d, J= 8.6 Hz, 1H), 1.69 (s, 9H).

^I3 C NMR (126 MHz, CDC1 ₃ ) S 148.2, 147.6, 147.1, 146.7, 145.0, 142.5, 128.7, 125.7, 119.8, 117.5, 99.7, 86.0, 28.1.

HRMS (APCI): calcd. for Ci ₅ Hi ₄ BrN ₃ 0 ₃ [M+H] ⁺ = 364.0291 ; found [M+H] ⁺ = 364.0294. The structural integrity of this compound was also confirmed by X-ray crystallography.

Preparative Example 60

A mixture of the product from Preparative Example 57 (127 mg, 0.393 mmol), K ₃ P0 ₄ (292 mg, 1.38 mmol), 4-(4,4,5,5-tetramethyl-l,3 _! 2-dioxaborolan-2-yl)isoxazole (80.5 mg, 0.413 mmol), and PdCl ₂ (dppf) (14.4 mg, 19.7 μπιοΐ) in 1,2-dimethoxyethane (2.8 mL) and ¾0 (0.7 mL) was stirred under N ₂ at 40 °C for 25 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (CH ₂ Cl2/EtOAc; 20:1). The product was obtained as a white solid (51 mg; 49 %).

^! H NMR (500 MHz, CDC1 ₃ ) δ 9.00 (s, 1H), 8.88 (s, 1H), 7.93 (s, 1H), 7.82 (d, J= 8.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 155.7, 148.4, 147.5, 146.8, 146.1, 145.3, 122.2, 119.9, 117.8, 99.7.

HRMS (APCI): calcd. for C ₁₀ H ₅ BrN ₂ O2 [M+H] ⁺ = 264.9607; found [M+H] ⁺ = 264.9603.

Preparative Example 61

Degassed 1-butanol (2.0 mL) and H ₂ 0 (0.4 mL) were placed into a 10 mL round bottom flask, Pd(OAc) ₂ (1 mg, 4 μπιοΐ) and SPhos (2.2 mg, 5.4 μηιοΐ) were added and the mixture was stirred at 25 °C for 3 min. Then, the product from Preparative Example 58 (25 mg, 90 μηιοΐ), [l,l'-biphenyl]-3-ylboronic acid (25 mg, 0.126 mmol) and TEA (1.0 mL, 7.2 mmol) were added. The mixture was stirred under N ₂ at 40 °C for 1 h, then at 50 °C for 2 h. The solvent was evaporated and the residue purified by column chromatography on silica gel (hexane/EtOAc; 1 :1) and then by preparative TLC (hexane/acetone; 10:7). The product was obtained as a white solid (7 mg; 22 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.57 - 8.53 (m, 1H), 8.18 (s, 1H), 8.14 - 8.10 (m, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.77 (d, J - 8.6 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.63 - 7.54 (m, 2H), 7.53 - 7.44 (m, 3H), 7.42 - 7.37 (m, 1H), 3.99 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) S 148.8, 147.6, 145.8, 145.2, 141.7, 141.4, 137.7, 131.3, 129.2, 128.9, 128.9, 127.5, 127.3, 126.5, 126.2, 125.9, 124.3, 121.4, 119.2, 115.7, 39.3. HRMS (APCI): calcd. for C ₂₃ H ₁₇ N ₃ 0 [M+H] ⁺ = 352.1444; found [M+H] ⁺ = 352.1449.

Preparative Example 62

The product from Preparative Example 60 (21 mg, 79.2 μηιοι), Pd(OAc) ₂ (1 mg, 4 μιηοΐ), SPhos (2 mg, 4.8 μπιοι), naphthalen-2-ylboronic acid (17.7 mg, 103 μπιοΐ), 1-butanol (2 mL), H ₂ 0 (0.4 mL) and TEA (1.0 mL, 7.17 mmol) were placed into a 10 mL round bottom flask. The mixture was stirred under N ₂ at 45 °C for 3 h. The solvent was evaporated, the residue was purified by column chromatography (hexane/EtOAc; 3:1) and then by preparative TLC (CH ₂ Cl2/EtOAc; 30:1). The product was obtained as a colorless wax (2,5 mg; 10 %).

