OA19646A

OA19646A - Pyridine derivative Inhibiting Raf kinase and vascular endothelial growth factor receptor, method for preparing same, pharmaceutical composition containing same, and use thereof.

Info

Publication number: OA19646A
Application number: OA1201800300
Authority: OA
Inventors: Eui Hwan Cho; Min Hyo Kl; Ho Seok Kwon; Hee Jong Shin; Jae Woong Lee; Jeong Ho Joo; Keun Kuk Lee; Jong Min Kim; Yong Bin Park; Sung Hyun Kang; Hyoung Min Cho; Hyun Tae Kim; Soon Kil Ahn; Sung Pyo Hong; Sung Hye Kim
Original assignee: Samjin Pharmaceutical Co., Ltd.; Incheon University Industry Academic Cooperation Foundation; Bamichem Co., Ltd.
Priority date: 2016-02-03
Filing date: 2017-01-11
Publication date: 2020-12-31

Abstract

The present invention provides a novel pyridine derivative, a pharmaceutically acceptable sait thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient. The pyridine derivative according to the present invention inhibits Raf kinase (B-Raf, Raf-1, or B-RafV600E) and a vascular endothelial growth factor receptor (VEGFR2) involved in angiogenesis, and thus, can be favorably used for the prévention or treatment of melanoma, colorectal cancer, prostate cancer, thyroid cancer, lung cancer, pancreatic cancer, ovarian cancer, or the like, which is induced by RAS mutation.

Description

[DESCRIPTION]

[Invention Title]

PYRIDINE DERIVATIVE INHIBITING RAF KINASE AND VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR, METHOD FOR PREPARING SAME, PHARMACEUTICAL COMPOSITION CONTAINING

SAME, AND USE THEREOF

[Technical Field ]

DÉPÔTS BOÎTE

Date de valeur

The présent invention relates to a pyridine dérivative that inhibits tyrosine kinases, particularly ail Raf kinases and vascular endothélial growth factor 2 (VEGFR2), a method for preparing the same, a pharmaceutical composition containing the same, and the use thereof.

[Background Art]

Cancer is a fatal disease that is one of the leading causes of adult deaths worldwide, and the incidence thereof is increasing. Currently, various drugs are used for the purpose of treating cancer. Most of the drugs treat cancer through their cytotoxicity, but show side effects, including cytotoxicity even against normal cells due to their low selectivity for cancer cells. Furthermore, résistance to anticancer drugs makes it more difficult to treat cancer. In an effort to overcome these problems, many new molecular-level targets hâve recently been identified through human genome sequencing and hâve become available for therapeutic use. Thus, studies hâve been actively conducted to maximize therapeutic effects while minimizing adverse effects by developing anticancer agents that selectively act on targets in cells, rather than using previous mechanisms of action that attack cells themselves.

Intracellular signaling pathways are functionally connected to each other and thereby form complex mechanisms that regulate cell prolifération, growth, metastasis, death and the like. Protein tyrosine kinases in signaling pathways play an important rôle in regulating intracellular functions, and abnormal expression and mutation thereof are commonly observed in cancer cells. Protein tyrosine kinases are enzyme which catalyzes the transfer of phosphate groups from ATP to tyrosines located on protein substrates. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal régulation of cell growth. However, under certain conditions, as a resuit of either mutation or overexpression, normal signaling by these receptors can become impossible, leading to various diseases. In addition, protein tyrosine kinase receptors play an important rôle in biochemical signaling cascades through the cellular plasma membrane. These transmembrane molécules typically contain an intracellular tyrosine kinase domain and an extracellular ligand-binding domain, which are linked to each other in the plasma membrane. Receptor-ligand binding simulâtes phosphorylation of tyrosine kinase residues between the receptor and another intracellular molécule, and changes caused by tyrosine phosphorylation elicit signaling through various cellular responses. Protein tyrosine kinases are classified into several families in association with growth factors. In particular, studies on vascular endothélial growth factor receptor (VEGFR) tyrosine kinases associated with VEGF hâve been actively conducted.

VEGFR tyrosine kinases consist of a receptor portion and a tyrosine kinase portion and are transmembrane proteins that transduce extracellular signais into cells. VEGFR tyrosine kinases are divided into VEGFR1, VEGFR2 and VEGFR3, and the major VEGFR involved in angiogenesis is known as VEGFR2 (KD R). Undesirable pathological angiogenesis is related to diseases such as retinopathy in diabetic patients, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma, angioma and the like [Trends Pharmacol. Sci, 1995, 16, 57-66 and Nature Medicine, 1995, 1, 27-31]. In contrast to FGFs, VEGF growth factors are relatively active only in certain endothélial cells due to limited expression of their receptors. It was recently reported that VEGFs act as an important stimulator of normal and pathological angiogenesis [Jakeman et al., Endocrimology 133: 848-859, 1993; and Kolch et al., Breast Cancer Research and Treatment 36: 139-155, 1995] and vascular permeability [Connolly étal., J. Biol. Chem. 264: 20017-20024, 1989], and that antagonism of VEGF action by séquestration of VEGF with antibody can resuit in inhibition of tumor growth [Nature, 1993, 362, 841-844].

The processes involved in tumor growth, progression and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central rôle in regulating mammalian cell growth by relaying extracellular signais from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase. Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylâtes and activâtes MEK1/2, which then phosphorylâtes and activâtes ERK1/2.

When activated, ERK1/2 phosphorylâtes several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important for cell prolifération, and RAF, and RAF plays an important rôle in MEK signaling in the Ras-Raf-MEK-ERK signaling pathway and plays a major rôle in tumor formation [Nature 2002, 417, 949-954]. Raf proteins include three isoforms (A-raf, B-raf, and C-raf) [Biochim. Biophys. Acta., 2003, 1653, 25-40], and among them, B-raf and C-raf play an important rôle in transducing signais from Ras to MEK. These Raf isoforms hâve very similar amino acid sequences, but hâve different biochemical activities and biological functions [Exp. Cell. Res. 1999, 253, 34-46]. Until now, the most frequent mutation of B-raf is a mutation of valine 600 to glutamic acid (V600E), which has been observed in more than 90% of human cancers. Therefore, anticancer agents that selectively target Braf hâve been approved by the FDA and used as therapeutic agents against malignant skin melanoma. However, it is known that these therapeutic agents stimulate the binding of B-raf to C-raf by paradoxical activation in RAS-mutated cells and activate the RAF dimer, thus stimulating cell prolifération [Nature 2010, 464, 431-435 and Cell, 2010, 140, 209-221]. This is because not only B-raf but also C-raf plays an important rôle in the growth of cancer cells with RAS mutations, and thus the inhibition of only B-raf cannot inhibit downstream signais [Cancer Discov, 2011, 1, 128-136]. In addition, clinical tests indicated that sélective B-raf inhibitors caused adverse effects such as cutaneous squamous cell carcinoma associated with RAS mutation [N. Engl. J. Med., 2011, 364, 2507-2516], and preclinical animal tests also indicated that sélective B-raf inhibitors rather stimulated the growth and metastasis of cancer cells with RAS mutations [Nature, 2010, 464, 431-435 and Sci. Signal, 2014, 7, ra30].

Thus, in order to inhibit the growth and prolifération of cancer cells with RAS mutations, ail Raf kinases (B-raf, raf-1, and B-raf V600E) should be inhibited, and in order to exhibit greater effects in vivo, vascular endothélial growth factor receptor 2 (VEGFR2) should also be inhibited.

International Patent Publication No. WO 2008/153947 and Korean Patent Publication No. 2012-0060744 disclose 3-(9H-purin-6-yl)-pyridin-2ylamino-based dérivative compounds which inhibit only B-raf among tyrosine kinase receptors.

Prior Art Documents

Patent Documents

International Patent Publication No. WO 2008/153947;

Korean Patent Publication No. 2012-0060744.

[Disclosure]

[Technical Problem]

It is an object of the présent invention to provide a pyridine dérivative, a method for preparing the same, a pharmaceutical composition comprising the same, and the use thereof.

Another object of the présent invention is to provide a pharmaceutical composition comprising the pyridine dérivative or a phamriaceutically acceptable sait thereof as an active ingrédient, which is used to prevent or treat an abnormal cell growth disease caused by RAS mutation, by inhibiting ail Raf kinases (B-Raf, Raf-1, and B-Raf V600E) and vascular endothélial growth factor receptor 2 (VEGFR2) which is involved in angiogenesis.

[Technical Solution]

The présent inventors hâve found that a pyridine dérivative according to the présent invention inhibits ail Raf kinases (B-Raf, Raf-1, and B-Raf V600E) and vascular endothélial growth factor receptor 2 (VEGFR2) which is involved in angiogenesis, thereby completing the présent invention.

[Advantageous Effects]

A pyridine dérivative and pharmaceutically acceptable sait thereof according to the présent invention may be used to prevent or treat an abnormal cell growth disease caused by RAS mutation, by inhibiting ail Raf kinases (BRaf, Raf-1, and B-Raf V600E) and vascular endothélial growth factor receptor 2 (VEGFR2) which is involved in angiogenesis.

[Description of Drawings]

FIG. 1 shows the results of observing the in vivo antitumor effects of Examples 21 and 30.

FIG. 2 shows the results of observing the in vivo antitumor effects of Examples 33, 36 and 63.

FIG. 3 shows the results of observing the in vivo antitumor effects of Examples 59 and 60 and Comparative Example 1.

FIG. 4 shows the results of observing the in vivo antitumor effects of Examples 65,135,139 and 154.

FIG. 5 shows the results of observing the in vivo antitumor effects depending on concentration of Example 135.

[Best Mode for Invention]

To achieve the above objects, the présent invention provides a pyridine 5 dérivative, a method for preparing the same, a pharmaceutical composition containing the same, and the use thereof.

Hereinafter, the présent invention will be described in further detail.

Pyridine Dérivative Compound

The présent invention provides a pyridine dérivative represented by the ίο following formula 1 and a pharmaceutically acceptable sait thereof:

[Formula 1]

wherein

XisCHorN;

Ri and R2 are each independently hydrogen, halogen, cyano, alkyl, or Ci^ alkoxy, wherein one or more hydrogen atoms in the alkyl may be substituted with halogen;

, H I

H Q

O ; and

B is Ci-g alkyl, aryl, or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, -NO₂, -OH, -SH, -CN, -NR3R4, -NHC(O)ORs, SO^C^ alkoxy, Ci-s thioalkoxy, Ci-s alkyl, cycloalkyl, 3- to 6-membered heterocycloalkyl, C&saryl, and 5- to 8-membered heteroaryl, wherein one or more hydrogen atoms in the alkoxy among the substituents may be each independently substituted with halogen, one or more hydrogen atoms in the Ci-s alkyl or C^ cycloalkyl among the substituents may be each independently substituted with 3- to 6-membered heterocycloalkyl which is unsubstituted or substituted with alkyl, -CN or C(O)NH₂, one or more hydrogen atoms in the 3 to 6-membered heterocycloalkyl among the substituents may be each independently substituted with C^ alkyl or -OH;

one or more hydrogen atoms in the C&s aryl or 5- to 8-membered heteroaryl among the substituents may be each independently substituted with halogen, -CF₃, -NO₂, -OH, -SH, -CN, -NR3R4, -NHC(O)ORs, -CCOjNRsFU, alkoxy, C^ thioalkoxy, or C^ alkyl, wherein Rs, R4, Rsand Reare each independently hydrogen or Ci^ alkyl, wherein one or more atoms in the C^ alkyl may be substituted with halogen.

According to one embodiment of the présent invention, the compound represented by formula 1 may be a pyridine dérivative represented by the following formula 4:

[Formula 4]

wherein

Xis CH or N;

Ri and R₂ are each independently hydrogen, halogen, cyano, C^ alkyl, or C-i-6, wherein one or more hydrogen atoms in the C^ alkyl may be substituted with halogen;

A is Ô , H , O , O or

B is C^ alkyl, aryl or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, -NO₂, -CN, -NR3R4, -NHC(O)ORs, -SO₂Re, Ci^ alkoxy, alkyl, cycloalkyl, 3 to 6-membered heterocycloalkyl, C53 aryl, and 5- to 8-membered heteroaryl, wherein one or more hydrogen atoms in the Ci^ alkoxy among the substituents may be each independently substituted with halogen, one or more hydrogen atoms in the Ci^ alkyl or C^ cycloalkyl among the substituents may be each independently substituted with 3- to 6-membered heterocycloalkyl which is unsubstituted or substituted with Ci^ alkyl, -CN or C(O)NH₂, one or more hydrogen atoms in the 3- to 6-membered heterocycloalkyl among the substituents may be each independently substituted with alkyl or -OH;

one or more hydrogen atoms in the aryl or 5- to 8-membered heteroaryl among the substituents may be each independently substituted with halogen, -CF₃, -NO₂, -CN, -NR3R4, -NHC(O)OR5, -C(O)NR3R4, alkoxy, or Ci-8 alkyl, wherein R3, R4, Rsand Re are each independently hydrogen or Ci-6 alkyl, wherein one or more atoms in the Ci^ alkyl may be substituted with halogen.

According to another embodiment of the présent invention, the compound represented by formula 1 may be a pyridine dérivative represented by the following formula 5:

[Formula 5]

Wherein

X is a nitrogen atom;

Ri and R₂are each independently hydrogen or halogen;

A is O or Ô ; and

B is aryl or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, and Cm alkyl, wherein one or more hydrogen atoms in the Cm alkyl among the substituents may be each independently substituted with -ON.

According to still another embodiment of the présent invention, in the formula 1 above,

X is a nitrogen atom;

Ri and R₂are each independently hydrogen, halogen, Cm alkyl, or Cm alkoxy, wherein one or more hydrogen atoms in the Cm alkyl may be substituted with halogen;

B is Cî-8 alkyl, aryl or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, -NO₂, -CN, -NR3R4, -NHC(O)OR5, -SO₂Re, alkoxy, alkyl, cycloalkyl, 3- to 6-membered heterocycloalkyl, C&b aryl, and 5- to 8-membered heteroaryl, one or more hydrogen atoms in the C1-8 alkoxy among the substituents may be each independently substituted with halogen;

one or more hydrogen atoms in the alkyl or Cau cycloalkyl among the substituents may be each independently substituted with 3- to 6-membered heterocycloalkyl which is unsubstituted or substituted with alkyl, -CN or C(O)NH₂, one or more hydrogen atoms in the 3- to 6-membered heterocycloalkyl among the substituents may each independently substituted with alkyl or OH, one or more hydrogen atoms in the aryl or 5- to 8-membered heteroaryl among the substituents may be each independently substituted with halogen or C-^ alkyl.

X is CH;

Ri and R2 are each independently hydrogen, halogen, Cm alkyl, or Cm alkoxy, wherein one or more hydrogen atoms in the Cm alkyl may be substituted with halogen;

H

XV

A is O ; and

B is aryl, wherein one or more hydrogen atoms in the aryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, Cm alkoxy or Cm alkyl, wherein one or more hydrogen atoms in the Cm alkyl among the substituents may be each independently substituted with -CN or-C(O)NH₂.

The term 'halogen' as used herein refers to fluorine, chlorine, bromine or iodine, unless otherwise indicated.

The term 'alkyl' as used herein refera to a straight, cyclic or branched hydrocarbon residue, unless otherwise indicated.

The term ‘cycloalkyl’ as used herein refera to a cyclic alkyl including cyclopropyl, etc., unless otherwise indicated.

The term ‘aryl’ as used herein refera to an aromatic group including phenyl, naphthyl, etc., unless otherwise indicated.

The term ‘heterocycloalkyl’ as used herein refera to a cyclic alkyl, e.g., mono-, bi- or polycyclic alkyl, which contains at least one, preferably one to four heteroatoms, selected from O, N and S, unless otherwise indicated. Examples of monoheterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and groups similar thereto.

The term ‘heteroaryl’ as used herein refers to a mono-, bi- or polycyclic aromatic group, which contains at least one heteroatom, preferably one to four heteroatoms, selected from O, N and S, and in which one or more carbon atoms of the ring is substituted with C=O, unless otherwise indicated. Examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and groups similar thereto. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, furinyl, furopyridinyl, oxochromene, dioxoisoindoline and groups similar thereto.

According to a preferred embodiment of the présent invention, the pyridine dérivative represented by formula 1 may be selected from the group consisting of thefollowing compounds:

) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3(trifluoromethyl)benzamide;

2) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4- methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)benzamide;

3) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-((4- ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

4) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4 difluorophenyl)isobutylamide;

5) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)thiophene -2-carboxamide;

6) N-(3-(3-(9H-purin-6-yl)pyridine-2-ylamino)-2₎4-difluorOphenyl)furan-2carboxamide;

7) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)isoxazole5-carboxamide;

8) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)thiazole-5carboxamide;

9) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2₎4-difluorophenyl)-3-(2cyanopropan-2-yl)benzamide;

10) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2₎4-difluorophenyl)-3-(4- methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide;

) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3thiomorpholino-5-(trifluoromethyl)benzamide;

12) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2₎4-difluorophenyl)-3-(4- hydroxypiperidin-1-yl)-5-(tiifluoromethyl)benzamide;

13) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4- methylpiperidin-1-yl)-5-(trifluoromethyl)benzamide;

14) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4thiomorpholino-3-(trifluoromethyl)benzamide;

15) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2₎4-difluorophenyl)-4-(4- methylpeperidin-1-yl)-3-(trifluoromethyl)benzamide;

16) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-chloro3-(trifluoromethyl)benzamide;

17) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorOphenyl)-2,3- dihydrobenzo[b][1,4]dioxine-6-carboxamide;

18) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3morpholino-5-(trifluoromethyl)benzamide;

19) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorOphenyl)-4(pyiTolidin-1-yl)-3-(trifluoromethyl)benzamide;

20) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(1- cyanocyclopropyl)benzamide;

) N-(5-(3-(9H-purin-6-yl)pyridÎn-2-ylamino)-2-fluorophenyl)-3-(2cyanopropan-2-yl)benzamide;

22) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorOphenyl)-3-(1- amino-2-methyl-1-oxopropan-2-yl)benzamide;

23) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3-(2-cyanopropan-2yl)benzamide;

24) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-chlorOphenyl}-3-(2cyanopropan-2-yl)benzamide;

25) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,6-difluorophenyl)-3-(2- cyanopropan-2-yl)benzamide;

26) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorOphenyl)-2- (trifluoromethyl)benzamide;

27) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorOphenyl)-4- (trifluoromethyl)benzamide;

28) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorOphenyl)-3-fluoro5-(trifluoromethyl)benzamide;

29) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-(2 cyanopropan-2-yl)benzamide;

30) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3(trifluoromethyl)benzamide;

) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- (trifluoromethyl)benzamide;

32) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(2- cyanopropan-2-yl)benzamide;

33) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-(2cyanopropan-2-yl)-5-fluorobenzamide;

34) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- nitrobenzamide;

35) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- methoxybenzamide;

36) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-fluoro-5(trifluoromethyl)benzamide;

37) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3cyanobenzamide;

38) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4- methoxy-3-(trifluoromethyl)benzamide;

39) N-(4-(3-(9H-purin-6-yl)pyridin-2-ylamino)-3-fluorophenyl)-3-(2cyanopropan-2-yl)benzamide;

40) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-nitro-5(trifluoromethyl)benzamide;

) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difIuorophenyl)-4-chloro3-(2-cyanopropan-2-yl)benzamide;

42) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-2-chloro3-(2-cyanopropan-2-yl)benzamide;

43) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~diÎluorOphenyl)-3-(2cyanopropan-2-yl)-5-fluorobenzamide;

44) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~difluorophenyl)-3-(2- cyanopropan-2-yl)-4,5-difluorobenzamide;

45) N-(3-(3-(9H-purin-6-yl)pyrdin-2-ylamino)-2,4~diÎluorophenyl)-3chlorobenzamide;

46) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~difluorophenyl)-3- (dimethylamino)benzamide;

47) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~drfluorophenyl)-3- methylbenzamide;

48) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3-chlorobenzamide,·

49) N-(3-(3-(9H-puriri-6-yl)pyridin-2-ylamino)-4-fluorOphenyl)-3-(2- cyanopropan-2-yl)benzamide;

50) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-4-fluorophenyl)-3- (trifluoromethyl)benzamide;

) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3(trifluoromethyl)benzamide;

52) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~drfluorophenyl)-4- nitrobenzamide;

53) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~drfluorophenyl)-4- methoxybenzamide;

54) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4~drfluorophenyl)-3- aminobenzamide;

55) methyl 3-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenylcarbamoyl)phenylcarbamate;

56) N-(3-(349H-purin-6-yl)pynriin-2-ylamino)-2,4-difIuorophenyl)pyrazine2-carboxamide;

57) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4- difluorophenyl)benzamide;

58) N-{2,4-difluoro-3-[3-(9H-purin-6-yl)pyridin-2-ylamino)-phenyl}-3,5- bistrifluoromethylbenzamide;

59) 1 -(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(3-(4methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl)urea;

60) 1-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4-((4ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;

) 4-chloro-N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3(trifluoromethyl)benzamide;

62) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3-nitro-5(trifluoromethyl)benzamide;

63) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3-methoxy5-(trifluoromethyl)benzamide;

64) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-(6- methylpyridin-2-yl)benzamide;

65) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3,5- bis(trifluoromethyl)benzamide;

66) N-{2-chloro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;

67) N-{2-chloro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3-fluoro-5 trifluoromethylbenzamide;

68) N-{2-methyl-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3trifluoromethylbenzamide;

69) N42-methoxy-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;

70) N-{4-methoxy-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;

) N-{4-methyl-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3trifluoromethylbenzamide;

72) N-{2,6-difluoro-3-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;

73) 2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino]-N-(3- trifluoromethylphenyl)benzamide;

74) 1-(4-chloro-3-trifluoromethylphenyl)-3-{2-fluoro-5-[3-(9H-purin-6- yl)pyridin-2-ylamino]phenyl}urea;

75) 1 -{3-fIuoro-4-[3-(9H-purin-6-yl)pyridin-2-ylamino]phenyl}-3-(3- trifluoromethylphenyl)urea;

76) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino]phenyl}-2-(3trifluoromethylphenyl)acetamide;

77) N-(3-cyanomethylphenyl)-4-fluoro-3-[3-(9H-purin-6-yl)pyridin-2- ylamino]benzamide;

78) N-4-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-3-fluorophenyl-4- (cyanomethyl)benzamide;

79) N-4-[3-(9H-purin-6-yl)pyridin-2-ylamino]phenyl-3- trifluoromethylbenzamide;

80) N-2-methoxy-4-[3-(9H-purin-6-yl)pyridin-2-ylamino]phenyl-3trifluoromethylbenzamide;

) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4fluorophenyl)-2-oxoimidazolidine-1-carboxamide;

82) N-(4-(3-(9H-purin-6-yl)pyridin-2-ylamino)-3-fluorophenyl)-3-(2cyanopropan-2-yl)benzamide;

83) N-(34347H-pyrrolo[2,3-d]pyrimidinM-yl)pyridin-2-ylamino)-2,4- difluorophenyl)-3-(1 -amino-2-methyl-1 -oxopropan-2-yl)benzamide;

84) N-(5-(3-(7H-pyrrolo[2,3-d]pyrimidinM-yl)pyridin-2-ylamino)-2,4- diflurophenyl)-3-(2-cyanopropan-2-yl)benzamide;

85) N-(34347H-pyirolo[2,3-d]pyrimidinM-yl)pyridin-2-ylamino)-2,4- difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide;

86) N-(34347H-pyrrolo[2,3-d]pyrimidinM-yl)pyridin-2-ylamino)-2- fluorophenyl)-3-(2-cyanopopan-2-yl)benzamide;

87) N-2-fluoro-5-[3-(7H-pynOlo[2,3-d]pyrimidinM-yl)pyridin-2- ylamino]phenyl-3-trifluoromethyl benzamide;

88) 3-fluoro-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidinM-yl)pyridin-2- ylamino]phenyl-5-trifluoromethyl benzamide;

89) 4-chloro-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidinM-yl)pyridin-2- ylamino]phenyl-5-trifluoromethyl benzamide;

90) N-2-fluoro-5-[3-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3,5-bistrifluoromethyl benzamide;

) 3-(2-cyanopropan-2-yl)-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidinMyl)pyridin-2-ylamino]phenyl benzamide;

92) 3-(2-cyanopropan-2-yl)-5-fluorc>-N-2-fluoro-5-[3-(7H-pyiTolo[2,3

d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide;

93) 4-chloro-3-(2-cyanopropan-2-yl)-N-2-fluoro-5-[3-(7H-pynOlo[2,3-

d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide;

94) 3-(2-cyanopropan-2-yl)-N-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4yl)pyridin-2-ylamino]phenyl benzamide;

95) 3-(2-cyanopropan-2-yl)-N-4-fluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4yl)pyridin-2-ylamino]phenyl benzamide;

