KR101893879B1 - Novel CDK inhibitory compounds, preparation method thereof, pharmaceutical composition for use in preventing or treating CDK relating diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel CDK inhibitory compound, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating a CDK-related disease containing the compound as an active ingredient. The novel CDK inhibitory compound, a stereoisomer or pharmaceutically acceptable salt thereof according to the present invention can excellently inhibit CDK (cyclin dependent kinase), is useful as a pharmaceutical composition for preventing or treating CDK-related diseases, and exhibits excellent disaster activity particularly in CDK 2 and CDK 5 to be usefully used as a pharmaceutical composition for cancer or neurodegenerative diseases, for example.

Description

TECHNICAL FIELD The present invention relates to a novel CDK inhibitory compound, a method for producing the same, and a pharmaceutical composition for preventing or treating CDK-related diseases containing the same as an active ingredient. the same as an active ingredient}

The present invention relates to a novel CDK inhibitory compound, a process for producing the same, and a pharmaceutical composition for preventing or treating CDK-related diseases containing the compound as an active ingredient.

Basic cellular processes such as cell division and gene transcription are regulated by cyclin-dependent serine / threonine kinases (CDKs). The activity of CDK is regulated by a high degree of association with specific cyclin regulatory subunits such as Cyclin A, Cyclin B, Cyclin C, Cyclin D, and Cyclin E. CDKs 1-4, 6, 10, and 11 are involved in each stage of cell division, and CDK 7-9 is involved in gene transcription by regulating RNA polymerase II.

The expression of each of these CDKs varies greatly depending on the specific stage of the cell cycle. CDK 1 complexing with cyclin A / B in mammalian cells regulates the progression from G2 to M phase, and CDK4 with cyclin D CDK 6 regulates the progression from G1-stage to S-phase to initiate DNA synthesis, CDK2 complexed with cyclin E / A completes the DNA synthesis process at the S-stage, and CDK 7-9 Complexes with cyclins H, C, and T regulate the basal transcription process.

CDK5, on the other hand, is activated by protein 35 (p35), its isomer p39, and its respective proteolytic fragments p25 and p29, unlike other CDKs that form complexes with cyclins. Activated CDK5 is a key function in the cortex's connection, survival, migration and development and is therefore associated with neurological diseases such as Alzheimer's disease and Parkinson's and Huntington's disease.

In addition, an abnormal change in the function of the cell cycle regulatory protein is characteristic of cancer development. Overexpression of CDK 1 is associated with an increased risk of cancer metastasis, and overexpression of CDK 2 is observed in more than 80% of cancers. Overexpression of CDK 4 and 6 is associated with poor prognosis of colorectal cancer, and CDK 5 activation is observed in various types of tumors including prostate and pancreatic cancer. In addition, CDK5 is involved in the expression of apoptotic ligand 1 (PD-L1), which induces immune tolerance in cancer cells.

Thus, the development of inhibitors targeting CDK enzymes has become an important research subject for CDK-related diseases and ultimately aims to develop drugs for the treatment of CDK-related diseases such as cancer or neurological diseases. However, until now, Only a palbociclib has been approved by the FDA (Patent Document 1), and a compound that still exhibits excellent inhibitory activity in the CDK family except for CDK 4 and 6 among CDKs, It is a situation that is required.

Accordingly, the present inventors have made efforts to develop a novel CDK inhibitor having excellent CDK inhibitory activity and preferably having a selective inhibitory activity against CDK 2 and CDK 5 among the CDK subfamily, and the novel CDK inhibition Compounds have excellent inhibitory activity against CDK 2 and CDK 5, and thus it can be usefully used for the prophylaxis or treatment of CDK-related diseases, particularly cancer and neurodegenerative diseases which are diseases associated with CDK 2 and CDK 5 Confirming that the present invention has been completed.

WO 2016030439 A1

It is an object of the present invention to provide novel CDK inhibitory compounds.

It is another object of the present invention to provide a method for producing the above CDK inhibitory compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating a CDK-related disease containing the CDK inhibitory compound as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing or ameliorating a CDK-related disease containing the CDK inhibitory compound as an active ingredient.

Another object of the present invention is to provide a method for treating, preventing or ameliorating a CDK-related disease comprising administering the CDK inhibitory compound to a subject in need of treatment.

In order to achieve the above object,

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ is substituted or unsubstituted C _3-10 cycloalkyl, substituted or unsubstituted C _3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, Substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted C _5-10 heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, substituted or unsubstituted C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, N, O, and substituted or unsubstituted ring containing at least one heteroatom selected from the group consisting of S _3- C ₁₀ heterocycloalkyl C _{1 -10} alkyl, a substituted or unsubstituted C _{6- 10} aryl C _{1 - 10} alkyl, or N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _5-10 heteroaryl C _{1 Lt; /} RTI >

Here, the cycle of the substituted C _3-10 alkyl, heteroaryl heterocycloalkyl substituted C _3-10 alkyl, aryl substituted C _6-10, a substituted C _5-10, optionally substituted C _{3- 10} cycloalkyl alkyl C _{1 - 10} alkyl, substituted C _{3- 10} heteroaryl cycloalkyl C _{1 - 10} alkyl, substituted C _{6- 10} aryl C _{1 - 10} alkyl and substituted C _5-10 heteroaryl C _1-10 alkyl is optionally substituted Or unsubstituted C _1-10 linear or branched alkyl, substituted or unsubstituted C _1-10 linear or branched alkoxy, halogen, cyano, hydroxy, phenyl, C _1-2 alkylphenyl, substituted or unsubstituted l, when, tert- butyloxycarbonyl (-Boc), amino, substituted or unsubstituted C _{1- 2} alkyl amino, substituted or unsubstituted di-C _{1 - 2} alkyl, amino, sulfonyl, C _{1 2} alkylsulfonyl, alkylsulfonyl C _{1 - 2} alkyl, amino-sulfonyl, C _{1- 2} alkyl aminosulfonyl and di-C _{1 -} at least one substitution is selected from the group consisting of _{2-alkylamino-sulfonyl} Fused with a ring which is optionally substituted, or selected from cycloalkyl, heterocycloalkyl, aryl, and the group consisting of C _5-10 heteroaryl C _6-10 of the C _3-10 of a C _3-10 (fused) And,