^! H NMR (500 MHz, CDC1 ₃ ) S 9.02 (s, 1H), 8.94 (s, 1H), 8.87 (s, 1H), 8.30 (s, 1H) _} 8.09 (dd, J= 8.5, 1.6 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.91 - 7.85 (m, 2H), 7.57 - 7.50 (m, 3H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 155.2, 148.5, 146.5, 146.1, 145.1, 133.8, 133.1, 128.5, 128.5, 127.9, 127.7, 126.6, 126.4, 126.3, 124.8, 122.8, 121.6, 119.5, 1 16.9.

HRMS (APCI): calcd. for C ₂ oH ₁₂ N ₂ 0 ₂ [M+H] ⁺ = 313.0972; found [M+H] ⁺ = 313.0975.

Preparative Example 63

By essentially same procedure set forth in Preparative Example 61, using [Ι,Γ-biphenyl]- 4-ylboronic acid instead of[l,l'-biphenyl]-3-ylboronic acid, the compound given below was prepared.

White solid.

Ή NMR (500 MHz, CDC1 ₃ ) S 8.28 - 8.24 (m, 2H), 8.16 (s, 1H), 8.04 (d, J = 2.9 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.76 - 7.72 (m, 2H), 7.70 - 7.66 (m, 2H), 7.50 - 7.45 (m, 3H), 7.40 - 7.35 (m, 1H), 4.00 (s, 3H).

1 ³ C NMR (126 MHz, CDC1 ₃ ) δ 148.8, 147.6, 145.8, 145.1, 141.0, 140.5, 137.7, 129.9, 129.0, 128.9, 127.6, 127.5, 127.4, 127.1, 124.3, 121.3, 119.2, 115.8, 39.3.

HRMS (APCI): calcd. for C ₂₃ H _n N ₃ 0 [M+H] ⁺ = 352.1441 ; found [M+H] ⁺ = 352.1442.

Preparative Example 64

By essentially same procedure set forth in Preparative Example 61, using [Ι, -biphenyl]- 2-ylboronic acid instead of[l,r-biphenyl]-3-ylboronic acid, the compound given below was prepared.

Colorless wax.

1H NMR (500 MHz, CDC1 ₃ ) δ 8.18 (d, J = 7.6 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.67 (d, J = 8.6 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.47 - 7.42 (m, 2H), 7.38 (d ₅ J = 8.6 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.30 - 7.22 (m, 3H), 7.17 (s, 1H), 3.97 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 148.5, 147.5, 146.6, 146.1, 142.2, 141.6, 137.7, 130.9, 130.6, 129.5, 129.1, 128.6, 128.3, 127.8, 127.6, 127.1, 124.1, 120.8, 119.0, 115.5, 39.3. HRMS (APCI): calcd. for C ₂₃ Hi ₇ N ₃ 0 [M+H] ⁺ - 352.1444; found [M+H] ⁺ = 352.1448.

Preparative Example 65

Degassed 1-BuOH (2.5 mL) and H ₂ 0 (0.5 mL) were placed into a 10 mL round bottom flask, then the product from Preparative Example 58 (40 mg, 144 μιηοΐ), 6-(4,4,5,5- tetramethyl-l,3 _; 2-dioxaborolan-2-yl)-lH-indazole (49.2 mg, 0.201 mmol), Pd(PPh ₃ ) ₄ (8.3 mg, 7.2 μιηοΐ) and K ₃ P0 ₄ (92 mg, 0.432 mmol) were added. The mixture was stirred under N ₂ at 90 °C for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (MeOH/EtOAc; 1 :10) and then by preparative TLC (CH ₂ Cl2/acetone; 3:2). The product was obtained as a white solid (10 mg; 22 %).

Ή NMR (500 MHz, acetone-d6) S 12.35 (b, 1H), 9.06 (d, J = 1.0 Hz, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 0.9 Hz, 1H), 7.95 (d, J - 8.7 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.68 (d, J= 8.6 Hz, 1H), 3.98 (s, 3H).

¹³ C NMR (126 MHz, acetone-d6) δ 150.2, 148.5, 147.3, 146.5, 142.0, 138.4, 134.8, 129.9, 129.9, 124.9, 123.6, 122.0, 121.6, 120.5, 120.3, 116.8, 109.7, 39.4.