96) 3-(2-cyanopropan-2-yl)-N-2,6-difluoro-3-[3-(7H-pyrrolo[2,3-

d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide;

97) N-{2-chloro-5-[3-(7H-pyrrOlo[2,3-d]pyrimidin-4-yl)pyiidin-2- ylamino]phenyl)-3-(2-cyanopropan-2-yl)benzamide;

98) 3-(2-cyanopropan-2-yl)-N-3-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4yl)pyridin-2-ylamino]phenyl benzamide;

99) 3-(2-cyanopropan-2-yl)-N-4-methyl-3-[3-(7H-pyrrolo[2,3-d]pyrimidin4-yl)pyridin-2-ylamino]phenylbenzamide;

100) 3-(2-cyanopropan-2-yl)-N-{4-methoxy-3-[3-(7H-pyrrolo[2,3d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl)benzamide;

101 ) N-{3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl}-3trifluoromethylbenzamide;

102) N-2-fluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

103) N-4-fluoro-3-[3-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

104) N-2,4-drfluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

105) N-2,6-difluoro-3-[3-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

106) N-2,4-difluoro-5-[3-(7H-pyiTolo[2,3-d]pyrimidin-2-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

107) N-2-chloro-5-[3-(7H-pynOlo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

108) N-4-methyl-3-[3-(7H-pynOlo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

109) N-4-methoxy-3-[3-(7H-pynOlo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

110) N-3-fluoro-5-[3-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;

111) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-fluoro-3(trifluoromethyl)benzamide;

112) 5-[3-(9H-purin-6-yl)amino]-N-[3-(2-cyanopropan-2-yl)phenyl]-2fluorobenzamide;

113) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3fluorobenzamide;

114) 5-[3-(9H-purin-6-yl)pyridin-2-yl]amino-N-(3,4-difluorophenyl)-2- fluorobenzamide;

115) 5-[3-(9H-purin-6-yl)pyridin-2-yl]amino-N-(3,5-difluorophenyl)-2- fluorobenzamide;

116) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluoropheny-3-(2- cyanopropan-2-yl)-4-fluorobenzamide;

117) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-chloro-3- (2-cyanopropan-2-yl)benzamide;

118) 1 -5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-[3- (trifluoromethyl)phenyl]urea;

119) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-6-(2cyanopropan-2-yl)picolinamide;

120) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2-fluoro-5(trifluoromethyl)benzamide;

121) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2-fluoro-3(trifluoromethyl)benzamide;

122) N-3-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- (trifluoromethyl)benzamide;

123) 1 -5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-[4- (trifluoromethyl)phenyl]urea;

124) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-chlorophenyl-3,5- bis(trifluoromethyl)benzamide;

125) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3(methylthio)benzamide;

126) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- (methylsulfonyl)benzamide;

127) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-chlorophenyl-3-(2- cyanopropan-2-yl)-5-fluorobenzamide;

128) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2,4- bis(trifluoromethyl)benzamide;

129) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3,4- bis(trifluoromethyl)benzamide;

130) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2,5bis(trifluoromethyl)benzamide;

131) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3(trifluoromethoxy)benzamide;

132) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3,5- dimethoxybenzamide;

133) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-fluoro-4(trifluoromethyl)benzamide;

134) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-methoxy3-(trifluoromethyl)benzamide;

135) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-chloro-5(trifluoromethyl)benzamide;

136) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-6- (trifluoromethyl)picolinamide;

137) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-fluoro-3methylbenzamide;

138) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-methyl-3(trifluoromethyl)benzamide;

139) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-methyl-5(trifluoromethyl)benzamide;

140) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-methoxy5-(trifluoromethoxy)benzamide;

141) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3cyclopropylbenzamide;

142) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-chloro-5- (trifluoromethoxy)benzamide;

143) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-fluoro-3(trifluoromethoxy)benzamide;

144) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4(trifluoromethyl)picolinamide;

145) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- methylbenzamide;

146) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- chlorobenzamide;

147) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-chloro-3(trifluoromethoxy)benzamide;

148) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-fluoro-2(trifluoromethyl)isonicotinamide;

149) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-5(trifluoromethyl)nicotinamide;

150) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-methoxy3-(trifluoromethoxy)benzamide;

151) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2(trifluoromethyl)isonicotinamide;

152) N-3-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-4-methoxyphenyl-3-(2- cyanopropan-2-yl)benzamide;

153) N-3-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-4-methylphenyl-3-(2- cyanopropan-2-yl)benzamide;

154) N-5-[(3-(9H-punn-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-(2cyanopropan-2-yl)-5-(trifluoromethyl)benzamide;

155) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-(2cyanopropan-2-yl)-5-methylbenzamide;

156) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2-bromo-3(2-cyanopropan-2-yl)-5-methoxybenzamide;

157) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-cyano-5(trifluoromethyl)benzamide; and

158) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-bromo-5(trifluoromethyl)benzamide.

The compounds according to the présent invention may form pharmaceutically acceptable salts. These pharmaceutically acceptable salts may be those formed from acids that form nontoxic acid addition salts containing pharmaceutically acceptable anions, but the scope of the présent invention is not limited thereto. Examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, and like; organic carbonic acids such as tartane acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and the like; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalensulfonic acid, and the like.

In addition, the compounds of formula 1 or pharmaceutically acceptable salts thereof according to the présent invention may also exist as solvatés or hydrates.

In addition, the compounds represented by formula 1 according to the présent invention may contain one or more asymmetric carbon atoms, and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. These isomers may be resolved using conventional methods. For example, isomers of the compounds represented by formula 1 may be resolved by column chromatography or HPLC. Altematively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.

Method for Préparation of Pyridine Dérivative

The présent invention provides a method for preparing the pyridine dérivative of the présent invention, the method comprising a step of reacting a compound of formula 2 with a compound of formula 3 according to the following reaction scheme 1, thereby obtaining a compound of formula 1:

[Reaction Scheme 1]

wherein X, A, B, R¹ and R² are as defined in formula 1 above, and Y is halogen.

In the préparation method according to the présent invention, lithium(bistrimethylsilyl)amide may be used as a base, and tetrahydrofuran may be used as a solvent. Specifically, the pyridine dérivative of formula 1 may be prepared by dissolving the compound of formula 2 and the compound of formula 3 in tetrahydrofuran as the solvent, and then adding lithium(bistrimethylsilyl)amide as the base, slowly thereto at 0°C, followed by stirring at room température for 1 hour.

Pharmaceutical Composition Comprising Pyridine Dérivative as Active Ingrédient, Use Thereof, and Treatment Method Usina the Same

The présent invention provides a pharmaceutical composition for prévention or treatment of an abnormal cell growth disease caused by RAS mutation, the composition containing, as an active ingrédient, the pyridine dérivative represented by the following formula 1 or a pharmaceutically acceptable sait thereof:

[Formula 1]

wherein X, A, B, |Ri and R₂ are as defined above.

The pyridine dérivative or pharmaceutically acceptable sait thereof according to the présent invention exhibits the effect of inhibiting ail Raf kinases (B-Raf, Raf-1, and B-RafV600E) and vascular endothélial growth factor receptor (VEGFR2) which is involved in angiogenesis. Thus, a pharmaceutical composition containing, as an active ingrédient, the pyridine dérivative or pharmaceutically acceptable sait thereof according to the présent invention, may be effectively used for the prévention or treatment of an abnormal cell growth disease (a disease caused by abnormal activation) caused by excessive activity of Raf kinases and vascular endothélial growth factor receptorwhich is involved in angiogenesis. Namely, the pharmaceutical composition may be effectively used for the prévention or treatment of an abnormal cell growth disease caused by RAS mutation.

In the présent invention, the abnormal cell growth disease caused by RAS mutation may be any one selected from the group consisting of gastric cancer, lung cancer, liver cancer, colorectal cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, ovarian cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, rénal cancer, sarcoma, prostate cancer, uréthral cancer, bladder cancer, leukemia, multiple myeloma, blood cancer, lymphoma, fibroadenoma, inflammation, diabètes, obesity, psoriasis, rheumatoid arthritis, hemangioma, acute or chronic rénal disease, coronary artery restenosis, autoimmune diseases, asthma, neurodegenerative diseases, acute infection, and ocular diseases caused by vascular disorders. More preferably, the abnormal cell growth disease caused by RAS mutation may be any one selected from the group consisting of melanoma, colorectal cancer, prostate cancer, thyroid cancer, and ovarian cancer.

The pharmaceutical composition according to the présent invention may further contain an agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiera, antihormonal agents, antiandrogen, cell differentiation/proliferation/survival inhibitore, apoptosis inhibitore, inflammation inhibitore, and P-glycoprotein inhibitore. The pharmaceutical composition according to the présent invention may be administered or formulated in combination with the additional agent.

The pharmaceutical composition according to the présent invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the intended use. The dose of the pharmaceutical composition varies depending on the patient’s weight, âge, sex, health condition and diet, the time of administration, the mode of administration, excrétion rate, the severity of the disease, and the like. The compound represented by formula 1 according to the présent invention may be administered once or several times at a daily dose of about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg.

The pharmaceutical composition according to the présent invention may contain a conventional pharmaceutically acceptable carrier, excipient or additive. The pharmaceutical composition according to the présent invention may be formulated according to a conventional method, and may be provided as various oral dosage forms such as tablets, pills, powdere, capsules, syrups, émulsions, microemulsions and the like, or dosage forms for parentéral administration such as intramuscular, intravenous or subcutaneous administration.

When the pharmaceutical composition of the présent invention is prepared as an oral formulation, examples of additives or carriers that may be used include cellulose, calcium silicate, com starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnésium stéarate, calcium stéarate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents and the like. When the pharmaceutical composition of the présent invention is prepared as an injectable formulation, examples of additives or carriers that may be used include water, saline, aqueous glucose solution, sugar-like solution, alcohol, glycol, ether (e.g., polyethyleneglycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactants, suspending agents, emulsifiers and the like. In addition, the pharmaceutical composition according to the présent invention may further contain a pharmaceutically acceptable additive. The phrase “pharmaceutically acceptable” refers to additives or compositions that are physiologically tolerable and do not typically produce an allergie or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to humans. Examples of the additives include carriers, excipients, diluents and the like. Examples of the additives include carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnésium stéarate, and minerai oil. In addition, the composition may further contain a filler, an anticoagulant, a lubricant, a wetting agent, fragrance, an emulsifier, a preservative and the like.

The présent invention also provides the use of the pyridine dérivative of formula 1 or a pharmaceutically acceptable sait thereof in the prévention or treatment of an abnormal cell growth disease caused by RAS mutation.

The présent invention also provide the use of the pyridine dérivative of formula 1 or a pharmaceutically acceptable sait thereof in préparation of a médicament for preventing or treating an abnormal cell growth disease caused by RAS mutation.

The présent invention also provide a preventing or treating an abnormal cell growth disease caused by RAS mutation, the method comprising administering a therapeutically effective amount of the pyridine dérivative represented by formula 1 or a pharmaceutically acceptable sait thereto to a subject in need of prévention or treatment of the abnormal cell growth disease caused by RAS mutation. In the présent invention, the “subject” includes mammals, particulariy humans.

As used herein, the term “therapeutically effective amount” refers to an amount of the pyridine dérivative represented by formula 1, which is effective for prévention or treatment of the abnormal cell growth disease caused by RAS mutation.

[Mode for Invention]

Hereinafter, the présent invention will be described in detail with reference to examples and experimental examples. It is to underatood, however, that these examples are only for better underatanding of the présent invention and are not intended to limit the scope of the présent invention.

Example 1. Préparation of N-(3-(3-(9H-purin-6-vDpvridin-2-ylamino)2,4-difluorophenvl)-3-(trifluoromethyl)benzamide

Step 1: Préparation of 2,6-difluoro-3-nitrobenzoic acid kno₃ o₂n

H2SO₄

To 2,6-difluorobenzoic acid (1.4 g, 9 mmol), concentrated suffuric acid (5 mL) was added, and potassium nitrate (1 g, 9.9 mmol) was added in small portions at 0°C. The reaction mixture was warmed to room température and stirred for 24 hours. Next, ice water was poured into the reaction solution, extracted with ethyl acetate, dried with anhydrous magnésium sulfate, and then concentrated under reduced pressure. The residue was filtered under reduced pressure, and the obtained solid was washed with diethyl ether and dried to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 8.37 (td, J= 9.2, 5.6 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H)

Step 2: Préparation of t-butyl 2,6-difluoro-3-nitrophenyl carbamate

NaN₃. t-BuOH □ CM/DMF

To a mixed solvent of dichloromethane and N,N-dimethyfformamide, 2,6difluoro-3-nutrobenzoic acid (16 g, 79 mmol) prepared in step 1 was added and oxalyl chloride (14 mL, 158 mmol) was added slowly. The reaction mixture was stirred at room température for 18 hours and concentrated the solvent, and the residue was diluted with dichloromethane and Ν,Ν-dimethyfformamide and cooled to 0°C. Sodium azide (5.6 g, 87 mmol) was added thereto in small portions. After the solution was stirred at room température for 30 minutes, tbutanol (40 mL) was added thereto. The reaction solution was stirred under reflux for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. After concentration, the residue was washed with aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was concentrated, dried with anhydrous magnésium sulfate, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 8.00 (m, 1H), 7.08 (m, 1H), 6.46 (bs, 1H), 1.51 (s, 9H)

Step 3: Préparation of t-butyl 3-amino-2,6-difluorophenyl carbamate

t-butyl 2,6-difluoro-3-nitrophenyl carbamate (1 g, 3.6 mmol) prepared in step 2 was dissolved in a methanol solvent, and palladium carbon (100 mg) was added thereto, followed by stirring for 15 hours under a hydrogen pressure. After completion of the reaction, the reaction solution was filtered through celite, concentrated under reduced pressure, and purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI3): δ 6.74 (m, 1H), 6.59 (m, 1H), 5.95 (bs, 1H), 3.62 (bs, 2H), 1.51 (s, 9H)

Step 4:Préparation of t-butyl 2,6-difluoro-3-(3(trifluoromethvl)benzamido)phenvl carbamate

t-butyl (3-amino-2,6-difluorophenyl)carbamate (30 mg, 0.12 mmol) prepared in step 3 was added to and dissolved in a dichloromethane solvent.

To the réaction solution, 3-(trifluoromethyl)benzoyl chloride (19 pL, 0.13 mmol) and triethylamine (25 pL, 0.18 mmol) were added, followed by stirring at room température for 1 hour. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 8.25 (m, 1H), 8.16 (s, 1H), 8.07 (d, J= 7.6 Hz, 1H), 7.99 (s, 1H), 7.86 (d, J= 7.6 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.02 (td, J = 9.2,1.6 Hz, 1 H) 6.06 (s, 1 H), 1.54 (s, 9H)

Step 5: Préparation of 6-chloro-9-(tetrahvdro-2H-pyran-2-vl)-9H-purine

6-chloro-9H-purine (500 mg, 3.2 mmol), 4-methanesuffonic acid (12 mg, 0.07 mmol) and 3,4-dihydro-2H-pyran (0.9 mL, 9.7 mmol) were added to an ethyl acetate solvent, followed by stirring. The reaction mixture was stirred at 90°C for about 1 hour until the solid was completely dissolved. After the solvent was removed by concentration, the residue was purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 8.77 (s, 1H), 8.36 (s,1H), 5.80 (dd, J= 10.4, 2.8 Hz, 1 H), 4.21 (m, 1 H), 3.80 (m, 1 H), 2.21-1.67 (m, 6H)

Step 6: Préparation of 6-(2-fluoropvridin-3-vl)-9-(tetrahvdrO-2H-pvran-2yl)-9H-purine

To a mixed solvent of éthanol and water (5/1 v/v), 6-chloro-9-(tetrahydro2H-pyran-2-yl)-9H-purine (239 mg, 1 mmol) prepared in step 5, 2-fluoropyridin3-yl boronic acid (189 mg, 1.3 mmol), potassium acetate (216 mg, 2.2 mmol) 5 and bis(di-t-butyl-(4-dimethylaminophenyl)phosphine)dichloropalladium (14 mg, 0.02 mmol) were added. The reaction mixture was stirred under reflux under a nitrogen atmosphère at 80°C for 2 hours. After completion of the reaction, the solution was concentrated, washed with water and brine, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate ίο and concentrated under reduced pressure, and the residue was purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 9.09 (s, 1H), 8.91 (s, 1H), 8.56 (m, 1H), 8.47 (m, 1H), 7.62 (m, 1H), 5.84 (dd, J = 10.8, 2.0 Hz, 1H), 4.04 (m, 1H), 3.76 (m, 1 H), 2.38 (m, 1 H), 2.03 (dd, J = 12.8, 2.6 Hz, 2H), 1.79-1.60 (m, 3H)

Step 7: Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahvdro-2H-pvran-2-vl)9H-purin-6-vl)pyridin-2-vlamino)phenvl)-3-(trifluoromethvl)benzamide

t-butyl-2,6-difluoro-3-(3-(trifluoromethyl)benzamido)phenyl carbamate (30 mg, 0.09 mmol) prepared in step 4 was dissolved in an ethyl acetate solvent, and 4 M hydrogen chloride solution (4 M solution in 1,4-dioxane) was added 5 thereto, followed by stirring at room température for 2 hours. After completion of the reaction, the solvent was concentrated, and the filtration under reduced pressure was performed to afford N-(3-amino-2,4-difluorophenyl)-3(trifluoromethyl)benzamide.

N-(3-amino-2,4-difluorophenyl)-3-(trifluoromethyl)benzamide (19 mg, ίο 0.06 mmol) obtained by the above and 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2Hpyran-2-yl)-9H-purine (16 mg, 0.054 mmol) prepared in step 6 were added to and dissolved in a tetrahydrofuran solvent, and then lithium(bistrimethylsilyl)amide (270 pL, 1.0 M solution in THF) was added slowly thereto at 0°C. The reaction solution was stirred at room température for 1 hour.

After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR(400MHz, CDCI₃): δ 11.66 (s, 1H), 9.68 (dd, J= 8.0, 2.0 Hz, 1H),

9.05 (s, 1H), 8.40 (s, 1H), 8.30 (dd, J= 4.8, 1.6 Hz, 1H), 8.23 (m, 1H), 8.19 (s, 1H), 8.07 (m, 2H), 7.84 (d, J = 7.6 Hz,1H), 7.66 (t, J= 7.6 Hz, 1H), 7.09 (td, J = 9.2, 2.0 Hz, 1H), 6.98 (dd, J= 8.0, 4.8 Hz, 1H), 5.91 (dd, J= 10.8, 2.4 Hz, 1H), 4.25 (m, 1H), 3.86 (m, 1H), 2.24-1.61 (m, 6H)

Step 8: Préparation of N-(3-(3-(9H-purin-6-vl)pvridin-2-ylamino)-2,4difluorophenyl)-3-(trifluorometrhvl)benzamide

N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2ylamino)phenyl)-3-(trifluoromethyl)benzamide (20 mg, 0.034 mmol) prepared in step 7 was added to 1M hydrochloric acid aqueous solution and stirred under reflux for 2 hours. After completion of the reaction, the reaction solution was washed with aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 9.72 (bs, 1H), 9.04 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 8.26 (d, J =7.2 Hz, 1H), 8.19 (dd, J= 4.0, 1.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.77 (t, J= 8.0 Hz, 1H), 7.63 (m, 1H), 7.15 (t, J = 9.6 Hz, 1H), 7.03 (dd, J =8.0, 4.8 Hz, 1 H)

Example 2. Préparation of N-(3-(3-(9H-purin-6-vl)pyridin-2-ylamino)2,4-difluorophenvl)-3-(4-methvl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamide

Step 1: Préparation of t-butyl 2,6-difluoro-3-(3-(4-methvl-1H-imidazol-1yl)-5-(trifluoiOmethvl)benzamido)phenvl carbamate

To a dichloromethane solvent, t-butyl-3-amino-2,6-difluorophenyl carbamate (30 mg, 0.12 mmol) prepared in step 3 of Example 1, 3-(4-methyl1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (48 mg, 0.18 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (35 mg, 0.18 mmol) and N,Ndimethylaminopyridine (15 mg, 0.12 mmol) were added, and the mixture was ίο stirred at room température for 2 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, MeOD): δ 8.42 (s, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.64 (d, J = Hz, 1H), 7.52 (s, 1H), 7.09 (td, J = Hz, 1H), 2.30 (s, 3H), 1.52 (s, 9H)

Step 2: Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahvdro-2H-pvran-2-vl)9H-purin-6-vl)pvridin-2-vlamino)phenvl)-3-(4-methvl-1 H-imidazol-1-vl)-540 (trifluoromethyl)benzamide

t-butyl 2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenyl carbamate (30 mg, 0.06 mmol) prepared in 5 step 1 was added to an ethyl acetate solvent, and hydrogen chloride solution (4 M solution in 1,4-dioxane) was added thereto, followed by stirring at room température for 2 hours. After completion of the reaction, the solvent was concentrated, and the filtration under reduced pressure was performed to afford N-(3-amino-2,4-difluorophenyl)-3-(4-methyl-1 H-pyrazol-1 -yl )-510 (trifluoromethyl)benzamide.

N-(3-amino-2,4-difluorophenyl)-3-(4-methyl-1 H-pyrazol-1 -yl )-5(trifluoromethyl)benzamide (26 mg, 0.07 mmol) obtained by the above processes and 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (18 mg, 0.059 mmol) prepared in step 6 of Example 1 were added to and 15 dissolved in a tetrahydrofuran solvent, and then lithium(bistrimethylsilyl)amide (295 pL, 1.0 M solution in THF) was added slowly thereto at 0°C. The reaction solution was stirred at room température for 1 hour. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.69 (s, 1 H), 9.67 (dd, J = 8.0, 2.0 Hz, 1 H), 9.04 (s, 1H), 8.45 (s, 1H), 8.42 (s, 2H), 8.24 (dd, J = 4.8, 1.6 Hz, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.10 (m, 2H), 6.95 (dd, J= 8.0, 4.8 Hz, 1H), 5.90 (m, 1H), 4.23 (m, 1H), 3.85 (m, 1H), 2.29 (s, 3H), 2.24-1.73 (m, 6H)

Step 3: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide

N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2ylamino)phenyl)-3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)benzamide (20 mg, 0.030 mmol) prepared in step 2 was added to 1M hydrochloric acid aqueous solution and stirred under reflux for 2 hours. After completion of the reaction, the reaction solution was washed with aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 9.65 (bs, 1H), 9.04 (s, 1H), 8.55 (s, 1H),

8.45 (s, 1H), 8.29 (s, 2H), 8.19 (d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 7.67 (m, 1H),

7.53 (s, 1 H), 7.16 (t, J = 9.2 Hz, 1 H), 7.04 (dd, J = 7.6, 4.8 Hz, 1 H), 2.30 (s, 3H)

Example 3. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-vlamino)2,4-difluorophenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethyl)benzamide

Step 1: Préparation of t-butyl-3-(4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethy)benzamido)-2,6-difluorophenyl carbamate h î EDCI, DMAP H

Il ⁺ I I \ O N ¹ OY â' °F

To a dichloromethane solvent, t-butyl-3-amino-2,6difluorophenylcarbamate (30 mg, 0.12 mmol) prepared in step 3 of Example 1, 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (50 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (35 mg, 0.18 mmol) and N,N-dimethylaminopyridine (15 mg, 0.12 mmol) were added. The mixture was stirred at room température for 2 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 8.16-7.98 (s, 5H), 6.98 (t, J = 9.2 Hz, 1H), 6.33 (s, 1H), 3.74 (s, 2H), 2.57 (bs, 8H), 2.47 (q, J = 7.2 Hz, 2H), 1.52 (s, 9H),

1.12 (t, 7=7.2 Hz, 3H)

Step 2: Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahvdro-2H-pvran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethyl)benzamide

4M HCl EtOAc

t-butyl-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethy)benzamido)2,6-difluorophenyl carbamate (30 mg, 0.06 mmol) prepared in step 1 was added to an ethyl acetate solvent, and hydrogen chloride solution (4 M solution in 1,4-dioxane) was added thereto, followed by stirring at room température for 2 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was filtered under reduced pressure to afford N(3-amino-2,4-difluorophenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethyl)benzamide.