Here again, the substituted C during straight-chain or branched alkyl, straight-chain or branched alkoxy, substituted benzoxazole of the optionally substituted C _1-10 of _1-10, substituted C _{1- 2} alkyl amino, di-substituted C _{1 - 2} alkylamino is substituted with one or more substituents selected from the group consisting of -CF ₃ , hydroxy, oxo, cyano, and halogen;

R ² is a substituted or unsubstituted C _{3- 5} cycloalkyl alkylene or N, O, and substituted heteroatom containing at least one member selected from the group consisting of S, or unsubstituted C _{3- 5} hetero cycloalkylene However,

Wherein the substituted C _{3- 5} cycloalkyl, alkylene and substituted C _{3- 5} hetero cycloalkylene is hydroxyl, halogen, a C _1-3 linear or branched alkyl, and straight or branched C _1-3 of Lt; / RTI >alkoxy; And

R ³ is hydroxy, triisopropyl room yloxy (-OTIPS), straight or branched chain C _1-10 alkoxy, carboxy, C _{1- 2} alkyl, ^{carboxy, -NH-CO-R 4,} -NH-R 4 ^{, -CO-NH-R 4,} -CO-R 4, -NH-CO-R 4 -CO-NH-R 5, -CO-NH-R 4 -CO-NH-R 5, -NH-CO- R ⁴ -NH-CO-R ⁵ , or -CO-NH-R ⁴ -NH-CO-R ⁵ ,

Wherein R ⁴ and R ⁵ are each independently a substituted or unsubstituted C _3-10 cycloalkyl, a substituted or unsubstituted alkylene group containing at least one heteroatom selected from the group consisting of N, O, and S, heterocycloalkyl, substituted or unsubstituted aryl of _6-10 ring C of _3-10 C, N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _5-10 ring a heteroaryl, a substituted or unsubstituted C _{3- 10} cycloalkyl, C _{1 -10} alkyl, N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _{3- 10} ring heterocycloalkyl C _{1 - 10} alkyl, substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S or unsubstituted _Gt; C10 < / RTI > heteroaryl Ci- ₁₀ alkyl,

Here again, the substituted C _3-10 cycloalkyl, of aryl heterocycloalkyl, substituted C _6-10 substituted C _3-10, substituted C _5-10 heteroaryl, substituted C _{3- 10} cycloalkyl C _{1 -10} alkyl, substituted C _{3- 10} heteroaryl cycloalkyl C _{1 - 10} alkyl, substituted C _{6- 10} aryl C _{1 - 10} alkyl and substituted C _5-10 heteroaryl C _1-10 alkyl is Substituted or unsubstituted C _1-10 straight-chain or branched alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, halogen, cyano, hydroxy, phenyl, C _1-2 alkylphenyl, substituted or unsubstituted l, when, tert- butyloxycarbonyl (-Boc), amino, substituted or unsubstituted C _{1- 2} alkyl amino, substituted or unsubstituted di-C _{1 - 2} alkyl, amino, sulfonyl, C _1-2 alkylsulfonyl, alkylsulfonyl C _{1 - 2} alkyl, amino-sulfonyl, C _{1- 2} alkyl aminosulfonyl and di-C _{1 -} at least one value selected from the group consisting of _{2-alkylamino-sulfonyl} Or substituted by group, or a C _3-10 cycloalkyl, fused with a ring selected from heterocycloalkyl, aryl, and the group consisting of C _5-10 heteroaryl C _6-10 of the C _3-10 (fused ),

Again here, the substituted C _1-10 straight or branched chain alkyl, when a straight-chain or branched-chain alkoxy, substituted benzoxazole of the optionally substituted C _1-10, substituted C _{1- 2} alkyl amino, di-substituted C _{1 - 2} alkylamino is substituted with one or more substituents selected from the group consisting of -CF ₃ , hydroxy, oxo, cyano, and halogen.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with 6-chloropurine to prepare a compound represented by the formula (3) (step 1);

Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2); And

Reacting a compound represented by the general formula (4) and R ¹ -NH ₂ represented by the general formula (5) to produce a compound represented by the general formula (1) (step 3) A method for producing the compound is provided.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , and R ³ are as defined in Formula 1;

B is -OTIPS or -NHBoc.

Further, the present invention provides a pharmaceutical composition for preventing or treating cancer or neurodegenerative disease containing the compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food for preventing or ameliorating cancer or a neurodegenerative disease containing the compound represented by the above-mentioned formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel CDK inhibitory compound, its stereoisomer or pharmaceutically acceptable salt thereof according to the present invention can excellently inhibit CDK (cyclin dependent kinase), and is useful as a pharmaceutical composition for preventing or treating CDK-related diseases, And exhibits excellent disaster activity particularly in CDK 2 and CDK 5, and can be usefully used as a pharmaceutical composition for cancer or neurodegenerative diseases, for example.

Hereinafter, the present invention will be described in detail.

The following description is provided to assist the understanding of the invention, and the present invention is not limited to the following description.