HRMS (APCI): calcd. for C ₁₈ Hi ₂ N ₅ 0 [M+H] ⁺ = 316.1193; found [M+H] ⁺ = 316.1197. Preparative Example 66

Degased 1-butanol (2.0 mL) and ¾0 (0.4 mL) were placed into a 5 mL round bottom flask. Then, the product from Preparative Example 58 (30 mg, 108 μπιοΐ), (4- carbamoylphenyl)boronic acid (26.7 mg, 0.162 mmol), Pd(PPh ₃ ) ₄ (6.2 mg, 5.4 μπιοΐ) and K ₃ P0 ₄ (68.6 mg, 0.323 mmol) were added. The mixture was stirred under N ₂ at 80 °C for 45 min. The solvent was evaporated and the residue was purified by column chromatography on silica gel (MeOH/EtOAc; 1 :10) and then by preparative TLC (MeOH/EtOAc; 1 :10). The product was obtained as a white solid (12 mg; 35 %).

]H NMR (500 MHz, acetone-d6) δ 8.68 (s, 1H), 8.50 - 8.45 (m, 2H), 8.28 (s, 1H), 8.10 - 8.05 (m, 3H), 7.95 (d, J = 8.7 Hz, 1H), 7.69 (d, J= 8.7 Hz, 1H), 3.97 (s, 3H).

! ³ C NMR (126 MHz, acetone-d6) δ 168.8, 150.5, 148.5, 147.8, 146.2, 138.2, 135.1, 134.3, 130.0, 128.9, 127.6, 124.8, 121.3, 120.4, 116.9, 39.4.

HRMS (APCI): calcd. for C _I8 H ₁₄ N ₄ 0 ₂ [M+H] ⁺ = 319.1190; found [M+H] ⁺ = 319.1187.

Preparative Example 67 By essentially same procedure set forth in Preparative Example 66, using (3-chloro-4- methoxyphenyl)boronic acid instead of (4-carbamoylphenyl)boronic acid, the compound given below was prepared.

White solid. 1H NMR (500 MHz, acetone-d6) S 8.56 (s, 1H), 8.43 (d, J= 2.1 Hz, 1H), 8.34 (dd, J= 8.6, 2.2 Hz, 1H), 8.22 (s, 1H), 8.07 (d, J = 0.6 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.25 (d, J= 8.6 Hz, 1H) ₅ 3.97 (d, J= 2.0 Hz, 6H).

¹³ C MR (126 MHz, acetone-d6) δ 155.5, 150.2, 148.3, 146.5, 146.2, 138.2, 129.8, 129.3, 127.6, 125.6, 124.8, 123.1, 120.4, 120.3, 116.8, 113.7, 56.7, 39.4.

HRMS (APCI): calcd. for C ₁₈ Hj ₄ ClN ₃ 0 ₂ [M+H] ⁺ = 340.0847; found [M+H] ⁺ - 340.0842.

Preparative Example 68

Degassed 1-butanol (2.0 mL) and ¾0 (0.4 mL) were placed into a 10 mL round bottom flask. Then, the product from Preparative Example 67 (25 mg, 0.074 mmol), phenylboronic acid (11.7 mg, 95.7 μιηοΐ), Pd(OAc) ₂ (1.0 mg, 3.7 μηιοΐ), SPhos (1.8 mg, 44 μιηοΐ) and K3PO4 (46.9 mg, 0.220 mmol) were added. The mixture was stirred under N ₂ at 80 °C for 4 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc) and then by preparative TLC (CH ₂ Cl ₂ EtOAc; 2:1; 3 runs). The product was obtained as a colorless wax (9 mg; 32 %).

Ή NMR (300 MHz, acetone-d6) <S 8.56 (s, 1H), 8.43 - 8.33 (m, 2H), 8.19 (s, 1H), 8.05 (d, J = 0.6 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.70 - 7.61 (m, 3H), 7.50 - 7.33 (m, 3H), 7.24 (d, J= 8.5 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H).

¹³ C NMR (75 MHz, acetone-d6) S 157.2, 150.0, 148.4, 146.6, 146.2, 139.9, 138.2, 131.7, 130.6, 130.4, 129.8, 129.0, 128.3, 127.9, 125.0, 124.8, 121.5, 120.1, 116.6, 112.9, 56.2, 39.4.