N-(3-amino-2,4-difluorophenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethyl)benzamide (22 mg, 0.05 mmol) obtained by the above processes and 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (14 mg, 0.05 mmol) prepared in step 6 of Example 1 were added to and dissolved in a tetrahydrofuran solvent, and lithium(bistrimethylsilyl)amide (225 pL, 1.0 M solution in THF) was added slowly thereto at 0°C. The solution was stirred at room température for 1 hour. After completion of the reaction, water was added to the reaction solution and an extraction with ethyl acetate was performed. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR(400MHz, CDCI₃): δ 11.65 (s, 1H), 9.68 (dd, J = 8.0, 2.0 Hz, 1H) 9.05 (s, 1H), 8.41 (s, 1H), 8.31 (dd, J= 4.8, 1.6 Hz, 1H), 8.18 (s, 1H), 8.02 (m, 3H), 7.07 (td, J= 9.2, 1.6 Hz, 1H), 6.99 (dd, J = 8.0, 4.8 Hz, 1H), 5.91 (dd, J = 10.4, 2.4 Hz, 1H), 4.23 (m, 1H), 3.86 (m, 1H), 2.47 (m, 10H), 2.25-1.71 (m, 6H), 1.10 (t,J= 7.6 Hz, 3H)

Step 3: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

To N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-ylamino)phenyI)-4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethyl)benzamide (20 mg, 0.03 mmol) prepared in step 2, 1M hydrochloric acid aqueous solution was added, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction solution was cooled to room température, and the produced solid was filtered under reduced pressure, washed with water and dichloromethane, and dried at room température to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 10.50 (dd, J = 8.0, 1.6 Hz, 1H), 9.13 (bs, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.19 (dd, J= 8.0, 1.6 Hz, 1H), 7.87 (m, 1H), 7.49 (dd, J= 7.6, 6.4 Hz, 1H), 7.43 (t, J =9.2 Hz, 1H), 4.15 (s,

2H), 3.54 (m, 2H), 3.26 (m, 6H), 2.80 (m, 2H), 1.39 (t, J = 7.6 Hz, 3H)

Example 4. Préparation of N-(3-(3-(9H-purïn-6-vl)pyridin-2-ylamino)2,4-difluorophenyl)isobutylamide

Step 1: Préparation of benzyl t-butyl(2,4-difluoro-1,3phenylene)dicarbamate

Benzyl chloroformate

DIEA, DCM

To a dichloromethane solvent, t-butyl 2,6-difluoro-3aminophenylcarbamate (305 mg, 1.25 mmol) prepared in step 3 of Example 1, 10 diisopropylethylamine (371 pL, 2.13 mmol) and benzyl chloride (194 pL, 1.38 mmol) were added. The mixture was stirred at room température for 5 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, filtered under reduced pressure, and then 15 concentrated. The residue was purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 7.94 (bs, 1H), 7.39 (m, 5H), 6.93 (td, J= 9.2, 1.6 Hz, 1 H), 6.82 (bs, 1 H), 5.98 (bs, 1 H), 5.23 (s, 2H), 1.52 (s, 9H).

Step 2: Préparation of benzyl 3-amino-2,4-difluorophenylcarbamate

4M HCl

EtOAc

t-butyl(2,4-difluoro-1,3-phenylene)dicarbamate (400 mg, 1.06 mmol) prepared in step 1 was added to an ethyl acetate solvent, and 4 M hydrogen chloride solution (4 M solution in 1,4-dioxane) was added thereto, followed by stirring at room température for 5 hours. After completion of the reaction, the solid obtained by concentrating the solvent and being filtered under reduced pressure was washed with diethyl ether, thereby obtaining the title compound.

¹H NMR (400MHz, CDCI₃): δ 7.40 (m, 6H), 6.80 (dd, J = 9.6, 2.0 Hz, 1H),

6.74 (bs, 1H), 5.23 (s, 2H), 3.76 (bs, 2H)

Step 3: Préparation of benzyl-2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl carbamate

3-amino-2,4-difluorophenylcarbamate (100 mg, 0.32 mmol) prepared in step 2 and 6-(2-fIuoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (86 mg, 0.29 mmol) prepared in step 6 of Example were added to and dissolved in anhydrous tetrahydrofuran, and then lithium(bistrimethylsilyl)amide (1.0 M solution in THF, 1.45 mL) was added slowly thereto at 0°C. The reaction mixture was stirred for 1 hour. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.57 (s, 1H), 9.66 (dd, J= 8.0, 2.0 Hz, 1H), 9.02 (s, 1 H), 8.39 (s, 1 H), 8.28 (dd, J = 4.4, 1.6 Hz, 1H ), 7.92 (bs, 1 H), 7.40 (m, 5H), 6.98 (m, 3H), 5.89 (dd, J = 10.4, 2.4 Hz, 1H), 5.24 (s, 2H), 4.22 (m, 1H), 3.84 (m, 1 H), 2.23-1.68 (m, 6H)

Step 4: Préparation of 2,6-difluoro-N-(3-(9-(tetrahydro-2H-pvran-2-yl)-9Hpurin-6-yl)pyridin-2-yl)benzene-1,3-diamine

Benzyl-2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-ylamino)phenyl carbamate (100 mg, 0.18 mmol) prepared in step 3 was dissolved in a methanol solvent, and palladium carbon (50 mg) was added thereto, followed by stirring under a hydrogen pressure for 1 hour. After completion of the reaction, the reaction solution was filtered through celite, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.49 (s, 1H), 9.63 (dd, J= 7.6, 1.6 Hz, 1H), 9.01 (s, 1H), 8.37 (s, 1H), 8.30 (dd, J= 4.8, 1.6 Hz, 1H ), 6.92 (m, 1H), 6.82 (td, J = 9.2, 2.0 Hz, 1H), 6.60 (td, J = 9.2, 5.2 Hz, 1H), 5.88 (dd, J = 10.4, 2.4 Hz, 1 H), 4.23 (m, 1 H), 3.83 (m, 1 H), 3.49 (bs, 2H), 2.22-1.69 (m, 6H)

Step 5: Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pvridin-2-ylamino)phenyl)isobutylamide

2,6-difluoro-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2yl)benzene-1,3-diamine (30 mg, 0.07 mmol) prepared in step 4, isobutyryl chloride (8 pL, 0.078 mmol) and triethylamine (20 pL, 0.14 mmol) were added to 5 a dichloromethane solvent, followed by stirring at room température for 2 hours.

After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

ίο ¹H N MR (400MHz, CDCI₃): δ 11.57 (s, 1H), 9.67 (dd, J= 8.0, 2.0 Hz, 1H), 9.03 (s, 1 H), 8.40 (s, 1 H), 8.28 (m, 1 H), 7.42 (s, 1 H), 6.99 (m, 2H), 5.90 (dd, J = 10.8, 2.4 Hz, 1H), 4.23 (m, 1H), 3.85 (m, 1H), 2.58 (m, 1H), 2.23-1.68 (m, 6H), 1.29 (d, J =6.8 Hz, 6H)

Step 6: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,415 difluorophenyDisobutylamide

To N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-ylamino)phenyl)isobutylamide (20 mg, 0.040 mmol) prepared in step 5, 1M hydrochloric acid aqueous solution was added, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was washed with aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by 5 column chromatography to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 11.69 (s, 1H), 9.67 (m, 2H), 8.98 (s, 1H), 8.64 (s, 1H), 8.19 (dd, J= 4.8, 1.6 Hz, 1H), 7.63 (m, 1H), 7.14 (t, J =9.2 Hz, 1H), 7.02 (dd, J = 7.6, 4.8 Hz, 1 H), 2.71 (m, 1 H), 1.10 (d, J = 6.8 Hz, 6H).

Example 5. Préparation of N-(3-(3-(9H-purin-6-vl)pvridin-2-ylamino)îo 2,4-dîfluorophenyl)thiophene-2-carboxamide

Step 1: Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)thiophene-2-carboxamide

2,6-difluoro-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2yl)benzene-1,3-diamine (30 mg, 0.07 mmol) prepared in step 4 of Example 4, thiophene-2-carbonyl chloride (8.3 pL, 0.078 mmol) and triethylamine (20 pL, 0.14 mmol) were added to a dichloromethane solvent. The mixture was stirred at room température for 2 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.61 (s, 1 H), 9.65 (m, 1 H), 9.02 (d, J = 5.2 Hz, 1H), 8.37 (d, J=6.8 Hz, 1H), 8.22 (m, 1H), 7.60 (m, 3H), 7.14 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 5.88 (m, 1H), 4.22 (m, 1H), 3.83 (m, 1H), 2.22-1.61 (m, 6H)

Step 2: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)thiophene-2-carboxamide

To N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-ylamino)phenyl)thiophene-2-carboxamide (20 mg, 0.037 mmol), prepared in step 1, 1M hydrochloric acid aqueous solution was added, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was washed with aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 11.65 (s, 1H), 10.26 (s, 1H), 9.68 (dd, J = 7.6, 1.6 Hz, 1 H), 9.05 (s, 1 H), 8.75 (s, 1 H), 8.23 (dd, J = 4.8, 1.6 Hz, 1 H), 8.03 (m, 1H), 7.88 (dd, J = 5.2, 1.2 Hz, 1H), 7.46 (m, 1H), 7.21 (m, 2H), 7.05 (m, 1H).

Example 6. Préparation of N-(3-(3-(9H-purin-6-yl)pyridine-2ylamino)-2,4-difluorophenyl)furan-2-carboxamide

Step 1 : Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahvdro-2H-pyran-2-vl)5 9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-2-carboxamide

2,6-difluoro-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2yl)benzene-1,3-diamine (30 mg, 0.07 mmol) prepared in step 4 of Example 4, furan-2-carbonyl chloride (8 pL, 0.078 mmol) and triethylamine (20 pL, 0.14 mmol) were added to a dichloromethane solvent. The mixture was stirred at room température for 2 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.62 (s, 1H), 9.65 (m, 1H), 9.02 (s, 1H), 8.37 (s, 1H), 8.25 (m, 1H), 7.51 (s, 1H), 7.17 (d, J = 3.6 Hz, 1H), 6.94 (m, 2H), 6.48 (dd, J = 3.6, 1.6 Hz, 1H), 5.88 (m, 1H), 4.24 (m, 1H), 3.83 (m, 1H), 2.221.69 (m, 6H)

Step 2: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)furan-2-carboxamide

To N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-65 yl)pyridin-2-ylamino)phenyl)furan-2-carboxamide (20 mg, 0.038 mmol) prepared in step 1, 1M hydrochloric acid aqueous solution was added, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was cooled to room température, and the produced solid was filtered under reduced pressure, washed with water and dichloromethane, and dried to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 13.86 (s, 1H), 11.61 (s, 1H), 10.10 (s,

H), 9.69 (s, 1 H), 9.05 (s, 1 H), 8.74 (s, 1 H), 8.22 (m, 1 H), 7.95 (m, 1 H), 7.35 (m, 4H), 7.05 (m, 1H), 6.70 (m, 1H)

Example 7. Préparation of N-(3-(3-(9H-purîn-6-yl)pyridin-2-ylamino)15 2,4-difluorophenyl)isoxazole-5-carboxamide

Step 1 : Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)isoxazole-5-carboxamide

TEA

DCM

2,6-difluoro-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared in step 4 of Example 4, idoxazole-5-carbonyl chloride (5.0 pL, 0.052 mmol) and triethylamine (7.9 pl_, 5 0.056 mmol) were added to a dichloromethane solvent. The mixture was stirred at room température for 2 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford ίο the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.67 (s, 1 H), 9.69 (dd, J = 7.6, 1.6 Hz, 1 H), 9.05 (s, 1 H), 8.46 (s, 1 H), 8.42 (d, J = 1.6 Hz, 1 H), 8.39 (s, 1 H), 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.22 (m, 1H), 7.08 (s, 2H), 7.00 (dd, J= 8.0, 4.8 Hz, 1H), 5.91 (dd, J = 10.8, 2.4 Hz, 1 H), 4.25 (m, 1 H), 3.86 (m, 1 H), 2.25-1.74 (m, 6H).

Step 2: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)isoxazole-5-carboxamide

To N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-ylamino)phenyl)isoxazole-5-carboxamide (20 mg, 0.039 mmol) prepared in step 1, 1M hydrochloric acid aqueous solution was added, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was cooled to room température, and the produced solid was filtered under reduced pressure, washed with water and dichloromethane, and dried to 5 afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 11.64 (s, 1H), 10.76 (s, 1H), 9.67 (s,

H), 9.03 (s, 1 H), 8.84 (d, J = 1.6 Hz, 1 H), 8.72 (s, 1 H), 8.22 (dd, J = 4.8, 2.0 Hz, 1H), 7.46 (m, 1H), 7.27 (m, 2H), 7.05 (dd, J= 8.0, 4.8 Hz, 1H)

Example 8. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)10 2,4-difluorophenyl)thiazole-5-carboxamide

Step 1: Préparation of N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pvridin-2-ylamino)phenyl)thiazole-5-carboxyamide

2,6-dlfluoro-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2yl)benzene-1,3-diamine (30 mg, 0.07 mmol) prepared in step 4 of Example 4, thiazole-5-carbonyl chloride (11 mg, 0.078 mmol) and triethylamine (11.8 pL, 0.084 mmol) were added to a dichloromethane solvent. Next, the reaction was stirred at room température for 3 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.64 (s, 1 H), 9.67 (dd, J = 8.0, 1.6 Hz, 1 H), 9.52 (s, 1 H), 9.04 (s, 1 H), 8.83 (d, J = 2.0 Hz, 1 H), 8.34 (m, 4H), 7.08 (td, J = 6.0, 2.0 Hz, 1 H), 6.97 (dd, J = 8.0, 4.8 Hz, 1 H), 5.90 (dd, J = 10.4, 2.4 Hz, 1 H), 4.24 (m, 1 H), 3.85 (m, 1 H), 2.24-1.73 (m, 6H).

Step 2: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)thiazole-5-carboxamide

To N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6yl)pyridin-2-ylamino)phenyl)thiazole-5-carboxyamide (20 mg, 0.037 mmol) prepared in step 1, 1M hydrochloric acid aqueous solution was added, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was cooled to room température, and the produced solid was filtered under reduced pressure, washed with water and dichloromethane, and dried to afford the title compound.

¹H NMR (400MHz, DMSO-d₆): δ 11.69 (s, 1 H), 10.10 (s, 1H), 9.68 (dd, J = 8.0, 2.0 Hz, 1H), 9.29 (s, 1H), 9.06 (s, 1H), 8.76 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.23 (dd, J= 4.8, 2.0 Hz, 1H), 7.76 (m, 1H), 7.24 (td, J= 9.2, 1.6 Hz, 1H), 7.07 (dd, J =8.0, 4.8 Hz, 1H)

Example 9. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)2,4-difluorophenyI)-3-(2-cyanopropan-2-yl)benzamide

Step 1: Préparation of 3-(2-cyanopropan-2-yl)-N-(2,4-difluoro-3-(3-(9(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzamide

2,6-dlfluoro-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2yl)benzene-1,3-diamine (40 mg, 0.095 mmol) prepared in step 4 of Example 4, 3-(2-cyanopropan-2-yl)benzoic acid (20 mg, 0.11 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (27 mg, 0.14 mmol) and N,Ndimethylaminopyridine (17 mg, 0.14 mmol) were added to a dichloromethane solvent, followed by stirring at room température for 18 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR (400MHz, CDCI₃): δ 11.64 (s, 1H), 9.68 (dd, J= 8.0, 2.0 Hz, 1H), 9.05 (s, 1H), 8.40 (s, 1H), 8.30 (dd, J= 4.8, 1.6 Hz, 1H), 8.22 (m, 2H), 7.77 (m, 2H), 7.55 (t, J = 7.8 Hz, 1 H), 7.08 (td, J = 9.2, 1.6 Hz, 1 H), 6.98 (dd, J = 8.0, 4.8 Hz, 1H), 5.91 (dd, J = 10.4, 2.4 Hz, 1H), 4.24 (m, 1H), 3.85 (m, 1H), 2.24-1.70 (m, 12H)

Step 2: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide

To 3-(2-cyanopropan-2-yl)-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzamide (20 mg, 0.034 mmol) prepared in step 1, 1M hydrochloric acid aqueous solution was added, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H N MR (400MHz, DMSO-d₆): δ 11.62 (s, 1H), 10.32 (s, 1H), 9.67 (dd, J = 7.6, 1.6 Hz, 1H), 9.05 (s, 1H), 8.74 (s, 1H), 8.23 (dd, J =4.8, 1.6 Hz, 1H), 8.11 (m, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.77 (m, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.49 (td, J = 8.4, 5.6 Hz, 1H), 7.24 (td, J = 10.4, 1.2 Hz, 1H), 7.06 (dd, J = 8.0, 4.8 Hz, 1H), 1.75 (s, 6H).

Example 10. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-dlfluorophenyl)-3-(4-methvlpiperazin-1-yl)-5(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.67 (s, 1 H), 9.74 (d, J = 6.8 Hz, 1 H), 9.06 (s, 1 H), 8.33 (m, 2H), 8.20 (m, 1 H), 8.03 (d, J = 2.4 Hz, 1 H), 7.61 (s, 1 H), 7.46 (s, 1 H), 7.08 (td, J = 7.6, 1.2 Hz, 1 H), 7.00 (m, 1 H), 3.38 (t, J = 4.8 Hz, 4H), 2.66 (s, 4H), 2.42 (s, 3H).

Example 11. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-thiomorpholino-5(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-thiomorpholino-5-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, DMSO-d₆): δ 11.62 (s, 1H), 10.36 (s, 1H), 9.67 (d, J = 6.4 Hz, 1H), 9.04 (s, 1H), 8.73 (s, 1H), 8.22 (dd, J = 2.8, 1.6 Hz, 1H), 7.72 (s, 1 H), 7.61 (s, 1 H), 7.48 (m, 1 H), 7.39 (s, 1 H), 7.24 (t, J = 9.2 Hz, 1 H), 7.04 (dd, J = 4.8, 2.8 Hz, 1H), 3.72 (m, 4H), 2.70 (s, 4H).

Example 12. Préparation of N-(3-(3-(9H-purin-6-vl)pyridin-2y lami no)-2,4-d if I uoropheny l)-3-(4-hydroxy piperid i n-1 -yl)-5(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that 3-(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5 (trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, MeOD): δ 9.53 (d, J = 7.2 Hz, 1H), 9.00 (s, 1H), 8.52 (s, 1H), 8.52 (dd, J = 3.2, 1.6 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.58 (m, 1H), 7.36 (s, 1H), 7.10 (t, J= 9.2 Hz, 1H), 7.00 (dd, J= 4.8, 3.2 Hz, 1H), 3.74 (m, 3H), 3.07 (m, 2H), 2.00 (m, 2H), 1.65 (s, 2H).

Example 13. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(4-methylpiperidin-1-yl)-5(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-(4-methylpiperidin-1-yl)-5-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.67 (s, 1H), 9.74 (s, 1H), 9.06 (d, J= 6.8 Hz, 1H), 8.32 (m, 2H), 8.14 (m, 2H), 7.59 (s, 1H), 7.30 (m, 2H), 7.00 (m, 2H), 3.79 (d, J= 9.2 Hz, 2H), 2.84 (m, 2H), 1.77 (m, 2H), 1.68(m, 1H), 1.32 (m, 2H), 1.00 (s, 3H)

Example 14. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-difluorophenyl)-4-thiomorpholino-3(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 4-thiomorpholino-3-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.67 (s, 1H), 9.74 (d, J= 6.8 Hz, 1H), 9.07 (s, 1H), 8.34 (s, 1H), 8.32 (dd, J =3.2, 1.6 Hz, 1H), 8.17 (m, 2H), 8.04 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.07 (m, 1H), 7.00 (m, 1H), 3.23 (t, J = 4.8 Hz, 4H), 2.82 (t, J =4.8 Hz, 4H).

Example 15. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-4(4-methylpeperidin-1-yl)-3(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.66 (s, 1 H), 9.72 (d, J = 7.2 Hz, 1 H), 9.06 (s, 1H), 8.32 (m, 2H), 8.17 (m, 2H), 7.97 (m, 2H), 7.32 (d, J= 8.8 Hz, 1H), 7.05 (m, 1 H), 6.99 (m, 1 H), 3.22 (d, J = 11.6 Hz, 2H), 2.77 (t, J = 11.2 Hz, 2H), 1.71 (d, J= 12.8 Hz, 2H), 1.53 (m, 1H), 1.47 (m, 2H), 1.01 (d, J =6.0 Hz, 3H)

Example 16. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-difluorophenvl)-4-chloro-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 4-chloro-3-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 9.63 (d, J = 7.2 Hz, 1H), 9.00 (s, 1H), 8.33 (d, J = 12.8 Hz, 2H), 8.20 (d, J = 3.2 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.77 (m, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.06 (t, J = 9.2 Hz, 1 H), 7.00 (m, 1 H)

Example 17. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamîno)-2,4-difluorophenyl)-2,3-dihvdrobenzorbiri.41dioxine-6carboxamide

The title compound was synthesized in the same manner as described in Example 2, except that 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.64 (s, 1H), 9.74 (d, J= 7.2 Hz, 1H), 9.05 (s, 1H), 8.33 (s, 2H), 8.25 (d, J= 5.2 Hz, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.40 (d, J=10Hz, 1H), 7.05 (m, 1H), 6.96 (m, 2H), 4.33 (m,4H)

Example 18. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-difluorophenyl)-3-morpholino-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-morpholino-5-(trifluoromethyl)benzoic acid was used 10 instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.68 (s, 1H), 11.55 (brs, 1H), 9.75 (d, J = 6.8 Hz, 1H), 9.06 (s, 1H), 8.32 (m, 2H), 8.19 (m, 1H), 8.05 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1 H), 7.27 (s, 1 H), 7.08 (m, 1 H), 7.00 (m, 1 H), 3.90 (m, 4H), 3.29 (m, 2H) 15 Example 19. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2- ylamino)-2,4-difluorophenvl)-4-(pyrrolidin-1-yl)-3(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 11.64 (s, 1 H), 9.73 (d, J = 6.4 Hz, 1 H), 9.06 (s, 1H), 8.32 (m, 2H), 8.24 (m, 2H), 8.17 (d, J= 2.4 Hz, 1H), 7.85 (m, 2H), 7.06 (d, J = 7.2, 5.0 Hz, 1H), 7.00 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.50 (m, 2H), 2.02 (m, 2H)

Example 20. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(1-cyanocyclopropyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-(1-cyanocyclopropyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, DMSO-d₆): δ 11.69 (brs, 1H), 10.29 (s, 1H), 9.67 (d, J = 7.2 Hz, 1H), 9.01 (s, 1H), 8.67 (s, 1H), 8.21 (dd, J = 2.0, 2.8 Hz, 1H), 7.91 (m, 2H), 7.58 (m, 2H), 7.47 (m, 1H), 7.23 (t, J= 8.0 Hz, 1H), 7.03 (m, 1H), 1.82 (m, 2H), 1.62 (m,2H)

Example 21. Préparation of N-(5-(3-(9H-purin-6-yl)pyridin-2ylamino)-2-fluorophenyl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl(3-amino-4fluorophenyl)carbamate was used instead of t-butyl(3-amino-2,65 difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 12.68 (brs, 1H), 10.30 (s, 1H), 9.77 (brs, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 8.36 (dd, J=1.6, 2.8 Hz, 1H), 8.10 (m,2H), 7.99 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.71 (m, 1 H), 7.63 (t, J = 8.0 Hz, 10 1 H), 7.29 (t, J = 9.6 Hz, 1 H), 7.04 (m, 1 H), 1.77 (s, 6H)

Example 22: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenvl)-3-(1-amino-2-methyl-1-oxopropan-2yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-(1-amino-2-methyl-1-oxopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, CDCI₃): δ 12.40 (brs, 1H), 11.67 (s, 1H), 9.71 (d, J =

7.2 Hz, 1H), 8.98 (s, 1H), 8.31 (s, 1H), 8.27 (dd, J= 1.6, 2.8 Hz, 1H), 8.24 (s, 1H), 8.14 (brs, 1H), 7.99 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.04 (t, J= 9.2 Hz, 1H), 6.96 (m, 1H), 6.11 (brs, 1 H), 5.53 (brs, 1 H), 1.64 (s, 6H)

Example 23. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)phenyl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (3aminophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 12.29 (brs, 1H), 9.65 (brs, 1H), 8.85 (s, 1H), 8.33 (d, J=2.8 Hz, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.51 (t, J= 7.6 Hz, 1H), 7.40 (m, 1 H), 7.30 (m, 2H), 6.90 (m, 1 H), 1.78 (s, 6H)

Example 24. Préparation of N-(5-(3-(9H-purin-6-yl)pyridin-2ylamino)-2-chlorophenvl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 1 of Example 2, t-butyl (3-amino-4chlorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.86 (brs, 1H), 12.75 (brs, 1H), 10.26 (s, 1H), 9.75 (brs, 1H), 9.14 (s, 1H), 8.71 (s, 1H), 8.39 (dd, J=2.0, 2.8 Hz, 1H), 8.15 (m, 2H), 8.01 (d, J = 7.6 Hz, 1H), 7.84 (dd, J = 2.8, 6.0 Hz, 1H), 7.80 (m, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.08 (m, 1 H), 1.77 (s, 6H)

Example 25. Réparation of N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)2,6-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (3-amino-2,4difluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.02 (brs, 1H), 10.36 (s, 1H), 9.92 (brs, 1H), 8.92 (s, 1H), 8.59 (m, 2H), 8.37 (d, J = 2.8 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.23 (m, 1H), 7.09 (m, 1H), 1.78 (s, 6H)

Example 26. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-2-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in

Example 1, except that 2-(trifluoromethyl)benzoyl chloride was used instead of 3-(trifluoromethyl)benzoyl chloride in step 4 of Example 1.