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ is substituted or unsubstituted C _3-10 cycloalkyl, substituted or unsubstituted C _3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, Substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted C _5-10 heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, substituted or unsubstituted C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, N, O, and substituted or unsubstituted ring containing at least one heteroatom selected from the group consisting of S _3- C ₁₀ heterocycloalkyl C _{1 -10} alkyl, a substituted or unsubstituted C _{6- 10} aryl C _{1 - 10} alkyl, or N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _5-10 heteroaryl C _{1 Lt; /} RTI >

Here, the cycle of the substituted C _3-10 alkyl, heteroaryl heterocycloalkyl substituted C _3-10 alkyl, aryl substituted C _6-10, a substituted C _5-10, optionally substituted C _{3- 10} cycloalkyl alkyl C _{1 - 10} alkyl, substituted C _{3- 10} heteroaryl cycloalkyl C _{1 - 10} alkyl, substituted C _{6- 10} aryl C _{1 - 10} alkyl and substituted C _5-10 heteroaryl C _1-10 alkyl is optionally substituted Or unsubstituted C _1-10 linear or branched alkyl, substituted or unsubstituted C _1-10 linear or branched alkoxy, halogen, cyano, hydroxy, phenyl, C _1-2 alkylphenyl, substituted or unsubstituted l, when, tert- butyloxycarbonyl (-Boc), amino, substituted or unsubstituted C _{1- 2} alkyl amino, substituted or unsubstituted di-C _{1 - 2} alkyl, amino, sulfonyl, C _{1 2} alkylsulfonyl, alkylsulfonyl C _{1 - 2} alkyl, amino-sulfonyl, C _{1- 2} alkyl aminosulfonyl and di-C _{1 -} at least one substitution is selected from the group consisting of _{2-alkylamino-sulfonyl} Fused with a ring which is optionally substituted, or selected from cycloalkyl, heterocycloalkyl, aryl, and the group consisting of C _5-10 heteroaryl C _6-10 of the C _3-10 of a C _3-10 (fused) And,

Here again, the substituted C during straight-chain or branched alkyl, straight-chain or branched alkoxy, substituted benzoxazole of the optionally substituted C _1-10 of _1-10, substituted C _{1- 2} alkyl amino, di-substituted C _{1 - 2} alkylamino is substituted with one or more substituents selected from the group consisting of -CF ₃ , hydroxy, oxo, cyano, and halogen;

R ² is a substituted or unsubstituted C _{3- 5} cycloalkyl alkylene or N, O, and substituted heteroatom containing at least one member selected from the group consisting of S, or unsubstituted C _{3- 5} hetero cycloalkylene However,

Wherein the substituted C _{3- 5} cycloalkyl, alkylene and substituted C _{3- 5} hetero cycloalkylene is hydroxyl, halogen, a C _1-3 linear or branched alkyl, and straight or branched C _1-3 of Lt; / RTI >alkoxy; And

R ³ is hydroxy, triisopropyl room yloxy (-OTIPS), straight or branched chain C _1-10 alkoxy, carboxy, C _{1- 2} alkyl, ^{carboxy, -NH-CO-R 4,} -NH-R 4 ^{, -CO-NH-R 4,} -CO-R 4, -NH-CO-R 4 -CO-NH-R 5, -CO-NH-R 4 -CO-NH-R 5, -NH-CO- R ⁴ -NH-CO-R ⁵ , or -CO-NH-R ⁴ -NH-CO-R ⁵ ,

Wherein R ⁴ and R ⁵ are each independently a substituted or unsubstituted C _3-10 cycloalkyl, a substituted or unsubstituted alkylene group containing at least one heteroatom selected from the group consisting of N, O, and S, heterocycloalkyl, substituted or unsubstituted aryl of _6-10 ring C of _3-10 C, N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _5-10 ring a heteroaryl, a substituted or unsubstituted C _{3- 10} cycloalkyl, C _{1 -10} alkyl, N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _{3- 10} ring heterocycloalkyl C _{1 - 10} alkyl, substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S or unsubstituted _Gt; C10 < / RTI > heteroaryl Ci- ₁₀ alkyl,

Here again, the substituted C _3-10 cycloalkyl, of aryl heterocycloalkyl, substituted C _6-10 substituted C _3-10, substituted C _5-10 heteroaryl, substituted C _{3- 10} cycloalkyl C _{1 -10} alkyl, substituted C _{3- 10} heteroaryl cycloalkyl C _{1 - 10} alkyl, substituted C _{6- 10} aryl C _{1 - 10} alkyl and substituted C _5-10 heteroaryl C _1-10 alkyl is Substituted or unsubstituted C _1-10 straight-chain or branched alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, halogen, cyano, hydroxy, phenyl, C _1-2 alkylphenyl, substituted or unsubstituted l, when, tert- butyloxycarbonyl (-Boc), amino, substituted or unsubstituted C _{1- 2} alkyl amino, substituted or unsubstituted di-C _{1 - 2} alkyl, amino, sulfonyl, C _1-2 alkylsulfonyl, alkylsulfonyl C _{1 - 2} alkyl, amino-sulfonyl, C _{1- 2} alkyl aminosulfonyl and di-C _{1 -} at least one value selected from the group consisting of _{2-alkylamino-sulfonyl} Or substituted by group, or a C _3-10 cycloalkyl, fused with a ring selected from heterocycloalkyl, aryl, and the group consisting of C _5-10 heteroaryl C _6-10 of the C _3-10 (fused ),

Again here, the substituted C _1-10 straight or branched chain alkyl, when a straight-chain or branched-chain alkoxy, substituted benzoxazole of the optionally substituted C _1-10, substituted C _{1- 2} alkyl amino, di-substituted C _{1 - 2} alkylamino is substituted with one or more substituents selected from the group consisting of -CF ₃ , hydroxy, oxo, cyano, and halogen.

Preferably, the compound is a compound represented by the following formula (2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

(2)

In Formula 2,

R ¹ and R ³ are as defined in claim 1,

A is a carbon or nitrogen atom.