HRMS (APCI): calcd. for C ₂₄ Hi ₉ N ₃ 0 ₂ [M+H] ⁺ = 382.1550; found [M+H] ⁺ = 382.1547.

Preparative Example 69 By essentially same procedure set forth in Preparative Example 66, using (4- formylphenyl)boronic acid MIDA ester instead of (4-carbamoylphenyl)boronic acid, the compound given below was prepared.

White solid.

Ή NMR (500 MHz, acetone-d6) 6 10.11 (s, 1H), 8.78 (s, 1H), 8.65 (d, J - 8.3 Hz, 2H), 8.32 (s, 1H), 8.11 (s, 1H), 8.09 - 8.04 (m, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H).

¹³ C NMR (126 MHz, acetone-d6) δ 192.6, 192.5, 150.7, 148.6, 148.6, 146.0, 138.3, 136.7, 130.9, 130.1, 128.2, 124.7, 121.0, 120.5, 117.1, 39.4.

HRMS (APCI): calcd. for Ci ₈ H ₁₃ N ₃ 0 ₂ [M+H] ⁺ = 304.1081; found [M+H] ⁺ = 304.1079.

Preparative Example 70

The product from Preparative Example 69 (31 mg, 0.102 mmol), NaBH ₄ (8 mg, 0.204 mmol) and MeOH (7 mL) were placed into a 10 mL round bottom flask. The mixture was stirred under N ₂ at 25 °C for 90 min. Aqueous saturated solution of NH ₄ C1 (10 mL) was added and the mixture was extracted with EtOAc (2x20 mL). The organic phase was washed with brine (10 mL), dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (MeOH/EtOAc; 1 : 12). The product was obtained as a white solid (26 mg; 84 %). Ή NMR (500 MHz, acetone-d6) δ 8.54 (s, IH), 8.33 - 8.29 (m, 2H), 8.25 (s, IH), 8.06 (d, J = 0.6 Hz, IH), 7.92 (d, J = 8.7 Hz, IH), 7.66 (d, J = 8.7 Hz, IH), 7.52 - 7.47 (m, 2H), 4.72 - 4.68 (m, 2H), 3.96 (s, 3H).

¹³ C NMR (126 MHz, acetone-d6) δ 150.2, 148.4, 146.7, 146.5, 142.9, 138.2, 130.6, 129.9, 127.8, 127.8, 124.9, 122.0, 120.2, 116.7, 64.7, 39.4.

HRMS (APCI): calcd. for Ci ₈ Hi ₅ N ₃ 0 ₂ [M+H] ⁺ = 306.1237; found [M+H] ⁺ = 306.1242.

Preparative Example 71 By essentially same procedure set forth in Preparative Example 66, using (4- (methylsulfonyl)phenyl)boronic acid instead of (4-carbamoylphenyI)boronic acid, the compound given below was prepared.

White solid.

1H NMR (300 MHz, acetone-d6) δ 8.78 (s, IH), 8.70 - 8.63 (m, 2H), 8.31 (s, IH), 8.12 - 8.02 (m, 3H), 7.98 (d, J = 8.7 Hz, IH), 7.71 (d, J= 8.7 Hz, IH), 3.97 (s, 3H), 3.17 (s, 3H). ¹³ C NMR (75 MHz, acetone-d6) δ 150.7, 148.7, 148.5, 145.9, 141.0, 138.2, 137.4, 130.1, 128.7, 128.3, 124.6, 120.6, 120.4, 117.1, 44.6, 39.4.

HRMS (APCI): calcd. for C _i8 H, ₅ N ₃ 0 ₃ S [M+H] ⁺ = 354.0907; found [M+H] ⁺ = 354.0901.

Preparative Example 72

By essentially same procedure set forth in Preparative Example 66, using (4- (methylthio)phenyl)boronic acid instead of (4-carbamoylphenyl)boromc acid, the compound given below was prepared.

White solid.

1H NMR (500 MHz, acetone-d6) 5 8.55 (s, 1H), 8.35 - 8.29 (m, 2H), 8.24 (s, 1H), 8.06 (d, J = 0.5 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.43 - 7.38 (m, 2H), 3.96 (s, 3H), 2.55 (s, 3H).