¹H NMR (400MHz, DMSO-d₆): δ 11.63 (s, 1H), 10.45 (s, 1H), 9.67 (d, J = 7.6 Hz, 1H), 9.02 (s, 1H), 8.68 (s, 1H), 8.21 (dd, J = 2.0, 2.8 Hz, 1H), 7.80 (m, 4H), 7.61 (m, 1 H), 7.22 (m, 1 H), 7.03 (m, 1 H)

Example 27. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenvl)-4-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 1, except that 4-(trifluoromethyl)benzoyl chloride was used instead of 3-(trifluoromethyl)benzoyl chloride in step 4 of Example 1.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (brs, 1H), 11.60 (s, 1H), 10.44 (s, 1H), 9.68 (brs, 1H), 9.05 (s, 1H), 8.73 (s, 1H), 8.23 (dd, J = 1.6, 2.8 Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.50 (m, 1H), 7.24 (m, 1H), 7.04 (m, 1H)

Example 28. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenvl)-3-fluoro-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-fluoro-5-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 1 of Example 2.

¹H NMR (400MHz, DMSO-d₆): δ 11.63 (brs, 1H), 10.54 (brs, 1H), 9.66 (d, J = 7.6 Hz, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.22 (m, 2H), 8.12 (d, J= 9.2 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1 H), 7.51 (m, 1 H), 7.25 (m, 1 H), 7.03 (m, 1 H)

Example 29. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2-fluorophenyl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (3-amino-2fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.61 (brs, 1H), 10.29 (s, 1H), 9.66 (d, J = 6.0 Hz, 1 H), 9.04 (s, 1 H), 8.72 (s, 1 H), 8.23 (dd, J = 2.0, 2.8 Hz, 1 H), 8.11 (t, J = 1.6 Hz, 1 H), 7.97 (m, 1 H), 7.77 (m, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.49 (m, 1 H), 7.23 (m, 1 H), 7.03 (m, 1 H), 1.76 (s, 6H)

Example 30. Préparation of N-(5-(3-(9H-purin-6-yl)pyridin-2ylamino)-2-fluorophenyl)-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 1, except that t-butyl (3-amino-4-fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6-difluorophenyl)carbamate in step 4 of Example 1.

¹H NMR (400MHz, DMSO-d₆): δ 12.76 (brs, 1H), 10.46 (s, 1H), 9.78 (d, J = 7.2 Hz, 1H), 9.04 (s, 1H), 8.59 (s, 1H), 8.33 (m, 3H), 8.12 (m, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.72 (m, 1H), 7.29 (t, J = 9.6 Hz, 1H), 7.03 (m, 1H)

Example 31. Préparation of N-(5-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 1, except that t-butyl (5-amino-2,4-difluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6-difluorophenyl)carbamate in step 4 of Example 1.

¹H NMR (400MHz, DMSO-d₆): δ 13.90 (brs, 1H), 12.88 (brs, 1H), 10.50 (s, 1H), 9.86 (brs, 1H), 9.07 (s, 1H), 8.80 (t, J = 8.4 Hz, 1H), 8.74 (s, 1H), 8.39 (dd, J = 2.0, 2.8 Hz, 1 H), 8.36 (s, 1 H), 8.31 (d, J = 7.6 Hz, 1 H), 8.01 (d, J = 7.2 Hz, 1 H), 7.82 (t, J = 7.6 Hz, 1 H), 7.53 (t, J = 10.4 Hz, 1 H), 7.11 (m, 1 H)

Example 32. Préparation of N-(5-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide < XJ.

H H zX N χχ<5χ/N χ/VXCN

Γ H T Λ

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (5-amino-2,4difluorophenyi)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.89 (brs, 1H), 12.87 (s, 1H), 10.32 (s, 1H), 9.85 (brs, 1H), 9.05 (s, 1H), 8.78 (t, J= 8.4 Hz, 1H), 8.72 (s, 1H), 8.38 (dd, J =2.0, 2.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J =7.6 Hz, 1H), 7.78 (m, 1H), 7.62 (t, J =8.0 Hz, 1H), 7.52 (t, J =10.0 Hz, 1H), 7.11 (m, 1H), 1.77 (s, 6H)

Example 33. Préparation of N-(5-(3-(9H-purin-6-yl)pyridin-2ylamino)-2-fluorophenyl)-3-(2-cyanopropan-2-yl)-5-fluorobenzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 1 of Example 2, t-butyl (5-amino-4fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)-5-fluoro-benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.64 (brs, 1H), 10.38 (s, 1H), 9.78 (brs, 1H), 9.13 (s, 1H), 8.72 (s, 1H), 8.36 (dd, J = 1.6, 2.8 Hz, 1H), 8.12 (m, 1H), 8.02 (s, 1H), 7.81 (d, J= 8.4 Hz, 1H), 7.72 (m, 2H), 7.30 (t, J= 9.2 Hz, 1 H), 7.06 (m, 1 H), 1.78 (s, 6H)

Example 34. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-nitrobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that 3-nitrobenzoyl chloride was used instead of 310 (trifluoromethyl)benzoyl chloride in step 4 of Example 1.

¹H NMR (400MHz, DMSO-d₆): δ 11.67 (brs, 1H), 10.62 (s, 1H), 9.67 (brs, 1H), 9.03 (s, 1H), 8.23 (s, 1H), 8.70 (s, 1H), 8.50 (m, 3H), 8.22 (dd, J= 1.6, 3.2 Hz, 1 H), 7.87 (m, 1 H), 7.51 (m, 1 H), 7.25 (t, J = 8.4 Hz, 1 H), 7.04 (m, 1 H)

Example 35. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-215 ylamino)-2,4-difluorophenyl)-3-methoxybenzamide

The title compound was synthesized in the same manner as described in Example 1, except that 3-methoxybenzoyl chloride was used instead of 3(trifluoromethyl)benzoyl chloride in step 4 of Example 1.

¹H NMR (400MHz, DMSO-d₆): δ 13.92 (brs, 1H), 11.65 (brs, 1 H), 10.16 (s, 1 H), 9.72 (brs, 1 H), 9.05 (s, 1 H), 8.73 (s, 1 H), 8.23 (dd, J = 3.2, 1.6 Hz, 1 H), 7.52 (m, 4H), 7.21 (m, 2H), 7.04 (m, 1H), 3.84 (s, 3H)

Example 36. Préparation of N-(5-(3-(9H-purin-6-vl)pyridin-25 ylamino)-2-fluorophenyl)-3-fIuoro-5-(trifluoromethvl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (3-amino-4fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,βίο difluorophenyl)carbamate, and 3-fluoro-5-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.87 (brs, 1H), 12.65 (brs, 1H), 10.55 (s, 1H), 9.79 (brs, 1H), 9.13 (s, 1H), 8.73 (s, 1H), 8.36 (dd, J=2.8, 1.6 Hz, 1H), 8.24 (s, 1H), 8.15 (d, J= 9.2 Hz, 1H), 7.72 (m, 1H), 7.31 (t, J=9.6 Hz, 1H), 7.05 15 (m, 1H)

Example 37. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-cyanobenzamide

H k, H N

O

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 1 of Example 2, 3-cyanobenzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.88 (brs, 1H), 11.64 (s, 1H), 10.43 (s, 1 H), 9.71 (d, J = 6.8 Hz, 1 H), 9.05 (s, 1 H), 8.74 (s, 1 H), 8.42 (s, 1 H), 8.28 (d, J = 5 7.6 Hz, 1 H), 8.23 (dd, J = 1.6, 2.8 Hz, 1 H), 8.09 (d, J = 7.6 Hz, 1 H), 7.77 (t, J = 8.0 Hz, 1 H), 7.50 (m, 1 H), 7.23 (m, 1 H), 7.04 (m, 1 H)

Example 38. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-difluorophenvl)-4-methoxy-3-(trifluoromethyl)benzamide

ίο The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 4-methoxy-3(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.87 (brs, 1H), 11.63 (brs, 1H), 10.31 (s, 1 H), 9.72 (brs, 1 H), 9.05 (s, 1 H), 8.74 (s, 1 H), 8.29 (m, 2H), 8.23 (dd, J = 3.2,

1.6 Hz, 1 H), 7.46 (m, 2H), 7.23 (t, J = 8.8 Hz, 1 H), 7.04 (m, 1 H), 3.99 (s, 3H)

Example 39: Préparation of N-(4-(3-(9H-purin-6-yl)pyridin-2ylamino)-3-fluorophenyl)-3-(2-cyanopropan-2-vl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (4-amino-2fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.88 (brs, 1H), 12.88 (s, 1H), 10.45 (s, 1H), 9.85 (d, J = 7.6 Hz, 1H), 9.02 (s, 1H), 8.67 (s, 1H), 8.62 (t, J= 9.2 Hz, 1H), 8.39 (dd, J = 2.8, 2.0 Hz, 1 H), 8.07 (s, 1 H), 7.96 (d, J = 7.6 Hz, 1 H), 7.88 (dd, J = 11.6, 2.0 Hz, 1 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.08 (m, 1 H), 1.77 (s, 6H)

Example 40. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-difluorophenyl)-3-nitro-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3-nitro-5(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.87 (brs, 1H), 11.71 (brs, 1H), 10.83 (s, 1 H), 9.74 (brs, 1 H), 9.05 (m, 2H), 8.75 (m, 2H), 8.23 (dd, J = 1.6, 2.8 Hz, 1 H), 7.55 (m, 1 H), 7.27 (t, J = 9.2 Hz, 1 H), 7.04 (m, 1 H)

Example 41. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-2,4-difluorophenyl)-4-chloro-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 4-chloro-3-(2-cyanopropan-2yl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.69 (s, 1H), 10.38 (s, 1H), 9.66 (d, J = 8 Hz, 1 H), 8.99 (s, 1 H), 8.64 (S, 1 H), 8.2 (m, 1 H), 8.07 (s, 1 H), 7.99 (d, J = 6.8 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.47 (m, 1 H), 7.03 (dd, J = 7.8 Hz, 4.4Hz, 1 H), 1.87 (S, 6H)

Example 42: Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenvl)-2-chloro-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 2-chloro-3-(2-cyanopropan-2yl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.66 (s, 1H), 10.50 (s, 1H), 9.66 (d, J = 6.4 Hz, 1H), 9.00(s, 1H), 8.66 (s, 1H) 8.21(dd, J= 4.8 Hz, 1.6 Hz, 1H), 7.67 (m, 2H), 7.59 (m, 1H), 7.53 (m, 1H), 7.23 (m, 1H), 7.03 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 1.84 (s, 6H)

Example 43. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(2-cvanopropan-2-vl)-5-fluorobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3-(2-cyanopropan-2-yl)-5fluorobenzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.64 (brs, 1H), 10.40 (s, 1H), 9.67 (brs, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.22 (dd, J = 4.8 Hz, 1.6Hz, 1H), 7.99 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.66 (m, 1H), 7.48 (m, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.04 (dd, J = 8 Hz, 4.8 Hz, 1 H), 1.76 (s, 6H)

Example 44. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)-4,5difluorobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3-(2-cyanopropan-2-yl)-4,5difluorobenzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.68 (brs, 1H), 10.41 (s, 1H), 9.67 (brs,

H), 9.01 (s, 1H), 8.68 (s, 1H), 8.21 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.09 (m, 1H), 7.91 (d, J= 5.6 Hz, 1H), 7.46 (m, 1H), 7.24 (m, 1H), 7.03 (dd, J= 8 Hz, 4.8 Hz, 1H), 1.82 (s, 1H)

Example 45. Préparation of N-(3-(3-(9H-purin-6-vl)pyrdin-2-ylamino)2,4-difluorophenyl)-3-chlorobenzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 1 of Example 2, 3-chlorobenzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.88 (brs, 1H), 11.61 (brs, 1H), 10.34 (s, 1 H), 9.71 (brs, 1 H), 9.05 (s, 1 H), 8.74 (s, 1 H), 8.23 (dd, J = 4.8 Hz, 2 Hz, 1 H), 8.03 (m, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.69 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.47 (m, 1 H), 7.23 (m, 1 H), 7.04 (dd, J = 4.8 Hz, 2 Hz, 1 H)

Example 46. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(dimethylamino)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3-(dimethylamino)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.64 (brs, 1H), 10.05 (s, 1H), 9.68 (brs,

1H), 9.02 (s, 1H), 8.69 (s, 1H), 8.22 (dd, J = 4.6 Hz, 2 Hz, 1H), 7.45 (m, 1H),

7.28 (m, 5H), 7.03 (dd, J= 7.6 Hz, 4.2 Hz, 1H), 6.94 (m, 1H), 2.96 (s, 6H)

Example 47. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-methylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3-methylbenzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.87 (brs, 1H), 11.59 (brs, 1 H), 10.13 (s, 1 H), 9.67 (brs, 1 H), 9.04 (s, 1 H), 8.72 (s, 1 H), 8.22 (dd, J = 4.6 Hz, 2 Hz, 1 H), 7.81 (s, 1H), 7.78 (m, 1H), 7.45 (m, 3H), 7.21 (m, 1H), 7.04 (dd, J = 7.6 Hz, 4.8Hz, 1H), 2.40 (s, 3H)

Example 48. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)phenyl)-3-chlorobenzamide < Xi H H

X/N ο

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (3aminophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-chlorobenzoic acid was used instead of 3-(4methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 12.67 (brs, 1H), 10.35 (s, 1H), 9.77 (brs, 1H), 9.04 (s, 1H), 8.61 (s, 1H), 8.36 (m, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.95 (m, 1 H), 7.68 (m, 1 H), 7.60 (m, 2H), 7.48 (m, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.04 (m, 1H)

Example 49. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-4-fluorophenyl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (5-amino-2fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(2-cyanopropan-2-yl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 12.85 (brs, 1H), 10.39 (s, 1H), 9.84 (brs, 1 H), 9.04 (s, 1 H), 8.96 (m, 1 H), 8.41 (m, 1 H), 8.06 (m, 1 H), 7.97 (d, J = 7.6 Hz, 1H), 7.76 (m, 1H), 7.61 (t, J= 7.6 Hz, 1H), 7.47 (m, 1H), 7.30 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 7.11 (dd, J = 4.8 Hz, 2.8 Hz, 1 H), 1.76 (s, 6H)

Example 50. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2vlamino)-4-fluorophenyl)-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (5-amino-2fluorophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 12.91 (brs, 1H), 10.55 (s, 1H), 9.84 (d, J = 8 Hz, 1H), 9.02 (s, 1H), 8.99 (dd, J= 7.6 Hz, 2.4 Hz, 1H), 8.68 (s, 1H), 8.42 (dd, J = 4.6 Hz, 1.6 Hz, 1 H), 8.30 (m, 2H), 7.98 (d, J = 7.2 Hz), 7.80 (t, J = 8 Hz, 1H), 7.50 (m, 1H), 7.31 (m, 1H), 7.12 (dd, J= 8 Hz, 4.8 Hz, 1H)

Example 51. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)phenyl)-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, t-butyl (3aminophenyl)carbamate was used instead of t-butyl (3-amino-2,6difluorophenyl)carbamate, and 3-(trifluoromethyl)benzoic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 12.61 (brs, 1H), 10.50 (s, 1H), 9.71 (brs, 1H), 9.10 (s, 1H), 8.72 (s, 1H), 8.39 (dd, J = 4.4 Hz, 2 Hz, 1H), 8.31 (m, 3H), 7.98 (d, J = 8 Hz, 1 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.58 (m, 1 H), 7.49 (m, 1 H), 7.34 (m, 1 H), 7.34 (t, J = 8 Hz, 1 H), 7.06 (dd, J = 8 Hz, 4.8 Hz, 1 H)

Example 52. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-281 ylamino)-2,4-difluorophenyl)-4-nitrobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 4-nitrobenzoic acid was used 5 instead of 3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.60 (brs, 1H), 10.54 (s, 1H), 9.66 (brs, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.38 (d, J= 8.8 Hz, 2H), 8.22 (m, 3H), 7.51 (m, 1 H), 7.24 (t, J = 8.8 Hz, 1 H), 7.04 (dd, J = 8 Hz, 4.4 Hz, 1 H)

Example 53. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2io ylamino)-2,4-difluorophenyl)-4-methoxybenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 4-methoxybenzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.61 (brs, 1H), 10.00 (s, 1H), 9.66 (brs,

H), 9.03 (m, 1 H), 8.70 (m, 1 H), 8.21 (m, 1 H), 7.97 (d, J = 9.2 Hz, 2H), 7.46 (m, 1 H), 7.19 (t, J = 9.2 Hz, 1 H), 7.04 (m, 3H), 3.84 (s, 3H)

Example 54. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-aminobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3-aminobenzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.60 (s, 1H), 9.95(s, 1H), 9.66 (d, J = 6.8 Hz, 1 H), 9.03 (s, 1 H), 8.70 (s, 1 H), 8.22 (dd, J = 4.8 Hz, 2 Hz, 1 H), 7.43 (m, 1H), 7.15 (m, 4H), 7.03 (dd, J = 7.6 Hz, 3.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 5.32 (s, 2H)

Example 55. Préparation of methyl 3-(3-(3-(9H-purin-6-yl)pyridin-210 ylamino)-2,4-difluorophenylcarbamoyl)phenylcarbamate

The title compound was synthesized in the same manner as described in Example 2, except that, in step 1 of Example 2, 3methoxycarbonylaminobenzoic acid was used instead of 3-(4-methyl-1 H15 imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 11.62 (s, 1H), 10.19 (s, 1H), 9.87 (s, 1 H), 9.67 (brs, 1 H), 9.03 (s, 1 H), 8.71 (s, 1 H), 8.22 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 8.03 (s, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.61 (d, J = 8 Hz, 1 H), 7.45 (m, 2H), 7.21 (t, J = 9.2 Hz, 1 H), 7.03 (dd, J = 7.6 Hz, 4.8 Hz, 1 H), 3.68 (s, 3H)

Example 56. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)pyrazine-2-carboxamide

The title compound was synthesized in the same manner as described in 5 Example 2, except that, in step 1 of Example 2, pyrazine-2-carboxylic acid was used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 11.63 (s, 1H), 10.51 (s, 1 H), 9.68 (s, 1 H), 9.31 (s, 1 H), 9.05 (t, 1 H), 8.97 (d, J = 2.4 Hz 1 H), 8.84 (t, 1 H), 8.73 (s, 1H), 8.24-8.23 (m, 1H), 7.75-7.70 (m, 1H), 7.26 (t, 1H), 7.06-7.03 (m, ίο 1H)

Example 57. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenyl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 1 of Example 2, benzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 11.60 (s, 1H), 10.18 (s, 1H), 9.69 (s, 1H), 9.05 (d, J= 7.2 Hz, 1H), 8.73 (s, 1H), 8.24-8.22 (m, 1H), 8.00 (d, J =7.2 Hz, 2H), 7.63-7.60 (m, 1H), 7.56-7.45 (m, 3H), 7.22 (t, 1H), 7.06-7.03 (m, 1H)

Example 58. Préparation of N-2,4-difluoro-3-r3-(9H-purin-6vl)pvridin-2-vlamino)-phenvl-3,5-bistrifluoromethylbenzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 1 of Example 2, 3,5-bistrifluoromethylbenzoic acid was used instead of 3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzoic acid.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 11.59 (s, 1H), 10.71 (s,

1H), 9.65 (s, 1H), 9.62 (d, 1H), 9.02 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 8.21 (q, 1H), 7.54-7.50 (m, 1H), 7.24 (t, 1H), 7.05-7.02 (m, 1H)

Example 59. Préparation of 1-(3-(3-(9H-purin-6-yl)pyridin-2-vlamino)2,4-d if luorophenyl)-3-(3-(4-methy 1-1 H-imidazol-1-yl)-5(trifluoromethyl)phenyl)urea

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 2,6-difluoro-[3-(3-(4methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenylureido]phenylcarbamate was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-585 (trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 11.66 (bs, 1H), 9.64 (d, J= 6.8 Hz, 1H), 9.53 (bs, 1H), 8.99 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 8.21 (s, 2H), 7.85 (m, 3H), 7.59 (s, 1H), 7.50 (s, 1H), 7.16 (t, J =9.6 Hz, 1H), 7.03 (m, 1H), 2.17 (s, 3H)

Example 60. Préparation of 1-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)2,4-difluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3(trifluoromethyl)phenyl)urea

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 2,6-difluoro-[3-(3-(4ethylpiperazin-1-ylmethyl)-3-(trifluoromethylphenyl)ureido]phenylcarbamate was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 11.58 (bs, 1H), 9.65 (d, J= 7.6 Hz, 1H), 9.61 (s, 1H), 9.04 (s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.22 (d, J = 3.6 Hz, 1H), 8.00 (s, 1H), 7.88 (m, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 3.79 (s, 2H), 3.11 (m, 6H), 2.50 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H).

Example 61. Préparation of 4-chloro-N-2-fluoro-5-r3-(9H-purin-6y Dpyrid in-2-y lam i no) pheny l-3-(trifl uoromethy Dbenzam ide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [3-(4-chloro-3-trifluoromethylbenzoylamino)-4-fluorophenyl]carbamic acid t-butyl ester was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.24 (s, 1H), 9.67 (dd, 1H), 9.52 (s, 1H), 9.15 (s, 1H), 8.96 (s, 1H), 8.66 (s, 1H), 8.41 (dd, 1H), 8.33 (dd, 1H), 8.09 (s, 1 H), 7.66-7.61 (m, 2H), 7.50-7.46 (m, 1 H), 7.22 (q, 1 H), 7.03 (q, 1 H)

Example 62. Préparation of N-2-fluoro-5-r3-(9H-purin-6-yl)pyridin-2vlamino)phenyl-3-nitro-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [4-fluoro-3-(3-nitro-5trifluoromethyl-benzoylamino)phenyl]carbamic acid t-butyl ester was used instead t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.59 (s, 1H), 10.81 (s, 1H), 9.73 (s, 1H), 9.11 (s, 1H), 9.07 (s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.71 (s, 1H), 8.35 (dd, 1H), 8.19 (dd, 2H), 7.73-7.69 (m, 1H), 7.32 (q, 1H), 7.04 (q, 1H)

Example 63. Préparation of N-2-fluoro-5-r3-(9H-purin-6-vl)pyridin-287 vlamino)phenvl-3-methoxy-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [4-fluoro-3-(3-methoxy-55 trifluoromethyl-benzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.59 (s, 1H), 10.44 (s, 1H), 9.74 (s, 1H), 9.11 (s, 1H), 8.35 (dd, 1H), 8.10 (dd, 1H), 7.92 (s, 1H), 7.84 (s, 10 1 H), 7.73-7.69 (m, 1 H), 7.50 (s, 1 H), 7.29 (t, 1 H), 7.04(dd, 1 H), 3.93 (s, 3H)

Example 64. Préparation of N-2-fluoro-5-r3-(9H-purin-6-yl)pyridin-2vlamino)phenyl-(6-methylpyridin-2-yl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, 4-fluoro-3-6-methylpyridine-2carbonyl)amino]phenylcarbamic acid t-butyl ester was used instead of t-butyl2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (brs, 1H), 12.48 (s, 1H), 10.38 (s,

1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.64 (dd, 1H), 8.35 (q, 1H), 8.01-7.96 (m, 2H), 7.65-7.61 (m, 1 H), 7.57 (dd, 1 H), 7.32 (dd, 1 H), 7.05(dd, 1 H), 2.63 (s, 3H)

Example 65. Préparation of N-2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2ylamino)phenyl-3,5-bis(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [3-(3,5bistrifIuoromethylbenzoylamino)-4-fluorophenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.51 (s, 1H), 10.71 (s, 1H), 9.68 (dd, 1H), 9.14 (s, 1H), 8.93 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 8.34 (dd, 1H), 8.17(dd, 1H), 7.73-7.69 (m, 1H), 7.30 (dd, 1H), 7.01 (dd, 1H)

Example 66. Préparation of N-2-chloro-5-[3-(9H-purin-6-yl)pyridin-2ylamino)phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [4-chloro-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-589 (trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.75 (s, 1H), 10.46 (s, 1H), 9.75 (d, 1H), 9.12 (s, 1H), 8.70 (s, 1H), 8.39-8.36 (m, 2H), 8.31 (d, 1H), 8.00 (d, 1 H), 7.86-7.80 (m, 2H), 7.50 (d, 1 H), 7.08 (dd, 1 H)

Example 67. Préparation of N-2-chloro-5-r3-(9H-purin-6-yl)pyridin-2ylamino)phenyl-3-fluoro-5-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [4-chloro-3-(3-fluoro-5trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.65 (s, 1H), 10.54 (s, 1H), 9.71 (dd, 1H), 9.19 (d, 1H), 8.96 (s, 1H), 8.39 (dd, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.16-8.14 (m, 2H), 8.00 (d, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7.08 (dd, 1H)