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Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

(1) (lr, 3r) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanol;

(2) (ls, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanol;

(3) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide;

(4) 6-Methyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(5S) -3- (6- (1- (methylsulfonyl) piperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) Picolinamide;

(6) N - ((1s, 3s) -3- (6- (3-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(7S) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutylcarbamoyl) pyrrolidine- Rate;

(8) N - ((1 s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) pyrrolidine-2-carboxamide;

(9) 1- (Methylsulfonyl) -N - ((1S, 3S) -3- (6- (pyridin- 3- ylmethylamino) -9H- purin-9- yl) cyclobutyl) piperidin- 4-carboxamide;

(10) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) morpholine-4-carboxamide;

(11) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) nicotinamide;

(12) N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) isonicotinamide;

(13) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) pyrazine-2-carboxamide;

(14) Synthesis of 1-methyl-N - ((ls, 3s) -3- (6- (pyridin- 3- ylmethylamino) -9H- purin- amides;

(15) 2-Phenyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide;

(16) 2-Cyclohexyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide;

(17) Synthesis of N - ((1 s, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H- purin-9-yl) cyclobutyl) -tetrahydro- amides;

(18) N - ((1 s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(19) 4-Methoxy-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(20) N - ((1s, 3s) -3- (6- (3-chlorophenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(21) N - ((1s, 3s) -3- (6- (3-fluorophenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(22) N - ((1 s, 3s) -3- (6- (4-methoxyphenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(23) 2,6-Dichloro-N - ((ls, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(24) 2,3-Dichloro-N - ((ls, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(25) 2,6-Difluoro-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(26) 4-Chloro-2-methoxy-N - ((ls, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(27) (lr, 3r) -Methyl 3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxylate;

(28) (lr, 3r) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxylic acid;

(29) N-phenyl-3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxamide;

(30) 6-Methyl-N - ((1s, 3s) -3- (6- (naphthalen-1-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(31) N - ((1 s, 3s) -3- (6- (4-cyanobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(32) N - ((1 R, 3S) -3- (6 - ((S) -2-hydroxy- 1 -phenylethylamino) -9H- purin-9-yl) cyclobutyl) Choline amide;

(33) N - ((1S, 3S) -3- (6 - ((R) -2-hydroxy-2- phenylethylamino) -9H- purin-9-yl) cyclobutyl) Choline amide;

(34) Synthesis of N- (1- (methylsulfonyl) piperidin-4-yl) -3- (6- (pyridin- 3- ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxamide ;

(35) 1-Methyl-N - ((ls, 3s) -3- (6- (pyridin- 3- ylmethylamino) -9H- purin- Carboxamide;

(36) 6-Methyl-N - ((ls, 3s) -3- (6- (pyridin-2-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(37) 6-Methyl-N - ((ls, 3s) -3- (6- (2-methylbenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(38) N - ((1 s, 3s) -3- (6- (2-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(39) N - ((1s, 3s) -3- (6- (2-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(40) N - ((1s, 3s) -3- (6- (2-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(41) 6-Methyl-N - ((1s, 3s) -3- (6- (3- (trifluoromethyl) benzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(42) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(43) N - ((1 s, 3s) -3- (6- (4- (Dimethylamino) benzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(44) 6-Methyl-N - ((ls, 3s) -3- (6- (pyridin-4-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(45) 6-Methyl-N - ((lS, 3s) -3- (6- (4- (trifluoromethyl) benzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(46) 6-Methyl-N - ((1s, 3s) -3- (6- (4- (trifluoromethoxy) benzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(47) N - ((1 s, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(48) 6-Methyl-N - ((ls, 3s) -3- (6- (4-sulfamoylbenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(49) N - ((1s, 3s) -3- (6- (Cyclohexylmethylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(50) N - ((1 S, 3S) -3- (6 - ((2,3-dihydrobenzo [b] [1,4] dioxin- 2- yl) methylamino) -9H- -Yl) cyclobutyl) -6-methylpicolinamide;

(51) 3,5-Dimethyl-N - ((ls, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(52) 3,4-Dimethyl-N - ((ls, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(53) 3- (dimethylamino) -N - ((1s, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;

(54) N - ((1s, 3s) -3- (6- (4-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(55) N - ((lr, 3r) -3- (6- (4-bromobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(56) N - ((lr, 3r) -3- (6- (3-bromobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(57) N - ((1 r, 3r) -3- (6- (2,4-dimethoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(58) N - ((lr, 3r) -3- (6- (3,4-Dimethoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(59) N - ((lr, 3r) -3- (6- (3-hydroxy-4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(60) N - ((lr, 3r) -3- (6- (4-hydroxy-3-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(61) N - ((lr, 3r) -3- (6- (3-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6- methoxypicolinamide;

(62) 6-Methoxy-N - ((lr, 3r) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(63) 6-Chloro-N - ((lr, 3r) -3- (6- (3-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(64) 6-Methyl-N - ((ls, 3s) -3- (6- (2-phenylacetamido) -9H-purin-9-yl) cyclobutyl) picolinamide;

(65) 6-Methyl-N - ((1s, 3s) -3- (6- (4-phenoxybenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(66) N - ((1 s, 3s) -3- (6- (4- (4-fluorophenoxy) benzylamino) -9H- purin-9-yl) cyclobutyl) -6-methylpicolinamide ;

(67) N - ((1 s, 3s) -3- (6- (3,5-Dichloro-4-methoxybenzylamino) -9H- purin-9- yl) cyclobutyl) -6- methylpicolinamide ;

(68) N - ((1s, 3s) -3- (6- (3-Bromo-4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(69) N - ((1s, 3s) -3- (6- (4- (Benzyloxy) benzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(70) N - ((1s, 3s) -3- (6- (4-Isopropoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(71) (6-Methylpyridin-2-yl) (3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) azetidin-1-yl) methanone;

(72) (3- (6- (3-Chlorobenzylamino) -9H-purin-9-yl) azetidin-1-yl) (6-methylpyridin-2-yl) methanone;

(73) (3- (6- (3-Bromobenzylamino) -9H-purin-9-yl) azetidin-1-yl) (6-methylpyridin-2-yl) methanone;

(74) N - ((1s, 3s) -3- (6- (3,4-Difluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(75) N - ((1s, 3s) -3- (6- (3,4-Dichlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(76) tert -Butyl 4- (9- (ls, 3s) -3- (6-methylpicolinamido) cyclobutyl) -9H-purin-6-ylamino) piperidine- ;