^I3 C NMR (126 MHz, acetone-d6) δ 150.2, 148.4, 146.7, 146.4, 139.0, 138.2, 129.9, 128.8, 128.3, 127.5, 124.9, 121.5, 120.2, 116.7, 39.4, 15.7.

HRMS (ACPI): calcd. for C ₁₈ H ₂₅ N ₃ OS [M+H] ⁺ = 322.1009; found [M+H] ⁺ = 322.1003.

Preparative Example 73

The product from Preparative Example 72 (13 mg, 40.4 μπιοΐ) and CH ₂ CI ₂ (2 mL) were placed into a 5 mL round bottom flask. The mixture was cooled to 0 °C ₅ then PJCPBA (7.0 mg, 40.4 mmol) was added and the mixture was stirred under N ₂ at 0 °C for 45 min. Aqueous saturated solution of NaHC0 ₃ (5 mL) and H ₂ 0 (5 mL) were added and the mixture was extracted with CH2CI2 (2* 10 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was evaporated and the residue was purified by preparative TLC on silica gel (EtOAc/MeOH; 20:1). The product was obtained as a yellow wax (5 mg; 38 %).

^! H NMR (300 MHz, acetone-d6) δ 8.70 (s, 1H), 8.63 - 8.55 (m, 2H), 8.29 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.7 Hz, 1H), 3.97 (s, 3H), 2.76 (s, 3H). ¹³ C NMR (75 MHz, acetone-d6) δ 150.4, 148.4, 147.8, 147.1, 146.1, 138.2, 134.6, 130.0, 128.4, 124.8, 124.7, 120.9, 120.4, 116.9, 44.4, 39.3.

HRMS (APCI): calcd. for Ci ₈ H ₁₅ N ₃ 0 ₃ S [M+H] ⁺ = 338.0958; found [M+H] ⁺ - 338.0955. Preparative Example 74

By essentially same procedure set forth in Preparative Example 66, using (3-(tert- butyl)phenyl)boronic acid instead of (4-carbamoylphenyl)boronic acid, the compound given below was prepared.

Colorless wax.

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.41 (d, J= 0.9 Hz, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.84 (m, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.42 (m, 3H), 3.97 (s, 3H), 1.44 (s, 9H).

i ³ C NMR (126 MHz, CDC1 ₃ ) δ 151.7, 148.6, 147.6, 145.9, 145.0, 137.7, 130.4, 128.8, 128.5, 124.8, 124.7, 124.4, 124.1 , 122.0, 119.1, 115.6, 35.0, 31.6, 31.0.

HRMS (APCI): calcd. for C ₂ iH ₂ iN ₃ 0 [M+H] ⁺ = 332.1757; found [M+H] ⁺ = 332.1754.

Preparative Example 75

6-chloro-5-methylpyridin-3-ol (2.51 g, 17.5 mmol), iodine (4.44 g, 17.5 mmol), H ₂ 0 (35 mL), THF (30 mL) and Na ₂ C0 ₃ (3.90 g, 36.8 mmol) were placed into a 100 mL round bottom flask. The mixture was stirred under N ₂ at 25 °C for 18 h. The solvent was evaporated and the solution was neutralized with 1 M aqueous solution of HC1 (38 mL). Then, saturated aqueous solution of NH ₄ C1 (30 mL) and H ₂ 0 (100 mL) were added and the mixture was extracted with CH ₂ C1 ₂ (80 mL) and EtOAc (2x80 mL). The organic phase was washed with brine (30 mL), dried over MgS0 ₄ , filtered, and the solvent was evaporated. The product was obtained as a white solid (4.24 g; 90 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.12 (d, J= 0.7 Hz, 1H), 2.31 (d, J= 0.7 Hz, 3H).

1 ³ C NMR (126 MHz, CDCI3) δ 124.8, 19.3.

HRMS (APCI): calcd. for C ₆ H ₅ C1IN0 [M+H] ⁺ = 269.9178; found [M+H] ⁺ = 269.9179.