Example 68. Préparation of N-2-methyl-5-r3-(9H-purin-6-yl)pyridin-2ylamino)phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, [4-methyl-3-(3 trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.81 (s, 1H), 12.63 (s, 1H), 10.27 (s,

1H), 9.74 (brs, 1H), 9.11 (s, 1H), 8.36-8.31 (m, 3H), 7.98 (d, 1H), 7.89 (d, 1H), 7.80 (t, 1H), 7.66 (dd, 1H), 7.01 (dd, 1H), 2.19 (s, 1H)

Example 69. Préparation of N-2-methoxv-5-r3-(9H-purin-6-yl)pyridin2-ylamino)phenyl-3-trifluoromethylbenzamide

ίο The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [4-methoxy-3-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.61 (s, 1 H), 9.99 (s, 1 H), 9.86 (d, 1 H),

9.11 (s, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 8.27 (d, 1H), 8.21 (dd, 1H), 8.02 (d, 1H), 7.97 (d, 1 H), 7.78 (t, 1 H), 7.55 (dd, 1 H), 7.18 (d, 1 H), 3.87 (s, 3H)

Example 70. Préparation of N-4-methoxy-5-r3-(9H-purin-6-yl)pyridin2-ylamino)phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [2-methoxy-5-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.98 (s, 1H), 10.50 (s, 1H), 9.83 (d, 1H), 9.12 (s, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.35 (dd, 1H), 8.33 (s, 1H), 8.29 (d, 1 H), 7.95 (d, 1 H), 7.78 (t, 1 H), 7.55 (dd, 1 H), 7.14-7.11 (m, 2H), 3.97 (s, 3H)

Example 71. Préparation of N-4-methyl-5-r3-(9H-purin-6-yl)pyridin-2ylamino)phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [2-methyl-5-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.34 (s, 1H), 10.46 (s, 1H), 9.77 (d, 1H), 9.06 (s, 1H), 8.70-8.65 (m, 2H), 8.34 (dd, 1H), 8.31 (s, 1H), 8.27 (d, 1H), 7.94 (d, 1 H), 7.77 (t, 1 H), 7.46 (dd, 1 H), 7.23 (d, 1 H), 7.02 (dd, 1 H), 2.44 (s, 3H)

Example 72. Préparation of N-2,6-difluoro-3-r3-(9H-purin-6vl)pvridin-2-vlamino)phenvl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, [2,4-difluoro-3-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.58 (s, 1H), 10.55 (s, 1H), 10.04 (dd, ίο 1H), 8.72-8.67 (m, 2H), 8.39 (s, 1H), 8.33 (d, 1H), 8.28 (dd, 1H), 8.20 (s, 1H), 8.03 (d, 1 H), 7.83 (t, 1 H), 7.20 (t, 1 H), 7.03 (dd, 1 H)

Example 73. Préparation of 2-fluoro-5-r3-(9H-purin-6-yl)pyridin-2ylamino]-N-(3-trifluoromethylphenvl)benzamide

trifluoromethylphenvlcarbamoyl)phenyHcarbamoic acid t-butyl ester

5-(t-butoxycarbonylamino)-2-fluorobenzoic acid (1 g, 4.6 mmol), (3trifluoromethyl)aniline (0.74 g, 4.6 mmol), 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (1.3 g, 6.9 mmol), and 1hydroxybenzotriazole (1.9 g, 6.9 mmol) were added to a DMF solvent, followed by stirring at room température for 12 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR(400MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.23 (S, 1H), 8.14 (d, 1H), 7.69 (d, 1 H), 7.55 (t, 1 H), 7.37 (d, 1 H), 6.58 (d, 2H), 4.25 (m, 1 H), 1.55 (s, 9H)

Step 2: Préparation of 2-fluoro-5-[3-(9H-purin-6-vl)pyridin-2-vlamino1-N(3-trifluoromethylphenyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [4-fluoro-3-(3trifluoromethylphenylcarbamoyl)phenyl]carbamic acid t-butyl ester_prepared in step 1 was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1H-imidazol-1-yl)5-(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.98 (s, 1H), 10.81 (s, 1H), 9.80 (d, 1H), 8.99 (s, 2H), 8.49 (s, 1H), 8.33-8.31 (m, 1H), 8.25 (s, 1H), 8.15 (dd, 1H), 8.05-8.01 (m, 1H), 7.94 (d, 1H), 7.61 (t, 1H), 7.47 (d, 1H), 7.33 (t, 1H), 7.03 (dd, 1H)

Example 74. Préparation of 1-(4-chloro-3-trifluoromethylphenyl)-3-294 fluoro-5-r3-(9H-purin-6-yl)pvridin-2-ylaminolphenylurea

Step 1: Préparation of 3-r3-(4-chloro-3-trifluorophenyl)ureidof-4fluorophenylcarbamic acid t-butyl ester

(3-amino-4-fluorophenyl)carbamic acid t-butyl ester (1 g, 4 mmol) and 1chloro-4-isocyanato-2-trifluoromethylbenzene (1 g, 4.6 mmol) were added to an ethyl acetate solvent, followed by stirring at 40°C for 2 hours. After completion of the reaction, the reaction solution was washed with water and brine and extracted with dichloromethane. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound.

¹H NMR(400MHz, DMSO-d₆): δ 9.06 (s, 1H), 8.79 (s, 1H), 8.37 (s, 1H),

8.32 (d, 1H), 7.77 (d, 1H), 7.56 (m, 1H), 7.07 (m, 1H), 6.92 (m, 1H), 4.22 (m, 15 1H), 1.55 (s, 9H)

Step 2: Préparation of 1-(4-chloro-3-trifluoromethylphenyl)-3-2-fluoro-5-r3(9H-purin-6-vl)pyridin-2-ylamino]phenylurea

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, 3-[3-(4-chloro-3trifluorophenyl)ureido-4-fluorophenyl]carbamic acid t-butyl ester prepared in step 1 was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1H-imidazol-1-yl)5-(trifluoromethyl)benzamido)phenylcarbamate.

NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 10.81 (s, 1H), 12.40 (s, 1H), 9.97 (s, 1H), 9.73 (d, 1H), 9.09 (s, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.39 (dd, 1H), 8.29 (dd, 1H), 8.09 (d, 1H), 7.67-7.61 (m, 2H), 7.61 (t, 1H), 7.47-7.43 (m, 1H), 7.25 (dd, 1H), 7.05 (dd, 1H)

Example 75. Préparation of 1-3-fluoro-4-r3-(9H-purin-6-yl)pyridin-2ylamino1phenyl-3-(3-trifluoromethylphenyl)urea

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, 2-fluoro-4-[3-(3trifluoromethylphenyl)ureido]phenylcarbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.86 (s, 1H), 12.75 (s, 1H), 9.80 (s, 1H), 9.33 (s, 1H), 9.15 (s, 1H), 8.72 (s, 1H), 8.39 (dd, 1H), 8.12 (dd, 1H), 8.04 (s, 1H), 7.95 (t, 1H), 7.56-7.50 (m, 2H), 7.42 (d, 1H), 7.31 (d, 1H), 7.05 (dd, 1H)

Example 76. Préparation of N-2-fluoro-5-r3-(9H-purin-6-yl)pyridin-2ylamino1phenyl-2-(3-trifluoromethylphenyl)acetamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, 4-fluoro-3-[2-(3trifluoromethylphenyl)acetylamino]phenylcarbamic acid t-butyl ester was used 5 instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.37 (s, 1H), 10.04 (s, 1H), 9.68 (brs, 1H), 9.06 (s, 1H), 8.70 (s, 1H), 8.31-8.26 (m, 2H), 7.73 (s, 1H), 7.67-7.54 (m, 4H), 7.22 (dd, 1 H), 7.01 (dd, 1 H). 3.88 (s, 2H) io Example 77. Préparation of N-(3-cyanomethylphenyl)-4-fluoro-3-r3(9H-purin-6-vl)pvridin-2-ylaminolbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [5-(315 cyanomethylphenylcarbamoyl)-2-fluorophenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.97 (s, 1H), 10.38 (s, 1H), 9.68 (brs, 1H), 9.83 (d, 1H), 9.20 (dd, 1H), 9.05 (s, 1H), 8.72 (s, 1H), 8.44 (dd, 2H), 7.87 (s,

1H), 7.72 (d, 1H), 7.66-7.63 (m, 1H), 7.46 (dd, 1H). 7.38 (t, 1H), 7.14 (dd, 1H), 7.08 (d, 1H), 4.07 (s, 2H)

Example 78. Préparation of N-4-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-3-fluorophenyl-4-(cvanomethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, 4-[4-(cyanomethyl)benzamido]2-fluorophenylcarbamic acid t-butyl ester was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-510 (trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.89 (s, 1H), 13.00 (s, 1H), 10.68 (s, 1H), 10.35 (s, 1H), 9.87 (d, 1H), 9.22 (d, 1H), 9.07 (s, 1H), 8.75 (s, 1H), 8.468.44 (m, 2H), 8.02 (d, 1H), 7.91 (d, 1H), 7.79 (d, 2H), 7.68-7.62 (m, 1H). 7.527.46 (m, 1H), 7.32 (d, 1H), 7.14 (dd, 1H), 4.01 (s, 2H)

Example 79. Préparation of N-443-(9H-purin-6-yl)pyridin-2ylamino]phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, [4-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.86 (s, 1H), 12.66 (s, 1H), 10.45 (s, 1H), 9.78 (s, 1H), 9.13 (s, 1H), 8.71 (s, 1H), 8.36 (dd, 1H), 8.31 (s, 1H), 8.27 (d, 1 H), 7.95 (d, 1 H), 7.85 (d, 2H), 7.80-7.74 (m, 3H). 7.01 (dd, 1 H)

Example 80. Préparation of N-2-methoxy-4-r3-(9H-purin-6-yl)pyridin2-ylamino1phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, [3-methoxy-4-(3trifluoromethylbenzoylamino)phenyl]carbamic acid t-butyl ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.86 (s, 1H), 12.69 (s, 1H), 9.83 (s, 1H), 9.78 (d, 1H), 9.16 (s, 1H), 8.72 (s, 1H), 8.39 (dd, 1H), 8.31 (s, 1H), 8.26 (d, 1 H), 7.95 (d, 1 H), 7.77 (t, 2H), 7.51 (d, 1 H). 7.40 (dd, 1 H), 7.04 (dd, 1 H)

Example 81. Préparation of N-(3-(3-(9H-purin-6-yl)pyridin-2ylamino)-2,4-difluorophenvl)-3-(4-fluorophenyl)-2-oxoimidazolidine-1carboxamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, (2,6-difluoro-3-[3-(4fluorophenyl)-2-oxo-imidazolidine-1 -carbonyl]aminophenyl)carbamic acid t-butyl 5 ester was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 11.64 (s, 1H), 10.60 (d, J=2.4Hz, 1H), 9.65 (brs, 1H), 8.72 (s, 1H), 8.24 (m, 1H), 8.01 (m, 1H), 7.63 (m, 2H), 7.28 (m, 3H), 7.25 (m, 1H), 3.96 (s, 4H) io Example 82. Préparation of N-(4-(3-(9H-purin-6-yl)pyridin-2ylamino)-3-fluorophenyl)-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, 4-[3-(2-cyanopropan-215 yl)benzamido]-2-fluorophenylcarbamic acid t-butyl ester was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.88 (brs, 1H), 12.88 (s, 1H), 10.45 (s,

100

H), 9.85 (d, J = 7.6 Hz, 1 H), 9.02 (s, 1 H), 8.67 (s, 1 H), 8.62 (t, J = 9.2 Hz, 1 H), 8.39 (dd, J = 2.8, 2.0 Hz, 1H), 8.07 (s, 1H), 7.96 (d, J= 7.6 Hz, 1H), 7.88 (dd, J = 11.6, 2.0 Hz, 1 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1H), 7.08 (m, 1H), 1.77 (s, 6H).(m, 1H), 7.63 (m, 2H), 7.28 (m, 3H), 7.25 (m, 1H), 3.96 (s, 4H)

Example 83. Préparation of N-(3-(3-(7H-pvrrolof2,3-d1pvrimidin-4yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(1-amino-2-methyl-1oxopropan-2-yl)benzamide

Step 1: Préparation of 4-(2-fluoropyridin-3-yl)-7H-pyrrolor2,3-d1pyrimidine

4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.65 mmol), 2fluoropyridin-3-ylboronic acid (119 mg, 0.846 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) and calcium carbonate (179 mg, 1.3 mmol) were added to a mixed solvent of dimethoxyethane and water. The solution was stirred under reflux at 100°C for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was aqueous sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. After drying with anhydrous magnésium sulfate, and then the purification by column

101 chromatography was performed to afford 33 mg (yield: 23.9%) of the title compound.

¹H NMR(400MHz, DMSO-d₆): δ 12.33 (brs, 1H), 8.87 (s, 1H), 8.43 (d, J=3.6Hz, 1H), 8.38 (t, J=8.8Hz, 1H), 7.65 (d, J=4.6Hz, 1H), 7.58 (t, J=5.5Hz, 1H), 6.55 (t, J=3Hz, 1H)

Step 2:Préparation of 4-(2-fluoropyridin-3-yl)-7-(methoxymethyl)7H-pyrrolof2,3-d1pyrimidine

4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.233 mmol) prepared in step 1 was dissolved in an Ν,Ν-dimethylformamide solvent. The solution was cooled to 0°C, and sodium hydride (60 % dispersion in minerai oil, 14 mg, 0.3495 mmol) was slowly added in portions thereto. Next, the solution was stirred at 0°C for 30 minutes, and then chloromethylether (0.02 mL, 0.2563 mmol) was added thereto, followed by stirring at room température for 3 hours. After completion of the reaction, the reaction solution was added to water and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford 46 mg (yield: 73.7%) of the title compound.

¹H NMR(400MHz, CDCI₃): δ 9.02 (s, 1H), 8.40-8.36 (m, 2H), 7.44-7.40 (m, 2H), 6.72 (t, J=4.1 Hz, 1 H), 5.68 (s, 2H), 3.35 (s, 3H)

Step 3: Préparation of 3-(2-cyanopropan-2-vl)-N-(2,4-difluoro-3-(3-(7(methoxymethvl)-7H-pvrrolo[2,3-d1pvrimidin-4-vl)pyridin-2102 ylamino)phenyl)benzamide

N-(3-amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide (30 mg, 0.1162 mmol) and 4-(2-fluoropyridin-3-yl)-7-(methoxymethyl)-7Hpyrrolo[2,3-d]pyrimidine (40 mg, 0.1278 mmol) prepared in step 2 were dissolved in a tetrahydrofuran solvent. The solution was cooled to 0°C, and lithium(bistrimethylsilyl)amide (1.0 M solution in THF, 0.581 mL, 0.3495 mmol) was slowly added in portions thereto. Next, the solution was stirred at 0°C for 20 minutes, and then stirred at room température for 5 hours. After completion of the reaction, the remaining lithium(bistrimethylsilyl)amide was removed by adding a small amount of 1M hydrochloric acid aqueous solution, and then aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford 57 mg (yield: 89 %) of the title compound.

¹H NMR(400MHz, CDCI₃): δ 10.86 (brs, 1H), 8.99 (s, 1H), 8.31-8.28 (m, 2H), 8.24-8.19 (m, 1H), 8.00 (brs, 2H), 7.79-7.73 (m, 2H), 7.53 (t, J = 7.8 Hz, 1 H), 7.48 (d, J = 3.5 Hz, 1 H), 7.05 (t, J = 9.4 Hz, 1 H), 6.95-6.91 (m, 2H), 5.07 (s, 2H), 3.35 (s, 3H), 1.78 (s, 6H)

Step 4: Préparation of N-(3-(3-(7H-pyrrolor2,3-d1pvrimidin-4-vl)pyridin-2ylamino)-2,4-difluorophenyl )-3-( 1 -amino-2-methyl-1 -oxopropan-2-yl)benzamide

103

3-(2-cyanopropan-2-yl)-N-(2,4-difluoro-3-(3-(7-(methoxymethyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)phenyl)benzamide (50 mg, 0.0975 mmol) prepared in step 3 was dissolved in a mixed solution of trifluoroacetic acid (1.8 mL) and water (0.2 mL). The solution was stirred under reflux at 80°C for 24 hours. The reaction solution was washed with sodium hydrogen carbonate solution and brine and extracted with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford 5 mg (yield: 9.7%) of the title compound.

¹H NMR(400MHz, CDCI₃): δ 10.88 (s, 1H), 9.80 (brs, 1H), 8.94 (s, 1H), 8.32 (d, J=7.5Hz, 1H), 8.28 (d, J=4.3Hz, 1H), 8.19 (brs, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=7.9Hz, 1H), 7.61 (d, J=7.9Hz, 1H), 7.50-7.45 (m, 2H), 7.04 (t, J=9Hz, 1H), 6.95-6.92 (m, 1H), 6.89 (brs, 1H), 5.57 (brs, 1H), 5.27 (brs, 1H),

1.64 (s, 6H)

Example 84. Préparation of N-(5-(3-(7H-pyrrolor2,3-d1pyrimidin-4yl)pvridin-2-vlamino)-2,4-diflurophenyl)-3-(2-cyanopropan-2-vl)benzamide

Step 1: Préparation of 4-(2-fluoropyridin-3-yl)-7H-pyrrolor2,3-dlpyrimidine

104

The title compound was obtained in the same manner as described in step 1 of Example 83.

Step 2: Préparation of N-(5-(3-(7H-pvrrolo[2,3-d]pyrimidin-4-yl)pyridin-2ylamino)-2,4-difluorophenyl)-3-(2-cyanopropan-2-vl)benzamide

4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.0934 mmol), prepared in step 1, and N-(5-amino-2,4-difluorophenyl)-3-(2-cyanopropan-2yl)benzamide (32 mg, 0.1027 mmol) were dissolved in a tetrahydrofuran solvent. The solution was cooled to 0°C, and lithium(bistrimethylsilyl)amide (1.0 M solution in THF, 0.467 mL, 0.467 mmol) was added slowly in small portions thereto. Next, the solution was stirred at 0°C for 20 minutes, and then stirred at room température for 5 hours. After completion of the reaction, the remaining lithium(bistrimethylsilyl)amide was removed by adding a small amount of 1M hydrochloric acid aqueous solution, and then aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnésium sulfate and concentrated under reduced pressure, and the obtained solid was washed with a mixed solution of methanol and dichloromethane, thereby obtaining 18 mg (yield : 37.8 %) of the title compound.

¹H NMR(400MHz, DMSO-d₆): δ 12.48 (brs, 1H), 11.98 (s, 1H), 10.24 (s, 1H), 8.92 (s, 1H), 8.66 (t, J= 8.4 Hz, 1H), 8.49 (d, J= 7.8 Hz, 1H), 8.35-8.33 (m, 1 H), 8.10 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.77-7.74 (m, 2H), 7.60 (t, J = 7.9 Hz,

105

H), 7.46 (t, J = 10.6 Hz, 1H), 7.09-7.05 (m, 1H), 6.94 (d, J = 3.6 Hz, 1H), 1.74 (s, 6H)

Example 85. Préparation of N-(3-(3-(7H-pyrrolor2,3-d1pyrimidin-4vl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(2-cyanopropan-2- vDbenzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide was used instead of N-(510 amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

¹H NMR(400MHz, CDCI₃):ô 10.91 (brs, 1H), 9.33 (brs, 1H), 8.97 (s, 1H), 8.33-8.28 (m, 2H), 8.25-8.19 (m, 1H), 8.00 (brs, 2H), 7.79-7.73 (m, 2H), 7.54 (t, J= 7.8 Hz, 1H), 7.46-7.45 (m, 1H), 7.08-7.03 (m, 1H), 6.96-6.93 (m, 1H), 6.916.90 (m, 1H), 1.78 (s, 6H)

Example 86. Préparation of N-(3-(3-(7H-pyrrolor2,3-d1pyrimidin-4vl)pyridin-2-ylamino)-2-fluorophenyl)-3-(2-cyanopopan-2-yl)benzamide

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(3-amino-2-fluorophenyl)

106

3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

¹H NMR(400MHz, DMSO-d₆):5 12.41 (brs, 1H), 12.01 (s, 1H), 10.26 (brs, 1H), 8.89 (s, 1H), 8.49-8.47 (m, 2H), 8.40-8.38 (m, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.77-7.74 (m, 2H), 7.60 (t, 1H), 7.19-7.13 (m, 2H), 7.11-7.08 (m, 1H), 6.93 (d, J=3.6 Hz, 1H)

Example 87. Préparation of Ν-2-ΑυοΓθ-5-Γ3-(7Η-ρνιτοΙοΓ2,3d1pvrimidin-4-yl)pvridin-2-vlaminolphenvl-3-trifluoromethyl benzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

¹H NMR(400MHz, DMSO-d6):ô ¹H NMR(400MHz, DMSO-d6):ô 11.49 (s, 1H), 8.96 (s, 1H), 8.38 (dd, 1H), 8.26-8.34 (m, 3H), 7.98-8.03 (m, 2H), 7.77-7.82 (m, 1H), 7.72 (d, 1H), 7.61-7.65 (m, 1H), 7.23-7.27 (q, 1H), 7.01-7.04 (q, 1H), 6.87 (d, 1H)

Example 88. Préparation of 3-fluoro-N-2-fluoro-5-r3-(7H-pyrrolor2,3d1pyrimidin-4-vl)pyridin-2-ylamino1phenyl-5-trifluoromethvl benzamide

107

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)3-fluoro-5-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

¹H NMR(400MHz, DMSO-d₆):ô 11.50 (s, 1 H), 8.96 (s, 1 H), 8.38 (dd, 1 H),

8.32 (dd, 1H), 8.22 (s, 1H), 8.11 (d, 1H), 8.03 (dd, 1H), 7.98 (d, 1H), 7.72 (d, 1H), 7.25 (t, 1 H), 7.03 (q, 1 H), 6.87 (d, 1 H)

Example 89. Préparation of 4-chloro-N-2-fluoro-5-r3-(7H-pyrrolor2,3d1pyrimidin-4-yl)pyridin-2-vlaminolphenyl-5-trifluoromethyl benzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)4-chloro-3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 90. Préparation of N-2-fluoro-5-r3-(7H-pyrrolor2,3d1pyrimidin-4-yl)pyridin-2-vlamino1phenvl-3,5-bistrifluoromethyl benzamide

108

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)3,5-bistrifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 91. Préparation of 3-(2-cyanopropan-2-yl)-N-2-fluoro-5-r3(7H-pvrrolor2,3-d1pyrimidin-4-vl)pyridin-2-ylamino1phenyl benzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)10 3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

¹H NMR(400MHz, DMSO-d₆):ô 12.44 (s, 1H), 11.49 (s, 1H), 10.25 (s, 1H), 8.96 (s, 1H), 8.38 (dd, 1H), 8.11 (s, 1H), 7.93-8.00 (m, 2H), 7.73-7.78 (m, 1H), 7.72 (d, 1H), 7.64-7.58 (m, 2H), 7.20-7.27 (m, 1H), 7.02(q, 1H), 6.87 (d, 15 1H), 1.75 (6H, s).