(77) tert-Butyl 4 - ((9 - ((1 s, 3s) -3- (6-methylpicolinamido) cyclobutyl) -9H- purin- - carboxylate;

(78) 6-Methyl-N - ((ls, 3s) -3- (6- (piperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride;

(79) 6-Methyl-N - ((ls, 3s) -3- (6- (piperidin-4-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride;

(80) N - ((lr, 3r) -3- (6- (3-bromobenzylamino) -9H-purin-9-yl) cyclobutyl) benzo [d] thiazol-2-amine;

(81) 6-Methyl-N - ((ls, 3s) -3- (6- (l -methylpiperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(82) N - ((1 s, 3s) -3- (6 - ((1 r, 4r) -4- hydroxycyclohexylamino) -9H- purin- 9- yl) cyclobutyl) -6- amides;

(83) tert -Butyl 3- (9 - ((ls, 3s) -3- (6-methylpicolinamido) cyclobutyl) -9H- purin-6-ylamino) pyrrolidine- ;

(84) 6-Methyl-N - ((ls, 3s) -3- (6- (pyrrolidin-3-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride;

(85) N - ((1 s, 3s) -3- (6- (1-Acetylpiperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(86) 6-Methyl-N - ((ls, 3s) -3- (6- (1- (2-phenylacetyl) piperidin- 4- ylamino) -9H- purin- ) Picolinamide;

(87) N - ((1 s, 3s) -3- (6 - ((1 s, 4s) -4- acetamidocyclohexylamino) -9H- purin- Choline amide;

-9H-purin-9-yl) cyclobutyl) -6-methylpiperazin-1-ylmethoxy) - N - ((1S, 3S) -3- (6- ( Choline amide;

(89) N2- (4S, 3S) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) , 6-dicarboxamide;

(90) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-cyanopicolinamide;

(91) N - ((1s, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-phenylpicolinamide;

(92) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-phenylpicolinamide;

(93) 6-Phenyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(94) 6-Ethyl-N - ((ls, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(95) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-ethylpicolinamide;

(96) N - ((ls, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6- (trifluoromethyl) picolinamide;

(97) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6- (trifluoromethyl) picolinamide;

(98) N - ((ls, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -2-methylthiazole-4-carboxamide;

(99) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -2-methylthiazole-4-carboxamide;

(100) N - ((1 s, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9- yl) cyclobutyl) -6- (trifluoromethyl) picolinamide ;

(101) 6-Methyl-N - ((ls, 3s) -3- (6- (pyridin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;

(102) N - ((1s, 3s) -3- (6- (3-methoxyphenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;

(103) N - ((1s, 3s) -3- (6- (3-chlorophenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide; And

(104) N - ((1 s, 3s) -3- (6- (3,4-Dimethoxyphenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by Formula 1 and pharmaceutically acceptable salts thereof.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with 6-chloropurine to prepare a compound represented by the formula (3) (step 1);

Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2); And

Reacting a compound represented by the general formula (4) and R ¹ -NH ₂ represented by the general formula (5) to produce a compound represented by the general formula (1) (step 3) A method for producing the compound is provided.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , and R ³ are as defined in Formula 1;

B is -OTIPS or -NHBoc.

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In the process for preparing a compound represented by the formula (1) according to the present invention, step 1 of Scheme 1 is a step of reacting a compound represented by the formula (2) with 6-chloropurine to prepare a compound represented by the formula (3).

At this time, step 1 is a step of introducing R ² substituent into purine, which is the parent compound of the compound of the present invention, and performing Mitsunobu reaction. Step 1 may be carried out by, for example, but not limited to, using triphenylphosphine, DIAD (diisopropyl azodicarboxylate), or the like. Alternatively, step 1 may be selectively used. The reaction temperature is not particularly limited, but may be preferably carried out at 0 ° C to 100 ° C, and as another example, the reaction may be carried out at 0 ° C to 20 ° C to 100 ° C. The reaction time is not limited thereto, but can be set to, for example, 2 hours to 10 hours. As another example, if heating is carried out, the temperature is raised for 20 minutes to 2 hours to the optimum temperature, Lt; / RTI > while maintaining the temperature.

On the other hand, the solvent used in the reaction is preferably THF, and other possible examples include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, Naphthalene-2-sulphonate, mandelate, and naphthalene-2-sulphonate, and salts and esters thereof, such as phenylbutyrate, chitrate, lactate, A mixture thereof, and it is preferable to use dimethylformamide (DMF).

In the process for preparing the compound represented by the general formula (1) according to the present invention, the step 2 of the above reaction scheme 1 is a step for preparing the compound represented by the general formula (4) from the compound represented by the general formula (3)

In this case, step 2 can be understood as a step of introducing an R ³ substituent, and a protective group may be removed from a substituent represented by B in the formula 1, and then R ³ may be selectively removed depending on the desired compound Can be introduced. For example, but not limited thereto, when B is NHBoc, the protecting group is first removed, and then various carboxylic acid derivatives are reacted with PyBOP and DIPEA to obtain the desired amide substituent.

The reaction time and the reaction temperature of the above step 2 are included in the scope of the present invention without limitation as long as those skilled in the art can easily change the reaction time and the reaction temperature with reference to the following examples. It is to be understood that the present invention is not limited as long as the conditions under which the compound to be displayed can be produced are included in the scope of the present invention. By way of one example, the reaction time may preferably be 1 to 5 hours, and the reaction temperature may be carried out at 20 to 40 ° C.

On the other hand, the solvent used in the reaction may preferably be DCM, and other possible examples include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, Naphthalene-2-sulphonate, mandelate, and naphthalene-2-sulphonate, and salts and esters thereof, such as phenylbutyrate, chitrate, lactate, A mixture thereof, and it is preferable to use dimethylformamide (DMF).