Preparative Example 76

The product from Preparative Example 75 (2,2 g, 8.16 mmol), degassed 1,4-dioxane (17 mL) and TEA (17 mL) were placed into a 100 mL round bottom flask. Then, ethynyltrimethylsilane (1.49 mL, 10.6 mmol), Cul (78 mg, 0.408 mmol) and PdCl ₂ (PPh ₃ )2 (114 mg, 0.163 mmol) were added. The mixture was stirred under N ₂ at 45 °C for 3 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane/EtOAc; 10:1). The product was obtained as an orange solid (930 mg, 47 %). 1H NMR (500 MHz, CDC1 ₃ ) δ 7.62 (s, 1H), 7.01 (d, J= 0.8 Hz, 1H), 2.48 (s, 3H), 0.36 (s, 9H).

¹³ C NMR (126 MHz, CDCI ₃ ) δ 169.5, 150.4, 147.1, 146.1, 127.3, 121.1, 116.5, 20.6, -1.9. HRMS (APCI): calcd. for C _n H _!4 ClNOSi [M+H] ⁺ = 240.0606; found [M+H] ⁺ = 240.0604.

Preparative Example 77

The product from Preparative Example 76 (0.90 g, 3.75 mmol), MeOH (28 mL) and KF (654 mg, 1 1.3 mmol) were placed into a 100 mL round bottom flask. The mixture was stirred under N ₂ at 25 °C for 14 h, then at 60 °C for additional 8 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane/EtOAc; from 10:1 to 5:1). The product was obtained as a white solid (560 mg, 88 %). 1H NMR (500 MHz, CDC1 ₃ ) δ 7.79 (d, J= 2.0 Hz, 1H), 7.65 (s, 1H), 6.89 (m, 1H), 2.49 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 149.3, 147.6, 147.4, 145.3, 127.8, 121.4, 107.7, 20.6.

HRMS (APCI): calcd. for C ₈ H ₆ C1N0 [M+H] ⁺ = 168.0211; found [M+H] ⁺ = 168.0209.

Preparative Example 78

Degassed 1,2-dimethoxyethane (4.0 mL) and H ₂ 0 (1.0 mL) were placed into a 25 mL round bottom flask. Then, the product from Preparative Example 77 (160 mg, 0.94 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (294 mg, 1.42 mmol), PdCl ₂ (dppf) (34 mg, 47 μιηοΐ) and K ₃ P0 ₄ (599 mg, 2.82 mmol) were added. The mixture was stirred under N ₂ at 80 °C for 5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH; from 1 :0 to 10:1) and then by another column chromatography (EtOAc). The product was obtained as a white solid (120 mg; 60 %).

1H NMR (500 MHz, CDC1 ₃ ) δ 7.90 (s, 1H), 7.82 (s, 1H), 7.76 (d, J= 2.3 Hz, 1H), 7.60 (s, 1H), 6.92 (dd, J= 2.2, 0.9 Hz, 1H), 3.97 (s, 3H), 2.56 (s, 3H).

I ³ C NMR (126 MHz, CDC1 ₃ ) S 148.6, 146.9, 145.3, 139.3, 137.0, 130.3, 126.6, 123.2, 120.4, 108.0, 39.1 , 21.6.

HRMS (APCI): calcd. for Ci ₂ HuN ₃ 0 [M+H] ⁺ = 214.0975; found [M+H] ⁺ = 214.0972.

Preparative Example 79

The product from Preparative Example 78 (115 mg ₅ 0.54 mmol) and CC1 ₄ (5 ^~ mL) were placed into a 100 mL round bottom flask. The mixture was cooled to -18 °C, then bromine (0.56 mL, 10.8 mmol) was added slowly. The mixture was allowed to warm to 12 °C and stirred under N ₂ for 60 min. The mixture was poured into a mixture of water (30 mL), ice (20 mL) and Na ₂ S ₂ 0 ₅ (2 g). The resulting mixture was extracted with CH2CI2 (20 mL) and EtOAc (2x15 mL). The organic phase was dried over MgS0 ₄ , filtered, and the solvent was evaporated. Toluene (12 mL) and DBU (0.241 mL, 1.62 mmol) were added to the residue and the mixture was stirred under N ₂ at 80 °C for 45 min. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc hexane; 1 :1) and then by preparative TLC (EtOAc/hexane; 2:1). The product was obtained as a white solid (19 mg, 12 %).