Example 92. Préparation of 3-(2-cyanopropan-2-yl)-5-fluoro-N-2fluoro-5-[3-(7H-pvrrolo[2,3-d1pyrimidin-4-vl)pyridin-2-vlamino1phenyl benzamide

109

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)3-(2-cyanopropan-2-yl)-5-fluorobenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

¹H NMR(400MHz, DMSO-d₆):ô 12.44 (brs, 1H), 11.50 (s, 1H), 10.25 (brs,

1H), 8.97 (s, 1H), 8.38 (dd, 1H), 8.32 (dd, 1H), 7.99-8.03 (m, 2H), 7.78-7.81 (m, 1 H), 7.72 (d, 1 H), 7.61-7.67 (m, 2H), 7.25 (q, 1 H), 7.02(q, 1 H), 6.87 (d, 1 H), 1.75 (6H, s)

Example 93. Préparation of 4-chloro-3-(2-cyanopropan-2-yl)-N-210 fluoro-5-r3-(7H-pvrrolor2,3-d1pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-fluorophenyl)15 4-chloro-3-(2-cyanopropan-2-yl)-5-fluorobenzamide was used instead of N-(5amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 94. Préparation of 3-(2-cyanopropan-2-yl)-N-3-r3-(7Hpyrrolor2,3-d1pyrimidin-4-yl)pyridin-2-ylamino1phenyl benzamide

110

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-aminophenyl)-3-(2cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 95. Préparation of 3-(2-cyanopropan-2-yl)-N-4-fluoro-3-r3(7H-pyrrolor2,3-d1pyrimidin-4-yl)pyridin-2-vlamino1phenvl benzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-4-fluorophenyl)3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 96. Préparation of 3-(2-cyanopropan-2-yl)-N-2,6-difluoro-3F3-(7H-pvrrolor2,3-d1pvrimidin-4-yl)pyridin-2-ylamino1phenyl benzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-2,6difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

111

Example 97. Préparation of N-2-chloro-5-f3-(7H-pvrrolor2,3d1pyrimidin-4-yl)pvridin-2-ylamino1phenyl-3-(2-cyanopropan-2yl)benzamide

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(5-amino-2-chlorophenyl)3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 98. Préparation of 3-(2-cyanopropan-2-yl)-N-3-fluoro-5-r310 (7H-pyrrolor2,3-d1pvrimidin-4-vl)pyridin-2-vlamino1phenylbenzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-5-fluorophenyl)3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,415 difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 99. Préparation of 3-(2-cyanopropan-2-yl)-N-4-methyl-3-r3(7H-pvrrolor2,3-d1pyrimidin-4-vl)pvridin-2-vlamino1phenvlbenzamide

112

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-4-methylphenyl)3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5-amino-2,45 difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 100. Préparation of 3-(2-cyanopropan-2-yl)-N-4-methoxy-3r3-(7H-pyrrolor2,3-d1pvrimidin-4-yl)pyridin-2-ylamino1phenylbenzamide

The title compound was synthesized in the same manner as described in ίο Example 84, except that, in step 2 of Example 84, N-(3-amino-4methoxyphenyl)-3-(2-cyanopropan-2-yl)benzamide was used instead of N-(5amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 101. Préparation of N-3-r3-(7H-pyrrolor2,3-d1pyrimidin-4yl)pyridin-2-vlaminolphenyl-3-trifluoromethvlbenzamide

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(3-aminophenyl)-3

113 trifluoromethylbenzamide was used instead of N-(5-amino-2,4-difluorophenyl)3-(2-cyanopropan-2-yl)benzamide.

Example 102. Préparation of N-2-fluoro-3-r3-(7H-pyrrolor2,3d1pyrimidin-4-vl)pyridin-2-ylaminolphenvl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-2-fluorophenyl)3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 103. Préparation of N-4-fluoro-3-r3-(7H-pyrrolor2,3d1pyrimidin-4-vl)pyridin-2-ylamino]phenvl-3-trifluoromethvlbenzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-4-fluorophenyl)3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 104. Préparation of N-2,4-difluoro-3-i3-(7H-pyrrolor2,3dlpvrimidin-4-vl)pvridin-2-ylaminolphenvl-3-trifluoromethvlbenzamide

114

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-2,4difluorophenyl)-3-trifluoromethylbenzamide was used instead of N-(5-amino5 2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 105. Préparation of N-2,6-difluoro-3-r3-(7H-pyrrolor2,3d1pvrimidin-4-yl)pyridin-2-ylamino1phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(3-amino-2,6difluorophenyl)-3-trifluoromethyIbenzamide was used instead of N-(5-amino2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 106. Préparation of N-2,4-difluoro-5-r3-(7H-pyrroloF2,3d1pvrimidin-2-yl)pyridin-2-vlamino1phenvl-3-trifluoromethylbenzamide

115

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2,4difluorophenyl)-3-trifluoromethylbenzamide was used instead of N-(5-amino2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 107. Préparation of N-2-chloro-5-r3-(7H-pyrrolor2,3d1pvrimidin-4-vl)pvridin-2-vlamino1phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(5-amino-2-chlorophenyl)3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 108. Préparation of N-4-methyl-3-r3-(7H-pyrrolor2,3d1pvrimidin-4-yl)pyridin-2-ylamino1phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in Example 84, except that, in step 2 of Example 84, N-(3-amino-4-methylphenyl)3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 109. Préparation of N-4-methoxy-3-r3-(7H-pyrrolor2,3d1pvrimidin-4-yl)pyridin-2-vlamino1phenyl-3-trifluoromethylbenzamide

116

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(3-amino-4rnethoxyphenyl)-3-trifluorornethylbenzamide was used instead of N-(5-amino5 2,4-difIuorophenyl)-3-(2-cyanopropan-2-yl)benzamide.

Example 110. Préparation of N-3-fluoro-5-r3-(7H-pyrrolor2,3d1pyrimidin-4-vl)pyridin-2-vlamino1phenyl-3-trifluoromethylbenzamide

The title compound was synthesized in the same manner as described in

Example 84, except that, in step 2 of Example 84, N-(3-amino-5-fluorophenyl)3-trifluoromethylbenzamide was used instead of N-(5-amino-2,4d ifl uorophenyl)-3-(2-cyanopropan-2-yl )benzam ide.

Example 111. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-4-fluoro-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(4-fluoro-3

117 (trifluoromethyl)benzamido)phenyl]carbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.50 (s, 1H), 10.48 (s, 1H), 9.69 (dd,

1H), 9.16 (s, 1H), 8.95 (s, 1H), 8.43-8.32 (m, 3H), 8.11 (dd, 1H), 7.74-7.66 (m, 2H), 7.27 (dd, 1H), 7.02 (q, 1H)

Example 112. Préparation of 5-r3-(9H-purin-6-yl)amino1-N-f3-(2cyanopropan-2-yl)phenyn-2-fluorobenzamide

The title compound was synthesized in the same manner as described in Example 73, except that, in step 2 of Example 73, t-butyl 3-[(3-(2-cyanopropan2-yl)phenyl)carbamoyl]-4-fluorophenylcarbamate was used instead of t-butyl [4fluoro-3-(3-trifluoromethylphenylcarbamoyl)phenyl]carbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.59 (s, 1H), 9.77 (d,

1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.34 (d, 3H), 7.89 (s, 1H), 7.73 (s, 1H), 7.28 (m, 4H), 7.03 (q, 1 H), 6.95 (m, 1 H), 1.44 (s, 6H).

Example 113. Préparation of N-5-r(3-(9H-purin-6-vl)pyridin-2yl)amino]-2-fluorophenyl-3-fluorobenzamide

118

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(3fluorobenzamido)phenyl]carbamate was used instead of t-butyl-2,6-difluoro-3(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.50 (s, 1H), 10.27 (s, 1H), 9.75 (s, 1H), 9.10 (s, 1H), 8.69 (s, 1H), 8.34 (q, 1H), 8.08 (dd, 1H), 7.86 (d, 1 H), 7.80 (dd, 1 H), 7.69 (m, 1 H), 7.58 (m, 1 H), 7.47 (m, 1 H), 7.28 (t, 1 H), 7.02 (q, 1H)

Example 114. Préparation of 5-r3-(9H-purin-6-yl)pyridin-2-yl1aminoN-(3,4-difluorophenyl)-2-fluorobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(3,4difluorobenzamido)phenyl]carbamate was used instead of t-butyl-2,6-difluoro-3(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.59 (s, 1H), 10.28 (s, 1H), 9.73 (d, 1H), 9.09 (s, 1H), 8.68 (s, 1H), 8.33 (q, 1H), 8.03 (m, 2H), 7.89 (q, 1 H), 7.72-7.62 (m, 2H), 7.25 (t, 1 H), 7.02 (q, 1 H)

Example 115. Préparation of 5-r3-(9H-purin-6-yl)pyridin-2-yl1aminoN-(3,5-difluorophenyl)-2-fluorobenzamide

119

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(3,5difluorobenzamido)phenyl]carbamate was used instead of t-butyl-2,6-difluoro-35 (3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.60 (s, 1H), 10.36 (s, 1H), 9.76 (s, 1H), 9.11 (s, 1H), 8.34 (q, 1H), 8.09 (q, 1H), 7.69 (m, 3H), 7.53 (m, 1H), 7.26 (t, 1H), 7.03 (q, 1H)

Example 116. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-210 vl)amino1-2-fluoropheny-3-(2-cyanopropan-2-yl)-4-fluorobenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-(2-cyanopropan-2yl)-4-fluorobenzamido]-4-fluorophenylcarbamate was used instead of t-butyl15 2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.62 (s, 1H), 10.32 (s, 1H), 9.77 (d, 1H), 9.11(s, 1H), 8.71 (s, 1H), 8.34 (q, 1H), 8.12-8.07 (m, 3H), 7.68 (t, 1 H), 7.48 (m, 1 H), 7.26 (t, 1 H), 7.02 (q, 1 H), 1.81 (s, 6H).

120

Example 117. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-4-chloro-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in

Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-(2-cyanopropan-2yl)-4-chlorobenzamido]-4-fluorophenylcarbamate was used instead of t-butyl2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.55 (s, 1H), 10.38 (s, 1H), 9.73 (d, ίο 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.34 (q, 1H), 8.13-8.10 (m, 2H), 8.01 (dd, 1H), 7.74 (d, 1 H), 7.68 (t, 1 H), 7.27 (t, 1 H), 7.03 (q, 1 H), 1.88 (s, 6H)

Example 118. Préparation of 1-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino]-2-fluorophenyl-3-r3-(trifluoromethyl)phenvnurea

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3-(3(trifluoromethyl)phenyl)ureido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

121 ¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.36 (s, 1H), 9.74 (d, 1 H), 9.43 (s, 1 H), 9.09 (s, 1 H), 8.70 (s, 1 H), 8.62 (s, 1 H), 8.43 n(d, 1 H), 8.32 (dd, 1 H), 8.01 (s, 1 H), 7.60-7.48 (m, 3H), 7.32 (d, 1 H), 7.20 (q, 1 H), 7.00 (q, 1 H)

Example 119. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-25 vl)aminol-2-fluorophenyl-6-(2-cyanopropan-2-yl)picolinamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[6-(2-cyanopropan-2yl)picolinamido]-4-fluorophenylcarbamate was used instead of t-butyl-2,610 difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.78 (t, 1H), 12.53 (s, 1H), 10.40 (s, 1H), 9.73 (s, 1H), 9.1O(S, 1H), 8.69 (s, 1H), 8.67 (s, 1H), 8.64 (t, 1H), 8.35 (q, 1H), 8.22-8.15 (m, 2H), 7.93 (q, 1H), 7.67-7.63 (m, 1H), 7.30 (dd, 1H), 7.03 (q, 15 1H), 1.82 (s, 6H)

Example 120. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-2-fluoro-5-(trifluoromethyl)benzamide

122

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(2-fluoro-5(trifluoromethyl)benzamido)phenyl]carbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.80 (s, 1H), 12.55 (s, 1H), 10.41 (s, 1H), 9.72 (s, 1H), 9.08 (s, 1H), 8.67 (s, 1H), 8.33 (q, 1H), 8.29 (d, 1H), 8.09 (d, 1 H), 8.01 (m, 1 H), 7.70-7.61 (m, 2H), 7.26 (t, 1 H), 7.02 (q, 1 H)

Example 121. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-2-fluoro-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(2-fluoro-3(trifluoromethyl)benzamido)phenyl]carbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (d, 1H), 12.52 (s, 1H), 10.47 (s, 1H), 9.72 (s, 1H), 9.10 (s, 1H), 8.69 (s, 1H), 8.34 (q, 1H), 8.27 (d, 1H), 8.02 (t, 1 H), 7.96 (t, 1 H), 7.66 (m, 1 H), 7.53 (t, 1 H), 7.26 (t, 1 H), 7.04 (q, 1 H)

Example 122: Préparation of N-3-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-3-(trifluoromethyl)benzamide

123

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 2-fluoro-3-[3(trifluoromethyl)benzamido]phenylcarbamate was used instead of t-butyl-2,65 difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (d, 1H), 12.89 (s, 1H), 10.48 (s, 1H), 9.83 (s, 1H), 9.01 (s, 1H), 8.71 (s, 1H), 8.58 (m, 1H), 8.42 (q, 1H), 8.36 (s, 1 H), 8.31 (d, 1 H), 8.00 (d, 1 H), 7.79 (t, 1 H), 7.18 (m, 2H), 7.11 (q, 1 H) io Example 123. Préparation of 1-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-r4-(trifluoromethyl)phenyl1urea

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3-(315 (trifluoromethyl)phenyl)ureido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

124 ¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.36 (s, 1H), 9.74 (d, 1H), 9.43 (s, 1H), 9.09 (s, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1 H), 8.01 (s, 1 H), 7.60-7.48 (m, 3H), 7.20 (m, 2H), 7.00 (q, 1 H)

Example 124. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-25 yl)amino1-2-chlorophenyl-3,5-bis(trifluoromethvl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-chloro-3-[3,5bis(trifluoromethyl)benzamido]phenylcarbamate was used instead oft-butyl-2,βίο difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (d, 1H), 12.73 (s, 1H), 10.70 (s, 1H), 9.73 (s, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.66 (s, 2H), 8.42 (s, 1H), 8.38 (q, 1H), 8.17 (d, 1H), 7.84 (q, 1H), 7.51 (d, 1H), 7.07 (q, 1H)

Example 125. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-3-(methylthio)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3

125 (methylthio)benzamido]phenylcarbamate was used instead of t-butyI-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.56 (s, 1H), 10.19 (s, 1H), 9.73 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.34 (q, 2H), 8.07 (t, 1H), 7.86 (s, 1H), 7.75 (d, 1H), 7.68 (t, 1H), 7.45 (m, 2H), 7.24 (t, 1H), 7.02 (q, 1H), 2.60 (s, 3H)

Example 126. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)aminot-2-fluorophenyl-3-(methylsulfonyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3(methylsulfonyl)benzamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.56 (s, 1H), 10.50 (s, 1H), 9.75 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.54 (q, 2H), 8.32 (m, 2H), 8.178.12 (m,2H), 7.83 (t, 1H), 7.70 (m, 1H), 7.27 (t, 2H), 7.03 (q, 1H), 1.35 (s, 3H)

Example 127. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)aminol-2-chlorophenyl-3-(2-cyanopropan-2-yl)-5-fluorobenzamide

126

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-(2-cyanopropan2-yl)-5-fluorobenzamido]-4-chlorophenylcarbamate was used instead of t-butyl5 2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.70 (s, 1H), 10.39 (s, 1H), 9.73 (d, 1H), 9.14(s, 1H), 8.72 (s, 1H), 8.38 (q, 1H), 8.13 (d, 1H), 8.04 (s, 1 H), 7.86-7.83 (m, 2H), 7.65 (d, 1 H), 7.50 (d, 1 H), 7.07 (q, 1 H), 1.77 (s, 6H) io Example 128. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenvl-2,4-bis(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[2,415 bis(trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

127 ¹H NMR (400MHz, DMSO-d₆): δ 13.82 (d, 1H), 12.43 (s, 1H), 10.56 (s, 1H), 9.71 (s, 1H), 9.10 (s, 1H), 8.70 (s, 1H), 8.33 (q, 1H), 8.28 (dd, 1H), 8.22 (d, 1 H), 8.20 (s, 1 H), 7.99 (d, 1 H), 7.85 (m, 1 H), 7.26 (t, 1 H), 7.03 (q, 1 H)

Example 129. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-3,4-bis(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3,4bis(trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-im idazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.81 (d, 1H), 12.57 (s, 1H), 10.69 (s, 1H), 9.75 (s, 1H), 9.11 (s, 1H), 8.70 (s, 1H), 8.45 (d, 1H), 8.34 (dd, 1H), 8.26 (d, 1H), 8.16 (dd, 1H), 7.70 (m, 1H), 7.28 (t, 1H), 7.03 (q, 1H)

Example 130. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-2,5-bis(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[2,5bis(trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of t

128 butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (d, 1H), 12.45 (s, 1H), 10.58 (s, 1H), 9.72 (s, 1H), 9.10 (s, 1H), 8.71 (s, 1H), 8.33 (dd, 1H), 8.28 (d, 1H), 8.17 (s, 5 1H), 8.12 (s, 2H), 7.67 (m, 1H), 7.26 (t, 1H), 7.03 (q, 1H)

Example 131. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-3-(trifluoromethoxy)benzamide

The title compound was synthesized in the same manner as described ίο in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3(trifluoromethoxy)benzamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (d, 1H), 12.55 (s, 1H), 10.36 (s, 15 1 H), 9.72 (s, 1 H), 9.11 (d, 1 H), 8.70 (s, 1 H), 8.35 (dd, 1 H), 8.09 (dd, 1 H), 8.06 (d, 1 H), 7.96 (s, 1 H), 7.68 (t, 2H), 7.63 (d, 1 H), 7.26 (t, 1 H), 7.02 (q, 1 H)

Example 132. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3,5-dimethoxybenzamide

129

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [3-(3,5dimethoxybenzamido)-4-fluorophenyl]carbamate was used instead of t-butyl2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (d, 1H), 12.54 (s, 1H), 10.12 (s, 1H), 9.73 (s, 1H), 9.12 (d, 1H), 8.72 (s, 1H), 8.34 (dd, 1H), 8.04 (dd, 1H), 7.67 (m, 1H), 7.26 (t, 1H), 7.17 (d,2H), 7.04 (q, 1H), 6.72 (t, 1H), 3.83 (s, 6H).

Example 133. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-fluoro-4-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3-fluoro-4(trifluoromethyl)benzamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.55 (s, 1H), 10.51 (s, 1H), 9.73 (s, 1H), 9.12 (d, 1H), 8.72 (s, 1H), 8.34 (dd, 1H), 8.12 (dd, 1H), 8.07 (d, 1H), 8.00 (m, 2H), 7.69 (m, 1H), 7.28 (t, 1H), 7.04 (q, 1H)

Example 134. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenvl-4-methoxv-3-(trifluoromethyl)benzamide

130

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[4-methoxy3-(trifluoromethyl)benzamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.55 (s, 1H), 10.28 (s, 1 H), 9.74 (s, 1 H), 9.11 (d, 1 H), 8.70 (s, 1 H), 8.34 (dd, 1 H), 8.30 (d, 2H), 8.08 (dd, 1 H), 7.67 (m, 1 H), 7.43 (d, 1 H), 7.25 (t, 1 H), 7.04 (q, 1 H)

Example 135. Préparation of N-5-lï3-(9H-purin-6-yl)pvridin-2yl)amino1-2-fluorophenyl-3-chloro-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-chloro-5(trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -y l)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.58 (s, 1H), 10.56 (s, 1H), 9.73 (s, 1H), 9.11 (s, 1H), 8.70 (s, 1H), 8.36-8.34 (m, 2H), 8.31 (s, 2H), 8.13-8.17 (m, 2H), 7.69 (m, 1H), 7.27 (t, 1H), 7.03 (q, 1H)

131

Example 136. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenvl-6-(trifluoromethyl)picolinamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[6(trifluoromethyl)picolinamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.53 (s, 1H), 10.30 (s, ίο 1H), 9.72 (s, 1H), 9.11 (s, 1H), 8.70 (s, 1H), 8.46 (q, 1H), 8.44 (d, 1H), 8.40 (d,

H), 8.38-8.35 (m, 1 H), 8.22 (d, 1 H), 7.66 (m, 1 H), 7.30 (t, 1 H), 7.03 (q, 1 H)

Example 137. Préparation of N-5-F(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenvl-4-fluoro-3-methylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(4-fluoro-3methylbenzamido)phenyl]carbamate was used instead of t-butyl-2,6-difluoro-3(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenylcarbamate.

132 ¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.53 (s, 1H), 10.13 (s, 1H), 9.72 (s, 1H), 9.11 (d, 1H), 8.70 (s, 1H), 8.34 (dd, 1H), 8.07 (dd, 1H), 7.96 (d, 1 H), 7.88 (m, 1 H), 7.67 (m, 1 H), 7.33-7.24 (m, 2H), 7.02 (q, 1 H), 2.32 (s, 3H)

Example 138. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-25 yl)aminol-2-fluorophenvl-4-methyl-3-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[4-methyl-3(trifluoromethyl)benzamido]phenylcarbamate was used instead of t-butyl-2,βίο difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.56 (s, 1H), 10.40 (s, 1H), 9.74 (d, 1H), 9.12 (d, 1H), 8.72 (s, 1H), 8.33 (dd, 1H), 8.30 (s, 1H), 8.18 (d, 1H), 8.08 (dd, 1 H), 7.67 (m, 1 H), 7.63 (d, 1 H), 7.28 (t, 1 H), 7.05 (q, 1 H), 2.50 (s, 3H)

Example 139. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-methyl-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3-methyl-5

133 (trifluoromethyl)benzamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.81 (s, 1H), 12.57 (s, 1H), 10.39 (s, 1H), 9.74 (s, 1H), 9.11 (s, 1H), 8.70 (s, 1H), 8.34 (q, 1H), 8.13-8.10 (m, 3H), 7.82 (s, 1 H), 7.69 (m, 1 H), 7.26 (t, 1 H), 7.03 (q, 1 H), 2.49 (s, 3H)

Example 140. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-3-methoxy-5-(trifluoromethoxy)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3-methoxy5-(trifluoromethoxy)benzamido]phenylcarbamate was used instead of t-butyl2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -y l)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.58 (s, 1H), 10.37 (s, 1H), 9.75 (d, 1H), 9.12 (s, 1H), 8.73 (s, 1H), 8.32 (q, 1H), 8.05 (t, 1H), 7.68 (t, 1H), 7.64 (s, 1 H), 7.54 (s, 1 H), 7.29 (t, 1 H), 7.21 (s, 1 H), 7.06 (q, 1 H), 3.90 (s, 3H)

Example 141. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenvl-3-cvclopropylbenzamide

134

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [3-(3cyclopropylbenzamido)-4-fluorophenyl]carbamate was used instead of t-butyl5 2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -y l)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.56 (s, 1H), 10.13 (s, 1H), 9.74 (d, 1H), 9.12 (s, 1H), 8.73 (s, 1H), 8.32 (q, 1H), 8.04 (dd, 1H), 7.75 (d, 1H), 7.687.65 (m, 2H), 7.33 (d, 1H), 7.27 (t, 1H), 7.05 (q, 1H), 2.06-1.99 (m, 3H), 1.0310 0.98 (m, 2H), 0.810-0.76 (m, 1 H)

Example 142. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-chloro-5-(trifluoromethoxy)benzamide

The title compound was synthesized in the same manner as described 15 in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-chloro-5(trifluoromethoxy)benzamido]-4-fluorophenylcarbamate was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

135 ¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.57 (s, 1H), 10.48 (s, 1H), 9.73 (s, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 8.34 (q, 1H), 8.14 (s, 1H), 8.11 (dd, 1 H), 7.94 (s, 1 H), 7.88 (s, 1 H), 7.69 (m, 1 H), 7.27 (t, 1 H), 7.03 (q, 1 H)

Example 143. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-25 vl)amino]-2-fluorophenyl-4-fluoro-3-(trifluoromethoxy)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[4-fluoro-3(trifluoromethoxy)benzamido]phenylcarbamate was used instead of t-butyl-2,βίο difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.57 (s, 1H), 10.40 (s, 1H), 9.74 (s, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 8.34 (q, 1H), 8.19-8.10 (m, 4H), 7.75-7.69 (m, 2H), 7.27 (t, 1 H), 7.03 (q, 1 H)

Example 144. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenvl-4-(trifluoromethyl)picolinamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[4

136 (trifluoromethyl)picolinamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.53 (s, 1H), 10.50 (s,

1H), 9.72 (s, 1H), 9.10 (s, 1H), 9.06 (d, 1H), 8.70 (s, 1H), 8.52 (d, 1H), 8.39 (s,

H), 8.35 (d, 1 H), 8.13 (d, 1 H), 7.66 (m, 1 H), 7.30 (t, 1 H), 7.03 (q, 1 H)

Example 145. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-methylbenzamide

io The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [4-fluoro-3-(3methylbenzamido)phenyl]carbamate was used instead of t-butyl-2,6-difluoro-3(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.53 (s, 1H), 10.10 (s,

1 H), 9.72 (s, 1 H), 9.11 (s, 1 H), 8.70 (s, 1 H), 8.34 (q, 1 H), 8.07 (dd, 1 H), 7.83 (s, 1H), 7.79 (t, 1H), 7.67 (m, 1H), 7.42 (d, 2H), 7.24 (t, 1H), 7.02 (q, 1H), 2.41 (s, 3H).