In the process for preparing a compound represented by the general formula (1) according to the present invention, in the step 3 of the above reaction scheme 1, the compound represented by the general formula (4) prepared in the above step 2 is reacted with R ¹ -NH ₂ represented by the general formula 1 < / RTI >

The reaction time and the reaction temperature of step 3 can be understood as the step of introducing the R ¹ substituent in the step 3, and the reaction time and the reaction temperature of the step 3 are not limited as far as they can be easily changed by those skilled in the art with reference to the following examples. Is included in the scope of the invention and is not particularly limited as long as the compound represented by the formula (1) desired to be produced in the step 3 can be produced, it should be understood that the compound is included in the scope of the present invention. By way of one example, preferably, the reaction time can be 1 to 10 hours, and the reaction temperature can be performed at 70 to 130 ° C. As a non-limiting example, R ¹ -NH ₂ may be first mixed with a solvent and then refluxed and reacted with the compound represented by Formula 4 to produce the desired compound of Formula 1.

On the other hand, the solvent used in the reaction may preferably be DCM, and other possible examples include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, Naphthalene-2-sulphonate, mandelate, and naphthalene-2-sulphonate, and salts and esters thereof, such as phenylbutyrate, chitrate, lactate, A mixture thereof, and it is preferable to use dimethylformamide (DMF).

Meanwhile, the compound represented by the formula (2), which is the starting compound in the step 1 of Scheme 1, can be prepared, for example, by following the reaction scheme 2 or the scheme 3:

[Reaction Scheme 2]

[Reaction Scheme 3]

Specific description of each of the above Reaction Formula 2 or Reaction Formula 3 can be explained as Production Example 1 and Production Example 3 of the present invention.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a CDK-related disease, which comprises the compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition may further comprise at least one compound selected from the group consisting of the compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is a novel CDK inhibitory compound of the present invention, which inhibits cyclin dependent kinase (CDK) And exhibits an effect of preventing or treating CDK-related diseases.

Specifically, the CDK subfamily exhibits cell cycle and various regulatory functions, and Table 1 below shows the function of each CDK 1-9.

Combined object In the cell cycle
function Warrior function Other features CDK 1 Cycline B Mitosis
mitosis + Stem cell self-renewal DNA damage recovery Epigenetic regulation
epigenetic regulation, CDK 2 Cycline E G1 / S transition + Stem cell self-renewal Cyclinea S phase Epigenetic regulation
epigenetic regulation, CDK 3 Cycline C G1 phase + DNA damage recovery CDK 4 Cycline D G1 phase Epigenetic regulation
epigenetic regulation, CDK 5 p35 Non-cell cycle function + Nerve function Epigenetic regulation
epigenetic regulation, Glycogen synthesis Insulin secretion CDK 6 Cyclin D G1 phase CDK 7 Cyclin H CDK-activation + CDK 8 CyclinC Multistage Control + Wnt / B-catenin signaling Inhibition of fat formation CDK 9 Cyclin T, K + (Cyclin T) DNA damage repair (cyclin K)

As long as the disease identified as being capable of alleviating, preventing or treating the disease state from inhibiting overexpression of CDK function identified in Table 1 above, the compound represented by Formula 1 of the present invention, its stereoisomer or its It should be understood that it is a CDK-related disease that can be prevented or treated with a pharmaceutically acceptable salt, and this is included in the scope of the present invention.

Preferably, the CDK-related disease is cancer or a neurodegenerative disease,

The present invention provides a pharmaceutical composition for preventing or treating cancer or a neurodegenerative disease.

The compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof may be used for preventing or treating cancer or neurodegenerative disease by inhibiting cyclin dependent kinase (CDK) The compositions may be used for the prophylaxis or treatment of cancer or neurodegenerative diseases.

Specifically, the cancer may be selected from the group consisting of a malignant myxoma, an intrahepatic bile duct cancer, a hepatoblastoma, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a myelodysplastic syndrome, a glioblastoma, a oral cancer, a laryngeal carcinoma, a bacterial sarcoma, an acute lymphoblastic leukemia, The present invention relates to a method of treating a cancer selected from the group consisting of cancer, ovarian cancer, ovarian cancer, ovarian cancer cell line, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Papillary carcinoma, papillary cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, stomach cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Neuroblastoma, neuroblastoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovary, vulvar cancer, ureter Cancer of the uterus, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, , Metastatic brain cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acne vulgaris, pancreatic cancer, salivary cancer, Kaposi sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung cancer, Epithelial cell cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma; And

Such neurodegenerative diseases include, but are not limited to, alcoholism, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, HIV-associated dementia, Alzheimer's disease, Alzheimer's disease, Lewy body dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, Argyrophilic Grain Disease, peak disease, amyotrophic lateral sclerosis (ALS) ), C-type Niemann-Pick Type C (NPC) and epilepsia, multiple sclerosis (MS), muscular dystrophy (MD) and hereditary frontotemporal dementia .

The present invention also provides a health functional food for preventing or ameliorating a CDK (cyclin dependent kinase) -related disease, which comprises the compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Preferably, the CDK-related disease is cancer or a neurodegenerative disease,

The compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof may prevent or treat a cancer or a neurodegenerative disease by inhibiting cyclin dependent kinase (CDK) and may be used as a health component Food can be used for the prevention or amelioration of cancer or neurodegenerative diseases.

Specifically, the cancer may be selected from the group consisting of a malignant myxoma, an intrahepatic bile duct cancer, a hepatoblastoma, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a myelodysplastic syndrome, a glioblastoma, a oral cancer, a laryngeal carcinoma, a bacterial sarcoma, an acute lymphoblastic leukemia, The present invention relates to a method of treating a cancer selected from the group consisting of cancer, ovarian cancer, ovarian cancer, ovarian cancer cell line, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Papillary carcinoma, papillary cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, stomach cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Neuroblastoma, neuroblastoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovary, vulvar cancer, ureter Cancer of the uterus, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, uterine sarcoma, , Metastatic brain cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acne vulgaris, pancreatic cancer, salivary cancer, Kaposi sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung cancer, Epithelial cell cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma; And

Such neurodegenerative diseases include, but are not limited to, alcoholism, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, HIV-associated dementia, Alzheimer's disease, Alzheimer's disease, Lewy body dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, Argyrophilic Grain Disease, peak disease, amyotrophic lateral sclerosis (ALS) ), C-type Niemann-Pick Type C (NPC) and epilepsia, multiple sclerosis (MS), muscular dystrophy (MD) and hereditary frontotemporal dementia .