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.93 (d, J= 2.3 Hz, 2H) ₅ 7.80 (s, 1H), 7.61 (s, 1H), 3.98 (s, 3H), 2.60 (s, 3H).

¹³ C NMR (126 MHz, CDC1 ₃ ) δ 149.2, 146.5, 146.1, 142.5, 139.3, 130.9, 127.9, 122.98 (s), 121.0, 99.5, 39.2, 21.7.

HRMS (APCI): calcd. for Ci ₂ H ₁₀ BrN ₃ O [M+H] ⁺ = 292.0080; found [M+H] ⁺ = 292.0075.

Preparative Example 80

Degassed 1-butanol (2.0 mL) and H ₂ 0 (0.4 mL) were placed into a 10 mL round bottom flask. Then, the product from Preparative Example 79 (15 mg, 51.3 μπιοΐ), naphthalen-2- ylboronic acid (13.3 mg, 77 μηιοΐ), Pd(PPh ₃ ) ₄ (3.0 mg, 2.6 μιηοΐ) and K ₃ P0 ₄ (32.7 mg, 0.154 mmol) were added. The mixture was stirred under N ₂ at 80 °C for 70 min. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/CH ₂ Cl ₂ ; 1 :2) and then by preparative TLC (EtOAc/CH ₂ Cl ₂ ; 2:3). The product was obtained as a colorless wax (8.5 mg; 49 % yield).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.88 (s, 1H), 8.18 (s, 1H), 8.14 - 8.07 (m, 2H), 7.97 - 7.84 (m, 4H), 7.64 (d, J= 0.5 Hz, 1H), 7.55 - 7.44 (m, 2H), 4.03 (s, 3H), 2.64 (s, 3H). ^,3 C NMR (75 MHz, CDC1 ₃ ) δ 148.1, 148.0, 144.9, 143.9, 139.8, 133.9, 133.0, 130.5, 128.6, 128.5, 128.4, 127.9, 126.5, 126.4, 126.3, 126.1, 125.0, 123.9, 121.4, 120.7, 39.3, 21.9.

HRMS (APCI): calcd. for C ₂₂ Hi ₇ N ₃ 0 [M+H] ⁺ = 340.1444; found [M+H] ⁺ = 340.1440.

Preparative Example 81

Degassed 1-butanol (2.0 mL) and H ₂ 0 (0.4 mL) were placed into a 10 mL round bottom flask. Then, the product from Preparative Example 58 (23.8 mg, 85.6 μηιοΐ), (4-(1Η- tetrazol-5-yl)phenyl)boronic acid (19.5 mg, 0.103 mmol), Pd(PPh ₃ ) ₄ (5.0 mg, 4.3 μιτιοΐ) and K ₃ P0 ₄ (54.5 mg, 0.257 mmol) were added. The mixture was refluxed under N ₂ for 150 min. The solvent was evaporated and the residue purified by column chromatography on silica gel (EtOAc/MeOH; from 3:1 to 2:1) and then by preparative TLC (THF/MeOH; 2:1). The product was obtained as a colorless semi-solid (12 mg; 41 %).

Ή NMR (300 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.37 - 8.30 (m, 2H), 8.20 - 8.13 (m, 3H), 8.05 (d, J= 0.7 Hz, 1H), 7.83 (d, J- 8.7 Hz, 1H), 7.57 (d, J= 8.7 Hz, 1H), 3.96 (s, 3H). ¹³ C NMR (75 MHz, CD ₃ OD) δ 149.9, 148.9, 147.3, 146.6, 138.4, 132.7, 130.7, 130.0, 128.2, 127.9, 126.5, 125.4, 122.0, 120.3, 116.9, 39.1.

HRMS (APCI): calcd. for C ₁₈ Hi ₃ N ₇ 0 [M+H] ⁺ = 344.1254; found [M+H] ⁺ = 344.1252.