Example 146. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-chlorobenzamide

137

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl [3-(3chlorobenzamido)-4-fluorophenyl]carbamate was used instead of t-butyl-2,65 difIuoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.54 (s, 1H), 10.38 (s, 1H), 9.74 (s, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 8.34 (q, 1H), 8.09-8.06 (m, 2H), 7.97 (d, 1H), 7.72-7.68 (m, 2H), 7.56 (t, 1 H), 7.26 (t, 1 H), 7.03 (q, 1 H) io Example 147. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-4-chloro-3-(trifluoromethoxy)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[4-chloro-315 (trifluoromethoxy)benzamido]-4-fluorophenylcarbamate was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

138 ¹H NMR (400MHz, DMSO-d₆): δ 12.57 (s, 1H), 10.46 (s, 1H), 9.72 (s, 1H), 9.11 (s, 1H), 8.70 (s, 1H), 8.34 (q, 1H), 8.14-8.08 (m, 3H), 7.91 (d, 1H), 7.69 (m, 1 H), 7.27 (t, 1 H), 7.03 (q, 1 H)

Example 148. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-25 yl)amino1-2-fluorophenyl-3-fluoro-2-(trifluoromethyl)isonicotinamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[3-fluoro-2(trifluoromethyl)isonicotinamido]phenylcarbamate was used instead of t-butyl10 2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.86 (s, 1H), 12.54 (s, 1H), 10.72 (s,

1H), 9.76 (s, 1H), 9.11 (s, 1H), 8.75 (d, 1H), 8.72 (s, 1H), 8.36 (q, 1H), 8.34 (t,

1H), 8.11 (t, 1H), 7.65 (m, 1H), 7.29 (t, 1H), 7.04 (q, 1H)

Example 149. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-5-(trifluoromethyl)nicotinamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[5

139 (trifluoromethyl)nicotinamido]phenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.57 (s, 1H), 10.70 (s, 1H), 9.74 (s,

1H), 9.42 (s, 1H), 9.21 (s, 1H), 9.11 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 8.34 (q, 1H), 8.17 (dd, 1H), 7.69 (m, 1H), 7.28 (t, 1H), 7.03 (q, 1H)

Example 150. Préparation of N-5-R3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenyl-4-methoxy-3-(trifluoromethoxv)benzamide

ίο The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[4-methoxy3-(trifluoromethoxy)benzamido]phenylcarbamate was used instead of t-butyl2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.60 (s, 1H), 10.21 (s,

1H), 9.77 (s, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.35 (q, 1H), 8.12-8.06 (m, 2H), 8.01 (s, 1 H), 7.68 (m, 1 H), 7.40 (d, 1 H), 7.25 (t, 1 H), 7.03 (q, 1 H), 3.96 (s, 3H)

Example 151. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)aminol-2-fluorophenyl-2-(trïfluoromethyl)isonicotinamide

140

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 4-fluoro-3-[2(trifluoromethyl)isonicotinamido]phenylcarbamate was used instead of t-butyl5 2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -y I )-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.58 (s, 1H), 10.72 (s,

1H), 9.72 (s, 1H), 9.11 (d, 1H), 9.01 (d, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 8.34 (q, 1H), 8.23 (d, 1H), 8.18 (q, 1H), 7.70 (m, 1H), 7.29 (t, 1H), 7.03(q, 1H) io Example 152. Préparation of N-3-r(3-(9H-purin-6-yl)pvridin-2yl)amino1-4-methoxyphenyl-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 5-[3-(2-cyanopropan15 2-yl)benzamido]-2-methoxyphenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.89 (s, 1H), 10.22 (s, 1H), 9.72 (s, 1H), 9.10 (s, 1H), 9.03 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.60 (s,

141

1H), 7.94 (d, 1H), 7.73 (d, 1H), 7.55 (t, 1H), 7.37 (d, 1H), 7.03 (d, 2H), 4.01 (s, 3H), 1.74 (s, 6H)

Example 153. Préparation of N-3-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-4-methvlphenyl-3-(2-cyanopropan-2-yl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 5-[3-(2-cyanopropan2-yl)benzamido]-2-methylphenylcarbamate was used instead of t-butyl-2,6difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.85 (s, 1H), 12.31 (s, 1H), 10.27 (s, 1H), 9.81 (s, 1H), 9.08 (s, 1H), 9.03 (s, 1H), 8.72 (s, 1H), 8.63 (d, 1H), 8.33 (q, 1 H), 8.04 (d, 1 H), 7.94 (d, 1 H), 7.73 (dd, 1 H), 7.57 (t, 1 H), 7.43 (dd, 1 H), 7.23 (d, 1 H), 7.03 (d, 2H), 2.49 (s, 3H), 1.75 (s, 6H)

Example 154. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-(2-cyanopropan-2-yl)-5(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-(3-(2

142 cyanopropan-2-yl)-5-(trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 12.58 (s, 1H), 10.57 (s, 1H), 9.74 (s, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.44 (s, 1H), 8.36-8.35 (m, 2H), 8.13 (dd, 1H), 8.08 (s, 1 H), 7.69 (m, 1 H), 7.28 (t, 1 H), 7.03 (q, 2H)

Example 155. Préparation of N-5-K3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-3-(2-cyanopropan-2-yl)-5-methylbenzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-(2-cyanopropan2-yl)-5-methylbenzamido]-4-fluorophenylcarbamate was used instead of t-butyl2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -y l)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.82 (s, 1H), 12.55 (s, 1H), 10.22 (s, 1H), 9.72 (s, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.35 (dd, 1H), 8.09 (dd, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.69 (m, 1H), 7.59 (s, 1H), 7.25 (t, 1H), 7.02 (q, 2H), 2.45 (s, 3H), 1.87 (s, 6H)

Example 156. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2yl)amino1-2-fluorophenyl-2-bromo-3-(2-cyanopropan-2-yl)-5methoxybenzamide

143

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[2-bromo-3-(2cyanopropan-2-yl)-5-methoxybenzamido]-4-fluorophenylcarbamate was used instead of t-butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.42 (s, 1H), 10.38 (s, 1H), 9.70 (s, 1H), 9.09 (d, 1H), 8.70 (s, 1H), 8.34 (dd, 1H), 8.27 (dd, 1H), 7.66 (m, 1H), 7.24 (t, 1H), 7.16 (d, 1H), 7.13 (d, 1H), 7.03 (q, 2H), 3.87 (s, 3H) io Example 157. Préparation of N-5-r(3-(9H-purin-6-yl)pyridin-2vl)amino1-2-fluorophenvl-3-cvano-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-cyano-515 (trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of tbutyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl )-5(trifluoromethyl)benzamido)phenylcarbamate.

144 ¹H NMR (400MHz, DMSO-d₆): δ 13.83 (s, 1H), 12.58 (s, 1H), 10.56 (s, 1H), 9.73 (s, 1H), 9.11 (s, 1H), 8.70 (s, 1H), 8.36-8.34 (m, 2H), 8.31 (s, 2H), 8.13-8.17 (m,2H), 7.69 (m, 1H), 7.27 (t, 1H), 7.03 (q, 1H)

Example 158. Préparation of N-5-[(3-(9H-purin-6-vl)pyridin-25 yl)amino1-2-fluorophenyl-3-bromo-5-(trifluoromethyl)benzamide

The title compound was synthesized in the same manner as described in Example 2, except that, in step 2 of Example 2, t-butyl 3-[3-bromo-5(trifluoromethyl)benzamido]-4-fluorophenylcarbamate was used instead of t10 butyl-2,6-difluoro-3-(3-(4-methyl-1 H-imidazol-1 -yl)-5(trifluoromethyl)benzamido)phenylcarbamate.

¹H NMR (400MHz, DMSO-d₆): δ 13.84 (s, 1H), 12.59 (s, 1H), 10.57 (s, 1H), 9.74 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.36-8.34 (m, 2H), 8.30 (s, 2H), 8.13-8.17 (m,2H), 7.68 (m, 1H), 7.27 (t, 1H), 7.02 (q, 1H)

Table 1 below summarizes the structures of the compounds prepared in

Examples 1 to 158.

[Table 1]

Example No.

Structure

Example No.

Structure

145

1		λ I „ ϊΑ	ί/^ορ₃	2	<1	A
	w₃
3	Η	X	ΧΜ	cf₃ χο^	4	H N N	A r¥^NY	Çn
			_FA> ⁰				An _fX	J ï
5		Η 0		Ν A	6	H N N	Aj	N J	Λ
			cw	S ^s			w	T s	Ό
7		<”3	,Ν Αχ	A	8	H N		Y^NV	0
			_F>W	0			Xn _fX	P O
9	Η Ν Ν	1	Η ί Η	ΑΧ	10	H κι	\ f H ζΐΧ		^NX X^N_x
11	Η Ν	?	1 Η Τ Η W1	CF₃ *\^s	12		H ί H χτ	A	^N A
13	Η fW V	§	Η ί Η ζΑΊ	cf₃A_a	14	H	ÿy	CF iyC	O CO \ \
15	Η V	A Λ	Η ί Η xN^xk .Ν.	cf₃ XX A^J	16	â	C«A	jX	cf₃ Y
		α	_Fw			c	j_fA	0

146

Example No.	Structure	Example No.	Structure
17		18	C“AÂ
19	w	20
21	W» H H AzN χχ^ίχχΝ AA\/^CN Γ ii \|\| T h A V^N ⁰	22
23	/N-r% <v H H A\/ⁿ[ il ¥ \| T A VA 0	24	/NV^N«\| n^Aⁿ rtAi H H N Χχ^ίχ/ N AvA^cN \| ï ï T ï A \A o Cl
25	AC _F h n N xUx, N U U_Ff^	26	Oçu tX
27		28	&A
29		30	H M Λ/^ν w^N >AAf \| H II I Ii ^CF3 ⁰

147

Example No.	Structure	Example No.	Structure
33	H m n^n H H J\/N xA^\.CN 1 II II T H A An <A 0 _F	34
35		36	\^ⁿ A H H s^^N Γ ii il T ii ^{c 3} ^.N A<?A o
37	H N	38	A-a
39	^é. w H	40	y^A.
41		42	W
43	H M CO _f „ Λ u_Für^	44	A. H Λ uQu AA
45		46

148

Example No.	Structure	Example No.	Structure
49	«XJ H H Y/N YY_V'^CN । t t । y a	50	<v H H >Y^N γΑ/^Ν ΥΥρρ \ Il II T II ³ F
51	nY AU I T 11 T II ³ Y-N AA ⁰	52	^; r« I » A”¹àw^NA
53	AfrA	54	^H N γ/ΥΧ-·
55		56
57	w	58	/AA
59	ÎL^ F Y a^ïV cf₃	60	H M N-^% _f Æⁿ/yⁿyⁿyy rp An _fA> o AAnA cf₃
61	ΑΆ T H H I \|T .A .N. JA rY YY t^^cf* A.aA 0 \/ ^_F	62	H M N·^ / if X Ψ°2 H H \| JA Ort^^cf3 As^N \zA 0

149

Example No.	Structure	Example No.	Structure
65	CF œ Λ H H \| Jx A. rY ΥΎ Y^^^CF30	66	ω A IZ O « IZ ^IZ^^Z
67	N-^% _F W“ A H H \| A. .N. AxA Γ H Y Ί Y cf₃ ks. ,N A.Y\ 0 ^_C\|	68	Q t V IZ TZ^J.Z
69	4 A/N rr\A A^A H H \| Jx Ax J< μ ΎΎ s^^CF3 <zA 0 I	70	H H I [Ύ ΥΎ i^^f₃ ^v/N JL^ 0 \χ o 1
71	ÎA% w H H Yx .N. A^J< fr ΥΎ t^^cf= ^l<^N /\A 0	72
73	ŒiX^'·	74	J! N-^k^U HH i T 1 T Y Ύ \| \_F — ^_C\|
75	LÆ Qzl N^xA H A. /X QT XXâXi H H	76	<v H H ^AsX ^{N N} NZX/^Z^³ U U T U \x — ^_F \/
77	H M “ά^^	78	N^/% ÇQ H Jx ^.N. /x fn Yb J ΛζΛ. X \x F N Ti ^1 H X^X^CN

150

79

H A. -N. ΙΊ. s V Α_ΒΛχγ^₃ ^H

80

4 A A ^N]f H 1 A. ,N. Λ [Y W u X A JL Æ A/ ^_N Y^Z ^H LJ

Example No.	Structure	Example No.	Structure
81	<A _F	82	A _w ^H O
83	^AiAA	84	vQ I H H I II α,π,Γ^
85	H N άΆ”^⁰	86
87	CHa ZI Q m zi T O	88	M ^TZK^
89	O Q Y y O-Ô IZ A	90	,v% _cf / li Ί Y^F3 vAJ Σ X ^h h JL X ί i Ύ i Y ³ Lz>n LxA\ o
91	Va GQ \| i_i h \| Π AJ-VV^NVaA/^CN U LA S ^x	92	ZI C^lD² ZI w n zi o=/ Av >< ' O Z
93	^^xzz Qv^zZI 0 Ί1 ZI °=Z ^\ O Z	94	Z O IZ P ₂çOj IZ A

151

Example No.	Structure	Example No.	Structure
97	CQ T H H f \|l Ci Uï ^x Tl	98	CO T H H Γ II ^{N N} OO\/^{C N} O TJ T λ F
99	Tzi Q~O T ZI O Z	100	Z 0 < IZ $ IZ 0— ^ZZK^
101	H M N-^/Ts OU, T H H Γ jl fï ΥΎ ¥^^CF3T^/^N T^ ⁰	102	^Όθ'·
103	CQ T H H I II ✓N. ,hL JT γΎ TT T^^CF3T^^n JC O 0	104	¾TO'^f
105		106	OQ T H H Γ II T\ .N. JC pY ΊΓν Y^^CF3O^n X^T 0 _F^ T/ ''p
107	rzzz T ZI 0 O ZI V q	108	ω A h IZ ' Ova ^IZ
109	CO T H H Γ il A. /5. .N. J<ix JT γΎ ΥΎ Y^^cf= T^N JC^J 0 1	110	N-^%, CO T H H Γ Π T\ .N. /T. JT [Ύ TY n Tz^ 0 F

152

Example No.	Structure	Example No.	Structure
115	Z=^ Z— Zï il zz A	116	H n^-A H H \| ^{N N} AvK/ ^{c N} I H T T T A F
117	H N-^^N^ ^νΧ^^ν T H H 1 II ^{N N} ^A/X/ ^{c N} \ T TT A ^^N < A. o	118	LL? O 0 IZ >° ΞΕΖ LL 0 TZ z—Z Az ^ζχΑχ TZ^Z !
119	H N^/N. W a“AA™	120	LL³ O ¥ 0 IZ ^z\Aw
121	M O vJ^ )=o IZ 11a IZ AU	122	^H M ⁿ¥X
123	N^/% H HH r T ΪΎ ¥ Ύ η A ,n o _F \/ ^cf₃	124	z'^'zz ?=(¥ zz 0 O ZT ¥· o
125	Z^ZI aH ZI ύ n ZI T ω \	126	<A?n AA H H I ✓N. / I \|7 Tl 1”^ Ά ¥¥ iî Je o ⁰⁰

153

127	^_Cl	128	Si-Xx χχ Τη η 1 \|Τ χ\ζ^Ν\/^;\/^Ν\ζχ/ [ ιτ ιι Τ π τ 0 CF₃ F ³
129	Ζ^ΖΤ <ΓΛ— ζ=χ ζ— ZI 0 -Π ζι Έ Ο ο	130	Ζ^ΖΙ ² ΖΙ η -π ζι ο=/ ο-^\ ο
131	LL? Ο 'ο y ΙΖ ^ζ \=ζ ΙΖ^Ζ	132	• À y ΙΖ ^Ζ\=ΛΛ_Α τζγζ

Example Νο.	Structure	Example Νο.	Structure
133	Η ^Nx^Ny ^n-A^n Zv^cf= Τη η ί Π 4χ .NL ΑΧ Χγ γ^γ Y^^Fχ^ν yx ο	134	/ ιτ Ο Ο y. « ΙΖ ^ΤΖχ^^Ζ
135	Η NxÆ ci 4 XI Λ [ Η Η I v^aA/Kc r Y Ύ ι π ^CF3 Χ^Ν ο	136	4. y ΤΖ ^ζγλν/ ^IZsX
137	4 A/N χχ F Η Η \| Γ η Ύ T Τ ΧχΑχ 0 \ζ \ζ _F	138	Η Μ 0V Η Η I ✓Νχ /^χ ✓Νχ A ΥΎ n ^CF3 _F
139	δ ΤΖ 11. 0 ΤΖ ^z\=rw ΤΖ^,Ζ	140	'Ζ.'^'Ζ.ΊΙ ζτ η -π ζτ Ο=Ζ \ %-° )=/ \ ο \ ο

154

Example No.	Structure	Example No.	Structure
151	LL O t b IZ ^ZJYJ IZ^Z	152	H N xwiAf Y 0 ' ^x I
153	H	154	H M CF A H H I X\/^N n/Xz ^N \zYYz^CN\ T T Π a _F

155

Experimental Example 1. Experiment on VEGFR-2 Tyrosine Kinase Inhibitory Activity

The inhibitory activities of the compounds of the présent invention against 5 VEGFR-2 tyrosine kinase were analyzed using ADP-GIo™ kinase assay kit commercially available from Promega. In the principle of the analysis, kinase, a substrate and ATP are reacted with one another, and then ADP-GIo™ solution is added thereto. The ATP is removed while leaving the produced ADP, and the remaining ADP is converted to ATP by use of a kinase détection reagent, 10 and the ATP is reacted with a luciferin substrate, and the emitted luminescence is measured. Specifically, 5 pl of each compound (5X) was added to each well, and 10 μΙ of kinase enzyme was added to each well, and then 10 μΙ of a 1:1 mixture of a kinase substrate and an ATP solution was added to each well (substrate: 5 μg/5 μΙ; ATP: 20 μΜ/5 μΙ). These substances were allowed to 15 react (30° C and 800 rpm) in a reactor under a light-shielded condition for 30 minutes, and 25 μ! of ADP-GIo™ solution was added to each well and allowed to react under a light-shielded condition for 40 minutes (RT; 150 to 170 rpm). 50 μΙ of a kinase détection reagent was added to each well and allowed to react under a light-shielded condition for 30 minutes (RT; 150 to 170 rpm), and then

156 the luminescence of each well was measured with a luminometer (Molecular Devices, LMax II 384) and converted to IC₅o values.

VEGFR-2 analysis

KDR: 50 ng;

Substrate: 5 pg;

ATP: 20 mM;

Tris-HCI: 40 mM;

MgCh: 20 mM;

DTT: 50 pM;

BSA: 0.1 mg/ml;

Reaction time: 30 min (30°C)/40 min/30 min;

Détection: LMaxll-384.

The solvents used in the experiment were dispensed and used as follows.

2X buffer: 400 pl of 5X buffer included in the kit, 1 pl of DTT (0.1 M), and 599 pl of DIW were mixed to make a volume of 1 ml.

1X buffer: 2X buffer was mixed with DIW at a ratio of 1:1.

Enzyme: Enzyme contained in a 10 pg/100 pl vial included in the kit was dispensed in an amount of 4 pl (400 ng) and stored at -70°C. For use, 76 pl of 1X buffer was added to the stored enzyme, and then 10 pl was added to each well.

ATP solution: 10 mM ATP included in the kit was dispensed in an amount of 25 pl and stored at -70°C. For use, the stored ATP was diluted with 2X buffer to a concentration of 250 pM (5X).

157

Substrate: a substrate contained in a 1 mg/1 ml vial included in the kit was dispensed in an amount of 40 pl (40 μg) and stored at -70°C. For use, the stored substrate was mixed with the ATP solution at a ratio of 1:1, and 10 μΙ of the mixture was added to well.

A compound disclosed in Example 18 of Korean Patent Application

Publication No. 2012-0060744 was synthesized and used as a control, and an experimental resuit value obtained for the compound was indicated as Comparative Example 1. The VEGFR inhibitory activities of the compounds of the présent invention and Comparative Example 1 are shown in Table 2 below.

[Table 2]

Example No.	VEGFR IÇso . (nM)	Example ‘ No.	VEGFR ICso (nM)	Example No.	VEGFR IC50 (nM)
1	11	2	4,700	3	5,380
4	2,720	5	3,080	6	2,550
7	2,070	8	2,360	9	12
10	4,710	11	4,980	12	3,440
13	6,050	14	4,980	15	6,050
16	5,060	17	3,370	18	4,150
19	4,970	20	335	21	4.1
22	925	23	14	24	191
25	8,500	26	5,900	27	229
28	74	29	12	30	11
31	4,100	32	29	33	126
34	646	35	846	36	12
37	526	38	760	39	5,031
40	96	41	82	42	1,300

158

43	127	44	340	45	147
46	347	47	118	48	590
49	10	50	90	51	182
52	887	53	2,500	54	887
55	14,800	56	10,000	57	969
58	11,000	59	5,400	60	6,060
61	45,000	62	1,000	63	1,100
64	394	65	21	66	89
67	40	68	800	69	950
70	1,548	71	1,600	72	300
73	52	74	43	75	982
76	11	77	35	78	28
79	982	80	1,495	81	121
82	1,425	83	394	84	21
85	89	86	1,548	87	210
88	109	91	76	92	87
135	184	139	126	154	253
Comparative Example 1	1,600

Experimental Example 2. Experiment on Raf Kinase Inhibitory

Activity

In order to examine the inhibitory activities of the compounds of the présent invention against Raf kinases (B-Raf, C-Raf, B-Raf^V600E), the following 5 experiment was performed.

(1) Consecutive Signal transduction reacion

To a centrifugation tube, 20 pl of a dilution solvent (20 mM MOPS, pH 7.2, 25 mM β-glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1

159 mM dithiothreitol) and 20 μΙ of a Mg/ATP mixture (500 μΜ ATP and 75 mM magnésium chloride) were added. Then, each of the dérivative compounds of formula 1 was added. As a control, 1 ng of activated raf, 0.4 ng of inactivated MEK1 and 1 pg of inactivated MAPK2 were added without adding Example compounds. The solutions in the tube were concentrated at the bottom of the tube by centrifugation, and then allowed to react at 30°C for 30 minutes, and 4 μΙ of the mixture solution was taken and used in the next experimental step.

(2) Phosphorylation of substrate protein MBP by MAPK2

To 4 μΙ of the mixture solution taken in (1), 10 μΙ of a dilution solvent, 20 μg of MBP as a substrate, and 10 μΙ of diluted [γ-32Ρ]ΑΤΡ (1 pCi/pL) were added. The solutions in the tube were concentrated at the bottom of the tube by centrifugation, and then allowed to react at 30°C for 30 minutes. 25 μΙ of the reaction solution was carefully placed on the center of 2 cm x 2 cm P81 filter paper for 30 seconds. Next, the filter paper was washed three times with 0.75% phosphoric acid solution for 10 minutes each time and washed once with acetone for 5 minutes. Next, the filter paper was transferred into a scintillation vial, and 5 ml of a scintillation cocktail was added thereto. Raf activity inhibition rate (IC₅o) was measured by reading the radioactivity with a scintillation counter in comparison with the control. The results of the measurement are shown in Table 3 below.

[Table 3]

Example

B-Raf

ICsoinM) _B__Rafv600E ~ _c__Raf

0.2

0.6

160

21	21	10	10
23	17	7	8
30	2.7	5.2	0.7
33	94	33	24
36	71	30	41
53	14	6	7
65	331	187	257
135	161	86	34

Experimental Example 3. MTT Assay

MTT assay is frequently used for the purpose of primary screening for the sensitivity of anticancer agents and to examine cytotoxicity. When cancer cells are treated with varying concentrations of any anticancer agent for a 5 predetermined time to induce death of the cells and are then treated with MTT, and when the formation of formazan is measured, the concentration of the anticancer agent, at which about 50% of the cells survive, can be determined. This concentration value is called IC₅₀. IC₅₀ values differ between drugs, and thus can be characteristic of the drugs. Using this method, the effects of ίο anticancer agents against cell prolifération can be quantitatively compared. Thus, in order to measure the cytotoxicity of samples, MTT assay was performed using CelITiter 96 Non-radioactive Cell Prolifération Assay Kit (Promega).

Cells in a cell suspension were counted with a hematocytometer, and 15 then 200 pL of the cell suspension was added to each well of a 96 well plate at a desired concentration (cell amount determined depending on a cell line). After cell seeding, the cells were incubated in a CO₂ incubator at 37°C overnight. After one day of cell stabilization, the cells were treated with desired

161 concentrations of the compounds. The cells were incubated in a CO2 incubator at 37°C for 3 days, and then the sample was removed, and 200 pL of MTT solution was added to each well. After 2 hours of incubation, the MTT dilution was carefully shaken, and 200 pL of DMSO was added to each well, followed by shaking with a plate shaker for 60 minutes. The absorbance at a wavelength of 570 nm was measured using an ELISA reader, thereby determining the IC50 value of each compound (the absorbance indicates the amount of MTT reduced by the cells and is proportional to the number of viable cells présent in each well).

A compound disclosed in Example 18 of Korean Patent Application Publication No. 2012-0060744 was synthesized and used as a control, and an experimental resuit value obtained for the compound was indicated as Comparative Example 1. The results are shown in Tables 4 and 5 below.