Meanwhile, the compound represented by the formula (1) according to the present invention can be administered in various formulations of oral and parenteral administration at the time of clinical administration, and when it is formulated, it is possible to use a compound such as fillers, extenders, binders, wetting agents, , ≪ / RTI > and the like.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.

Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on adult patients weighing 70 kg, and may be administered once a day It may be divided into several doses.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following Production Examples, Examples and Experimental Examples are illustrative of the present invention, and the contents of the present invention are not limited thereto.

< Manufacturing example  1> ( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Of cyclobutanol  Produce

Step 1: ( 1r, 3r ) -3 - (( Triisopropylsilyl ) Oxy ) Cyclobutane -1-ol

A cyclobutyl derivative of trans was synthesized first to prepare a cis-form of cyclopentyl group at the 9th nitrogen of Purine using the Mitsunobu reaction.

Specifically, the cyclobutyl derivative of trans produced compound b using benzyl bromide and mercuric chloride, compound a, and compound c using methyl ((methylsulfanyl) methyl) sulfan and n-BuLi. Then, a ketone compound d was prepared using HClO ₄ and reduced with NaBH ₄ to obtain an alcohol compound e. Compound (f) was obtained by replacing the alcohol compound e with TIPSCl (triisopropyl chloride) by OTIPS (triisopropyloxy) protecting group to remove benzyl group by using 10% Pd / C and hydrogen gas and formic acid Respectively. Compound h was then obtained through a Mitsunobu reaction using p-nitrobenzoic acid, tri-phenylphosphine, and diethylazodicarboxylate (DEAD). The final target compound i was then obtained using K ₂ CO ₃ .

Compound b: 1H NMR (300 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 4.67 (s, 2H), 3.85-3.78 (m, 1H), 3.59 (d, J = 1.6 Hz, 2H), 3.57 (d, J = 1.6 Hz, 2H); LCMS (OT / Z) 309.1 (M + H) +;

Compound c: 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 4.46 (d, J = 3.6 Hz, 2H), 4.38-4.07 (m, 1H), 2.78-2.14 (m, 4H) , 2.43 (s, 3 H), 2.11 (s, 3 H); LCMS (m / z) 271.1 (M + H) &lt; + &gt;;

Compound d: 1 H NMR (300 MHz, CDCl 3)? 7.40-7.29 (m, 5H), 4.56 (s, 2H), 4.92-4.34 (m, 1H), 3.29-3.10 (m, 4H); LCMS (m / z) 177.1 (M + H) &lt; + &gt;;

Compound e: 1H NMR (300 MHz, CDCl3)? 7.37-7.26 (m, 5H), 4.42 (s, 2H), 3.96-3.87 m, 2 H), 1.98-1.89 (m, 2 H); LCMS (m / z) 179.1 (M + H) &lt; + &gt;;

Compound f: 1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 5H), 4.41 (s, 2H), 3.97-3.87 (m, 1H), 3.62-3.53 (m, 1H), 2.68-2.60 ( m, 2H), 2.02-1.96 (m, 2H), 1.05 (s, 3H), 1.03 (br s, 18H); LCMS (m / z) 335.1 (M + H) &lt; + &gt;;

Compound g: 1H NMR (300 MHz, CDCl3)? 3.93-3.77 (m, 2H), 2.77-2.69 (m, 2H), 1.95-1.86 , &Lt; / RTI &gt; 3H), 1.02 (s, 18H); LCMS (m / z) 245.1 (M + H) &lt; + &gt;;

Compound h: 1H NMR (300 MHz, CDCl3) δ 8.29-8.27 (m, 2H), 8.23-8.21 (m, 2H), 5.42-5.38 (m, 1H), 4.71-4.66 (m, 1H), 2.59- 2.48 (m, 4 H), 1.06 (s, 3 H), 1.05 (s, 18 H); LCMS (m / z) 394.1 (M + H) &lt; + &gt;; And

Compound i: 1H NMR (300 MHz, CDCl3) δ 4.67-4.58 (m, 1H), 4.54-4.46 (m, 1H), 2.24 (t, J = 5.1 Hz, 4H), 1.03 (s, 18H), 1.02 (s, 3 H); LCMS (m / z) 245.1 (M + H) &lt; + &gt;.

Step 2: ( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Of cyclobutanol  Produce

Compound j was obtained from compound i prepared in the above step 1 and Mitsunobu reaction using 6-chloropurine, triphenylphosphine and diisopropylazodicarboxylate, and using 3-picolylamine Compound k was obtained. Here, the protecting group TIPS was removed by using TBAF (Tetrabutylammonium fluoride) to prepare the alcohol compound 1 as the final target compound.

Specifically, compound k (24.6 mg, 0.054 mmol) and 2 mL of THF were added to a 7 mL vial and dissolved. Then 1.0 M TBAF in THF (0.082 mL, 0.082 mmol) was added and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction using TLC, the solvent was removed using a rotary condenser, and the final target compound 1 was obtained as a white solid (12 mg, 75%) using Prep TLC (DCM: MeOH = 20: 1).

Compound l: 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.51 (d, J = 4.4 Hz, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 7.6 Hz, 4.4 Hz), 6.44 (t, J = 5.6 Hz, 1H), 4.90 (s, 2H), 4.60-4.49 4.24 (m, 1H), 3.08-3.00 (m, 2H), 2.47-2.37 (m, 2H); LCMS (m / z) 297.1 (M + H) &lt; ⁺ & gt ^; .