ASSAYS:

In vitro essays were performed by the company Merck Millipore in their KinaseProfiler radiometric protein kinase assay as paid commercial service. The compounds' IC50 values for inhibition of individual protein kinases were determined. Dose-response curves were plotted from inhibition data generated, each in duplicate, from 10 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against % kinase activity. To generate IC ₅₀ values, the dose-response curves were fitted to a standard sigmoidal curve and IC50 values were derived by standard nonlinear regression analysis. All tested compounds were prepared in 100% DMSO to final assay concentrations either 0.5 mM (for the concentration row A, see below) or 0.05 mM (for the concentration row B). This working stock of the compound was added to the assay well as the first component in the reaction, followed by the remaining components as detailed below. The stock solution was added to the individual assay wells in such amounts that the concentrations of the compound were either in the row A (0.001 μΜ, 0.003 μΜ, 0.01 μΜ, 0.03 μΜ, 0.1 μΜ, 0.3 μΜ, 1.0 μΜ, 3.0 μΜ, and 10.0 μΜ) or in the row B (0.0001 μΜ, 0.0003 μΜ, 0.001 μΜ, 0.003 μΜ, 0.01 μΜ, 0.03 μΜ, 0.1 μΜ, 0.3 μΜ, and 1.0 μΜ). There was no pre-incubation step between the compound and the kinase prior to initiation of the reaction.

The positive control wells contained all components of the reaction, except the compound of interest; however, DMSO (at a final concentration of 2%) was included in these wells to control for solvent effects. The blank wells contained all components of the reaction, with staurosporine as a reference inhibitor replacing the compound of interest. This abolished kinase activity and established the base-line (0% kinase activity remaining).

CLK2 assay

CLK2 (h) was diluted in the buffer (20 mM MOPS (3~(N-morpholino)propanesulfonic acid), 1 mM EDTA (ethylendiaminotetraacetic acid), 0.01% Brij-35 (detergent), 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of CLK2(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 20 μΜ YRRAAVPPSPSLSRHSSPHQS(p) EDEEE in such amount that the resulting concentration of CLK2(h) was 2.1 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- ³³ Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) was 15 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μί of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

CLK4 assay

CLK4 (h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of CLK4(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 200 μΜ YRRAAVPPSPSLSRHSSPHQS(p) EDEEE in such amount that the resulting concentration of CLK4(h) was 140.8 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- P-ATP] (specific activity approx. 500 cpm/pmol) was 15 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ΐ, of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

HIPK1 assay

HIP l(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of HIPKl(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0,2 mM EDTA, and 0.33 mg/mL myelin basic protein in such amount that the resulting concentration of HIP l(h) was 4.7 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- ³³ Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) was 45 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μΐ _^ of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. HIPK2 assay

HIPK2(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/niL BSAs) to the concentration of 1.01 mg/niL prior to addition to the reaction mix.

The above stock solution of HIPK2(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 0.33 mg/mL myelin basic protein in such amount that the resulting concentration of HIPK2(h) was 1.4 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- ³³ Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) was 10 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μϋ, of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

HIP 3 assay

HIP 3(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of HIPK3(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 1.0 mg/mL myelin basic protein in such amount that the resulting concentration of HIPK3(h) was 6.4 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- ³³ Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) was 15 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μΕ of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

FLT3 assay FLT3(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/niL BSAs) to the concentration of 1.01 mg/n L prior to addition to the reaction mix.

The above stock solution of Flt3(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 50 uM EAIYAAPFAKKK, in such amount that the resulting concentration of FLT3(h) was 28.3 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- ³³ Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) was 200 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μΙ_. of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. TRKA assay

TRKA(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of TRKA(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 250 μΜ KSPGEYVNIEFG, in such amount that the resulting concentration of TRKA(h) was 28.2 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [γ- ³³ Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) was 120 μΜ. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ΐ, of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. Results

A: IC ₅₀ < 0.100 μΜ

Β: Ι0 ₅ ο < 1.00 μΜ

C: IC ₅₀ < 5.00 μΜ compound CLK2 CLK4 FLT3 HIPK1 HIPK2 HIPK3 DYRK2 TR A

6A B A B B C C

6D C B C C

7A A A B B B

7B A A A A A C

7C C C C

7D C C C B C

7F B B B A

8B B B C

8C C C C

8D C

8E C C C

9 A A A A B C

12B C B

17E C C

23 B B C

54 C C B B

55 B B

61 A A B A C

62 C C B B

65 A B B

66 B B C

70 B B C

71 B C C compound CLK2 CLK4 FLT3 HIPK1 HIPK2 HIPK3 DYRK2 TRKA

73 C C

74 B C

80 B

81 C C C