[Table 4]

		Oilllfc Example No.
Example No.	MTT assay IC50 (nM) KRAS mutant (Colon) LS513 KRAS^G12V	MTT àssay IC_;/, (nM) Example KRAS mutant No. (Colon) LS513 KRAS^G12V	MTT assay ICæ (nM)
KRAS mutant (Colon) LS513T ^J KRAS^G12V 1,272
Comparative Example 1	>50,000	36	250	72
1	1,177	37	>10,000	73	80
2	>10,000	38	1,857	74	68
3	4,033	39	>10,000	75	>10,000
4	>10,000	40	163	76	426
5	>10,000	41	475	77	145137
6	>10,000	42	1,331	78	137
7	>10,000	43	402	79	>10,000

162

8	>10,000	44	1,322	80	>10,000
9	656	45	>10,000	81	388
10	1,172	46	7,091	82	>10,000
11	996	47	>10,000	83	394
12	1,021	48	2,485	84	118
13	1,152	49	192	85	676
14	851	50	221	86	>10,000
15	1,671	51	5,670	87	2,183
16	2,784	52	>10,000	88	609
17	1,159	53	>10,000	91	1,123
18	3,024	54	>10,000	92	1,513
19	939	55	>10,000
20	2,603	56	>10,000
21	333	57	>10,000
22	>10,000	58	407
23	687	59	2,140
24	476	60	>10,000
25	>10,000	61	439
26	>10,000	62	702
27	>10,000	63	690
28	958	64	300
29	978	65	100
30	143	66	135
31	>10,000	67	6,586
32	173	68	6,586
33	199	69	7,105
34	>10,000	70	757
35	>10,000	71	565

Example No.

MTT assay IC_;O(nM)

Example No.

MTT assay IC_M'^! Example i MTT assay IC50 (nM) No. (nM)

163

	KRAS mutant (Colon)		KRAS mutant (Colon)		KRAS mutant (Colon)
LS513 KRAS^G12V	LS513 KRAS^G12V	LS513 KRAS^G12V
Comparative Example 1	>50,000	127	591	145	1,033
110		128	1,205	146	1,705
111	300	129	652	147	502
112	>10,000	130	1,049	148	529
113	1,477	131	102	149	890
114	3,458	132	585	150	250
115	4,281	133	5,597	151	350
116	587	134	72	152	2,958
117	868	135	80	153	447
118	153	136	2,297	154	326
119	>10,000	137	1,059	155	145
120	3,375	138	403	156	517
121	304	139	99	157	464
122	6,583	140	294	158	283
123	392	141	445
124	888	142	128
125	767	143	559
126	1,114	144	444

[Table 5]

' Melanoma

Example No.

A-375P I SK-MÉL2

BRAF^ NRAS°^1K ]» /If®#· ίΐβϊ/ - LiSie MTT assay IC(nM) '

IjlBa/IIIIBT KRAS mutant ,

HCT-116 LS513 SW620 | kras^g,d KRAS^G12V KRAS^g'^2V

BRAF mutant (Colon)

WiDR braf^w-^oe liSÎI

HUVEC -| (VEGF) j___Za

164

1	95		101	278	849	115	22
9	40	106	75	138	643	58	44
21	24	129	63	160	249	28	40
23	12	58	50	95	321	62	28
30	246	122	145	79	864	636	13
36	271	388	117	126	675	644	15
53	4	35	17	29	180	391	5.8
65	-	-	208	322	700	247	850
135	-	-	74	88	317	68	733
139	-	-	-	96	-	116	-
154	-	-	-	326	-	97	-
Comparative Example 1	2	4,338	15,500	55,300	50,000	335	15,000

Experimental Example 4. Antitumor Effect on Human Colorectal Cancer LS513 Cell Line Xenograft

The LS513 human colorectal cancer cell line was purchased from the 5 ATCC and incubated in a 5% CO2 incubator with RPMI-1640b medium containing 10% fêtai bovine sérum and 1% penicillin-streptomycin at 37°C.

In this experiment, 5 to 6-week-old female Balb/c nu/nu nude mice (weighed 18 to 20 g) were used. The mice were provided from Nara Biotech Co., Ltd. During the experiment, ail the animais were housed on a mouse 10 constant temperature/constant humidity shelf (Individually Ventilated Cages System, LAB & BIO).

Each cage (37.2 cm length x 19.2 cm width x 13.1 cm height) was sterilized with a sterilizer, and eight mice were received in each cage. The mice were maintained in a hygienic environment controlled to a température of 20 to

165

24°C and a humidity of 40 to 70% with a 12-hr light/12-hr dark cycle. The mice were allowed to access sterilized feed and drinking water ad libitum. The care and treatment of these animais were carried out according to the Laboratory Animal Care Guidelines of Samjin Pharmaceutical Co., Ltd.

The mice were acclimated to the housing facility for 1 week, and then 0.1 mL of a cell suspension containing 1 x 10⁷ cells was injected subcutaneously into the right flank of each mouse. After cell transplantation, the volume of the formed tumor was measured, and mice with formed tumors having a volume of 150 mm³ or more were randomly divided into groups (each consisting of 7 to 8 animais) for treatment with the test compounds and a control. Vehicle (cremophor ELP/dimetylacetamide/hydroxypropyl-p-cyclodextrin/DW,

19.2/6.4/16/58.8%, w/w, pH 3) was orally administered to the control group twice a day, and the test compounds were orally administered to the test groups twice a day at a dose of 60 mg/kg or 30 mg/kg. Administration of the drugs was continued for 14 days. Among the test groups, the test compounds of Example 65, 135, 139 and 154 were orally administered to the test groups once a day at a dose of 50 mg/kg, and administration of the drugs was continued for 13 days. In addition, the test compound of Example 135 was orally administered once at a concentration of 12.5 mg/kg, 25 mg/kg and 50 mg/kg, respectively, and and administration of the drugs was continued for 21 days. At 3-day intervals from the starting day of the administration, the long axis and short axis of the tumor were measured with digital vernier calipers, and the tumor volume was calculated using the following équation and recorded:

Tumor volume (TV)= Long axis x short axis²/2.

166

Tumor growth inhibition for absolute tumor volume was calculated using the following équation. In the following équation, V_o is the tumor volume on the first day of drug administration (day 0), and V_t is the tumor volume after last drug administration.

Tumor growth inhibition (TGI)⁼ [1^-(Vt-Vo)TOmpound-treatedgroup/(XA/o)vehicle control group] X 1 θθ %

The results of observation of the in vivo antitumor effects of the compounds of Examples 21 and 30 indicated that the two compounds ail showed higher antitumor effects than the control, and the antitumor effects were proportional to the concentrations of the compounds. For the compound of Example 21, an antitumor effect of about 66.7% (P<0.01) compared to the control group was observed in the group treated with 30 mg/kg of the compound, and an antitumor effect of 90.3% (P<0.01) was observed in the group treated with 60 mg/kg of the compound. Similarly, for the compound of Example 30, an antitumor effect of 76.9% (P<0.01) was observed in the group treated with 30 mg/kg of the compound, and an antitumor effect of 88.7% (P<0.01) was observed in the group treated with 60 mg/kg of the compound (FIG. 1).

The compounds of Examples 33, 36 and 63 also showed excellent antitumor effects compared to the vehicle control. The antitumor effects were 96.0% (P<0.01) for the compound of Example 33, 78.5% (P<0.01) for the compound of Example 36, and 57.9% (P<0.01 ) for the compound of Example 63 (FIG. 2).

The in vivo antitumor effects of the compounds of Example 59 and 60 and Comparative Example 1 (the compound of Example 18 of Korean Patent

167

Application Publication No. 2012-0060744) were comparatively observed, and as a resuit, it was observed that the compound of Comparative Example 1 showed an antitumor effect of 3.82% (P>0.05) compared to the vehicle control, and the compound of Example 59 showed an antitumor effect of 83.51% 5 (P<0.01), and the compound of Example 60 showed an antitumor effect of 69.06% (P<0.01) (FIG. 3).

The in vivo antitumor effects of the compounds of Example 65, 135, 139 and 154 were comparatively observed, and as a resuit, it was observed that the compound of Example 65, 135, 139 and 154 showed an antitumor effect of 10 95.42% (P<0.01), 92.66% (P<0.01), 91.04% (P<0.01), and 83.19% (PO.01), respectively (FIG. 4)

The in vivo antitumor effects according to the concentration of Example 135, it was observed that an antitumor effect in 12.5 mg/kg of Example 135 was 52.36%, an antitumor effect in 25 mg/kg of Example 135 was 74.73%, and an 15 antitumor effect in 50 mg/kg of Example 135 was 86.85% (FIG. 5).

Claims

[CLAIMS] [Claim 1 ]

A pyridine dérivative represented by the following formula I to III and a pharmaceutically acceptable sait thereof:

5 [Formula I]

[Formula II]

[Formula III]

wherein

Xis CH or N;

169 |Ri and R₂ are each independently hydrogen, halogen, cyano, C-i-6 alkyl, or C1-6 alkoxy, wherein one or more hydrogen atoms in the alkyl may be substituted with halogen and both Ri and R₂ cannot be H at the same time; R< and R₂’are halogen;

u ^H J. NX

O ; and

B is C1-8 alkyl, aryl, or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF3, -NO₂, -OH, -SH, -CN, -NR3R4, -NHC(O)OR5, SO₂Re, C1-8 alkoxy, thioalkoxy, alkyl, C^e cycloalkyl, 3- to 6membered heterocycloalkyl, Cssaryl, and 5-to 8-membered heteroaryl, wherein one or more hydrogen atoms in the C1-8 alkoxy among the substituents may be each independently substituted with halogen, one or more hydrogen atoms in the C1-8 alkyl or cycloalkyl among the substituents may be each independently substituted with 3- to 6-membered heterocycloalkyl which is unsubstituted or substituted with Ci^ alkyl, -CN or C(O)NH₂, one or more hydrogen atoms in the 3- to 6-membered heterocycloalkyl among the substituents may be each independently substituted with alkyl or-OH;

170 one or more hydrogen atoms in the C^aryl or 5- to 8-membered heteroaryl among the substituents may be each independently substituted with halogen, -CF₃, -NO₂, -OH, -SH, -CN, -NR₃R4, -NHC(O)OR5, -C(O)NR₃R4, Ci-s alkoxy, C^ thioalkoxy, or C^ alkyl, wherein Rs, R4, Rsand Reare each independently hydrogen or Ci^ alkyl, wherein one or more atoms in the C1.6 alkyl may be substituted with halogen.

[Claim 2]

The pyridine dérivative or pharmaceutically acceptable sait thereof according to claim 1, wherein

X is CH or N;

Ri and R₂ are each independently hydrogen, halogen, C1-6 alkyl, or C^ alkoxy, wherein one or more hydrogen atoms in the C1-6 alkyl may be substituted with halogen and both R-ι and R₂ cannot be H at the same time;

RF and R₂’are halogen;

and

B is C1-8 alkyl, aryl or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, -NO₂, -CN, -NR₃R4, -NHC(O)OR₅, -SO₂Re,Ci-8

171 alkoxy, alkyl, cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 aryl, and 5- to 8-membered heteroaryl, wherein one or more hydrogen atoms in the C1-8 alkoxy among the substituents may be each independently substituted with halogen, one or more hydrogen atoms in the CA alkyl or CA cycloalkyl among the substituents may be each independently substituted with 3- to 6-membered heterocycloalkyl which is unsubstituted or substituted with CA alkyl, -CN or C(O)NH₂, one or more hydrogen atoms in the 3- to 6-membered heterocycloalkyl among the substituents may be each independently substituted with C1-8 alkyl or-OH;

one or more hydrogen atoms in the C^aryl or 5- to 8-membered heteroaryl among the substituents may be each independently substituted with halogen, -CF3, -NO₂, -CN, -NR3R4, -NHC(O)ORs, -C(O)NR₃R4, C1-8 alkoxy, or C^ alkyl, wherein R₃, R4, Rsand Re are each independently hydrogen or C1-6 alkyl, wherein one or more atoms in the C1-6 alkyl may be substituted with halogen.

[Claim 3]

The pyridine dérivative or pharmaceutically acceptable sait thereof according to claim 1, wherein,

XisN;

172

Ri and R2 are each independently hydrogen, halogen, Cm alkyl, or Cm alkoxy, wherein one or more hydrogen atoms in the Cm alkyl may be substituted with halogen and both Ri and R₂ cannot be H at the same time; Rf and R₂’ are halogen;

and

B is Cm alkyl, aryl or heteroaryl, wherein one or more hydrogen atoms in the aryl or heteroaryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, -NO2, -CN, -NR₃R4, -NHC(O)OR5, -SO2R6, Cm alkoxy, Cm alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 aryl, and 5- to 8-membered heteroaryl, one or more hydrogen atoms in the Cm alkoxy among the substituents may be each independently substituted with halogen;

one or more hydrogen atoms in the Cm alkyl or C^ cycloalkyl among the substituents may be each independently substituted with 3- to 6-membered heterocycloalkyl which is unsubstituted or substituted with Cm alkyl, -CN or C(O)NH₂, one or more hydrogen atoms in the 3- to 6-membered heterocycloalkyl among the substituents may each independently substituted with Cm alkyl or -OH,

173 one or more hydrogen atoms in the Cs-saryl or 5- to 8-membered heteroaryl among the substituents may be each independently substituted with halogen or Cm alkyl.

[Claim 4]

The pyridine dérivative or pharmaceutically acceptable sait thereof according to claim 1, wherein

X is CH;

Ri and R₂ are each independently hydrogen, halogen, Cm alkyl, or Cm alkoxy, wherein one or more hydrogen atoms in the Cm alkyl may be substituted with halogen and both R-ι and R₂ cannot be H at the same time;

RT and R₂’are halogen;

A is O ; and

B is aryl, wherein one or more hydrogen atoms in the aryl may be each independently substituted with a substituent selected from the group consisting of halogen, -CF₃, Cm alkoxy or Cm alkyl, wherein one or more hydrogen atoms in the Cm alkyl among the substituents may be each independently substituted with -CN or-C(O)NH₂.

[Claim 5]

The pyridine dérivative or pharmaceutically acceptable sait thereof according to claim 1, wherein the pyridine dérivative is selected from the

174 group consisting of the following compounds:

1) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- (trifluoromethyl)benzamide;
2) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4- methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)benzamide;
3) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-((4- ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;
4) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4- difluorophenyl)isobutylamide;
5) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)thiophene -2-carboxamide;
6) N-(3-(3-(9H-purin-6-yl)pyridine-2-ylamino)-2,4-difluorophenyl)furan-2carboxamide;
7) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)isoxazole5-carboxamide;
8) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)thiazole-5carboxamide;
9) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(2- cyanopropan-2-yl)benzamide;
10) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4- methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide;

11 ) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3thiomorpholino-5-(trifluoromethyl)benzamide;
12) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4- hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamide;

175
13) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4methylpiperidin-1-yl)-5-(trifluoromethyl)benzamide;
14) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4thiomorpholino-3-(trifluoromethyl)benzamide;
15) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-(4- methylpeperidin-1-yl)-3-(trifluoromethyl)benzamide;
16) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-chloro3-(trifluoromethyl)benzamide;
17) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-2,3dihydrobenzo[b][1,4]dioxine-6-carboxamide;
18) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- morpholino-5-(trifluoromethyl)benzamide;
19) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4- (pyrrolidin-1-yl)-3-(trifluoromethyl)benzamide;
20) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(1- cyanocyclopropyl)benzamide;
21) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-(2cyanopropan-2-yl)benzamide;
22) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(1- amino-2-methyl-1-oxopropan-2-yl)benzamide;
24) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-chlorophenyl)-3-(2cyanopropan-2-yl)benzamide;
25) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,6-difluorophenyl)-3-(2- cyanopropan-2-yl)benzamide;
26) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-2-

176 (trifluoromethyl)benzamide;
27) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4(trifluoromethyl)benzamide;
28) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-fluoro5-(trifluoromethyl)benzamide;
29) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-(2cyanopropan-2-yl)benzamide;
30) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3- (trifluoromethyl)benzamide;
31) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- (trifluoromethyl)benzamide;
32) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(2- cyanopropan-2-yl)benzamide;
33) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-(2cyanopropan-2-yl)-5-fluorobenzamide;
34) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- nitrobenzamide;
35) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- methoxybenzamide;
36) N-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2-fluorophenyl)-3-fluoro-5(trifluoromethyl)benzamide;
37) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- cyanobenzamide;
38) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4- methoxy-3-(trifluoromethyl)benzamide;

177
40) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-nitro-5(trifluoromethyl)benzamide;
41) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-chloro3-(2-cyanopropan-2-yl)benzamide;
42) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-2-chloro3-(2-cyanopropan-2-yl)benzamide;
43) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(2- cyanopropan-2-yl)-5-fluorobenzamide;
44) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(2- cyanopropan-2-yl)-4,5-difluorobenzamide;
45) N-(3-(3-(9H-purin-6-yl)pyrdin-2-ylamino)-2,4-difluorophenyl)-3- chlorobenzamide;
46) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- (dimethylamino)benzamide;
47) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- methylbenzamide;
52) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4- nitrobenzamide;
53) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4- methoxybenzamide;
54) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3- aminobenzamide;
55) methyl 3-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4difluorophenylcarbamoyl)phenylcarbamate;
56) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)pyrazine-

178

2-carboxamide;
57) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4- difluorophenyl)benzamide;
58) N-{2,4-difluoro-3-[3-(9H-purin-6-yl)pyridin-2-ylamino)-phenyl}-3,5- bistrifluoromethylbenzamide;
59) 1-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(3-(4methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl)urea;
60) 1-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4-((4ethylpi perazin-1 -yl )m ethyl )-3-(trifluoromethyl)phenyl )urea ;
61) 4-chloro-N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3(trifluoromethyl)benzamide;
62) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3-nitro-5(trifluoromethyl)benzamide;
63) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3-methoxy5-(trifluoromethyl)benzamide;
64) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-(6- methylpyridin-2-yl)benzamide;
65) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3,5- bis(trifluoromethyl)benzamide;
66) N-{2-chloro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;
67) N-{2-chloro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3-fluoro-5trifluoromethylbenzamide;
68) N-{2-methyl-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;

179
69) N-{2-methoxy-5-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;
72) N-{2,6-difluoro-3-[3-(9H-purin-6-yl)pyridin-2-ylamino)phenyl}-3- trifluoromethylbenzamide;
73) 2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino]-N-(3- trifluoromethylphenyl)benzamide;
74) 1-(4-chloro-3-trifluoromethylphenyl)-3-{2-fluoro-5-[3-(9H-purin-6- yl)pyridin-2-ylamino]phenyl}urea;
76) N-{2-fluoro-5-[3-(9H-purin-6-yl)pyridin-2-ylamino]phenyl}-2-(3trifluoromethylphenyl)acetamide;
81) N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-(4- fluorophenyl)-2-oxoimidazolidine-1-carboxamide;
83) N-(3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-2,4- difluorophenyl)-3-(1-amino-2-methyl-1-oxopropan-2-yl)benzamide;
84) N-(5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-2,4- diflurophenyl)-3-(2-cyanopropan-2-yl)benzamide;
85) N-(3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-2,4- difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide;
86) N-(3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-2- fluorophenyl )-3-(2-cyanopopan-2-yl )benzam ide;
87) N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethyl benzamide;
88) 3-fluoro-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-5-trifluoromethyl benzamide;
89) 4-chloro-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-

180 ylamino]phenyl-5-trifluoromethyl benzamide;
90) N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3,5-bistrifluoromethyl benzamide;
91) 3-(2-cyanopropan-2-yl)-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4yl)pyridin-2-ylamino]phenyl benzamide;
92) 3-(2-cyanopropan-2-yl)-5-fluoro-N-2-fluoro-5-[3-(7H-pyrrolo[2,3d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide;
93) 4-chloro-3-(2-cyanopropan-2-yl)-N-2-fluoro-5-[3-(7H-pyrrolo[2,3-

d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide;
96) 3-(2-cyanopropan-2-yl)-N-2,6-difluoro-3-[3-(7H-pyrrolo[2,3-

d]pyrimidin-4-yl)pyridin-2-ylamino]phenyl benzamide;
97) N-{2-chloro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl)-3-(2-cyanopropan-2-yl)benzamide;
102) N-2-fluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifIuoromethylbenzamide;
104) N-2,4-difluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;
105) N-2,6-difluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-triflLioromethylbenzamide;
106) N-2,4-difluoro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyridin-2- ylamino]phenyl-3-trifluoromethylbenzamide;
107) N-2-chloro-5-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2- ylamino]phenyl-3-trifluoromethyibenzamide;
111) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-fluoro-3(trifluoromethyl)benzamide;

181
112) 5-[3-(9H-purin-6-yl)amino]-N-[3-(2-cyanopropan-2-yl)phenyl]-2fluorobenzamide;
113) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- fluorobenzamide;
114) 5-[3-(9H-purin-6-yl)pyridin-2-yl]amino-N-(3,4-difluorophenyl)-2- fluorobenzamide;
115) 5-[3-(9H-purin-6-yl)pyridin-2-yl]amino-N-(3,5-difluorophenyl)-2- fluorobenzamide;
116) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluoropheny-3-(2cyanopropan-2-yl)-4-fluorobenzamide;
117) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-chloro-3(2-cyanopropan-2-yl)benzamide;
118) 1 -5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-[3- (trifluoromethyl)phenyl]urea;
119) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-6-(2cyanopropan-2-yl)picolinamide;
120) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2-fluoro-5(trifluoromethyl)benzamide;
121) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluoropheriyl-2-fluoro-3(trifluoromethyl)benzamide;
122) N-3-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- (trifluoromethyl)benzamide;
123) 1 -5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-[4- (trifluoromethyl)phenyl]urea;
124) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-chlorophenyl-3,5-

182 bis(trifl uoromethyl )benzam ide;
125) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- (methylthio)benzamide;
126) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- (methylsulfonyl)benzamide;
127) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-chlorophenyl-3-(2- cyanopropan-2-yl)-5-fluorobenzamide;
128) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2,4- bis(trifluoromethyl)benzamide;
129) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3,4- bis(trifluoromethyl)benzamide;
130) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2,5- bis(trifluoromethyl)benzamide;

131 ) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- (trifluoromethoxy)benzamide;
132) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3,5- dimethoxybenzamide;
133) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-fluoro-4(trifluoromethyl)benzamide;
134) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-methoxy3-(trifluoromethyl)benzamide;
135) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-chloro-5(trifluoromethyl)benzamide;
136) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-6- (trifluoromethyl)picolinamide;

183
137) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-fluoro-3methylbenzamide;
138) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-methyl-3(trifluoromethyl)benzamide;
139) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-methyl-5(trifluoromethyl)benzamide;
140) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-methoxy5-(trifluoromethoxy)benzamide;
141) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- cyclopropylbenzamide;
142) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-chloro-5(trifluoromethoxy)benzamide;
143) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-fluoro-3(trifluoromethoxy)benzamide;
144) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4- (trifluoromethyl)picolinamide;
145) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- methylbenzamide;
146) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3- chlorobenzamide;
147) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-chloro-3(trifluoromethoxy)benzamide;
148) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-fluoro-2(trifluoromethyl)isonicotinamide;
149) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fIuorophenyl-5-

184 (trifluoromethyl)nicotinamide;
150) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-4-methoxy3-(trifluoromethoxy)benzamide;
151) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-2- (trifluoromethyl)isonicotinamide;
154) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-(2- cyanopropan-2-yl)-5-(trifluoromethyI)benzamide;
155) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-(2- cyanopropan-2-yl)-5-methylbenzamide;
156) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyI-2-bromo-3(2-cyanopropan-2-yl)-5-methoxybenzamide;
157) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-cyano-5(trifluoromethyl)benzamide; and
158) N-5-[(3-(9H-purin-6-yl)pyridin-2-yl)amino]-2-fluorophenyl-3-bromo-5(trifluoromethyl)benzamide.

[Claim 6]

A method for preparing the pyridine dérivative or pharmaceutically acceptable sait thereof according to claim 1, the method comprising a step of reacting a compound of formula 2 with a compound of formula 3 according to the following reaction scheme 1, thereby obtaining a compound of formula 1: [Reaction Scheme 1]

185

wherein X, A, B, Ri and R₂ are as defined in claim 1, and Y is halogen.

[Claim 7]

A pharmaceutical composition for use in a method for prévention or treatment of an abnormal cell growth disease caused by RAS mutation, the composition containing, as an active ingrédient, the pyridine dérivative or pharmaceutically acceptable sait thereof according to any one of daims 1 to 5.

[Claim 81

The pharmaceutical composition for use of claim 7, wherein the abnormal cell growth disease caused by RAS mutation is any one selected from the group consisting of gastric cancer, lung cancer, liver cancer, colorectal cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, ovarian cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, rénal cancer, sarcoma, prostate cancer, uréthral cancer, bladder cancer, leukemia, multiple myeloma, blood cancer, lymphoma, fibroadenoma,

186 inflammation, diabètes, obesity, psoriasis, rheumatoid arthritis, hemangioma, acute or chronic rénal disease, coronary artery restenosis, autoimmune diseases, asthma, neurodegenerative diseases, acute infection, and ocular diseases caused by vascular disorders.

[Claim 9]

The pharmaceutical composition for use of claim 8, wherein the abnormal cell growth disease caused by RAS mutation is any one selected from the group consisting of melanoma, colorectal cancer, 10 prostate cancer, thyroid cancer, and ovarian cancer.