< Manufacturing example  2> ( 1r, 3r ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Of cyclobutanol  Produce

From the compound g which is the cis cyclobutyl derivative prepared in the intermediate step of the above-mentioned Step 1 of Preparation Example 1, the same procedure as in Step 2 of Preparation Example 1 was repeated using the Mitsunobu reaction to convert the cyclobutyl group into trans Lt; / RTI &gt;

< Manufacturing example  3 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Cyclobutyl ) Preparation of acetamide

Step 1: tert -Butyl (3-hydroxycyclobutyl) carbamate &lt; / RTI &gt;

Compound r was obtained through a three-step reaction using SOCl ₂ , NaN ₃ , and t-BuOH as a starting material, compound q. Thereafter, the compound s was reduced by using alcohol with L-Selectride to obtain a compound t, followed by the compound t using p-nitrobenzoic acid, triphenylphosphine and DEAD. This was reacted again with K ₂ CO ₃ to give compound u.

Specifically, compound t (624 mg, 1.85 mmol) was dissolved in methanol (14 mL), and K ₂ CO ₃ (99 mg, 0.72 mmol) was added. After stirring for 9 hours at room temperature and washing the organic layer with water and ethyl acetate, the excess water was removed with anhydrous sodium sulfate and the final objective compound u was obtained as a white solid using column chromatography (426 mg, 98 %).

Compound (u): 1H NMR (300 MHz, CDCl3)? 6.43 (br s, IH), 4.49 (s, IH), 3.79 (s, IH), 2.32-2.30 ), 1.48 (s, 9H); LCMS (m / z) 188.1 (M + H) &lt; + &gt;.

Step 2: N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Cyclobutane Yl) acetamide &lt; / RTI &gt;

The compound u prepared in the above step 1 was treated with 4M HCl in dioxane to obtain the hydrochloride compound v from which the protecting group Boc was removed. Thereafter, the amide compound w was prepared using PyBOP, which is a coupling agent. At this time, various reactions were conducted using EDC, HOBt, HATU, HOBt, HOAt and T3P, Yield was the best). The CDK inhibitory compound of the present invention was prepared by introducing various amines into the prepared compound w (the x 'was prepared in the above figure and finally the CDK inhibitory compound was prepared as the y' compound). For example, , And then reacted with acetic anhydride, TEA and DCM to prepare compound x, and then 3-picolylamine was reacted in ethanol at 90 ° C for 3 hours to obtain N - ((1s , 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide. In this way, CDK inhibitory compounds having various amines introduced therein were prepared as in the following examples.

Compound y: 1H NMR (300 MHz, CDCl3) δ 8.68 (br s, 1H), 8.55 (s, 1H), 8.44 (br s, 1H), 7.22 (s, 1H), 6.79 (s, 1H), 6.22 (m, 2H), 2.95-2.74 (m, 2H), 2.07 (m, IH), 4.93 (s, 3 H); LCMS (m / z) 338.1 (M + H) &lt; + &gt;.

A general method for producing a general CDK inhibitory compound according to the present invention as described in Preparation Example 3 will be described.

First, a carboxylic acid compound containing a substituent to be finally introduced into a round bottom flask is added and dissolved in DCM. Add DIPEA and PyBOP and stir for 5 minutes. (1 eq., 0.076 mmol), carboxylic acid compound (1 eq., 0.076 mmol), DIPEA (2.7 eq., 0.207 mmol), and the mixture was stirred at -78 & ), PyBOP (1.3 eq, 0.099 mmol), DCM 5 mL). After stirring for 2 hours at room temperature and confirming the completion of the reaction using TLC and LC-MS, the reaction is terminated by adding water. Thereafter, the organic layer is extracted at least twice using a funnel for separating the aqueous solution of baking soda and dichloromethane, and then the water is completely removed using magnesium sulfate, and the filtrate is concentrated under reduced pressure, and an amide compound is prepared by using column chromatography.

In the next step, the amide compound prepared above is added to a round bottom flask and dissolved in EtOH. The amine compound to be substituted is then added (amide compound x '(1 eq, 0.03 mmol), amine compound (2 eq, 0.06 mmol), ethanol 1 mL). And refluxed while heating at 90 占 폚 for 3 hours. After confirming the termination of the reaction using TLC and LC-MS, the flask was cooled at room temperature, and then the organic layer was extracted twice or more with a separating funnel of water and ethyl acetate, and an excess of water was removed using anhydrous sodium sulfate , Concentrated under reduced pressure, and then subjected to column chromatography to prepare a compound y 'which is the final desired CDK inhibiting compound.

Based on the above-described Production Example 1, Production Example 2, Production Example 3 and a method equivalent thereto, the following CDK inhibitory compounds of each of the following Examples 1-134 were produced and shown in Examples 1 to 134 described below.

< Example  1> ( 1r, 3r ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Of cyclobutanol  Produce

The procedure of Preparation Example 2 was repeated to produce the target compound.

^{1 H NMR (300 MHz, CDCl3} ) δ 8.66 (s, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 7.80 (s, 1H), 7.74-7.72 (m, 1H), 7.27-7.24 (m, 1H), 6.15 (bs, IH), 5.27-5.23 (m, IH), 4.91 (bs, IH), 4.81-4.79 (m, 2H), 2.27 (bs, 1 H,) 1.67 (bs, 1 H).

< Example  2> ( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutanol

The procedure of Preparation Example 1 was repeated to produce the target compound.

^{1 H NMR (300 MHz, CDCl3} ) δ 8.64 (s, 1H), 8.51 (d, J = 4.4 Hz, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.70 (d, J = 7.6 2H), 4.60-4.49 (m, 1H), 4.32-4.24 (m, 1H), 7.23 (dd, J = 7.6 Hz, 4.4 Hz), 6.44 (t, J = 5.6 Hz, m, 1 H), 3.08-3.00 (m, 2 H), 2.47-2.37 (m, 2 H); LCMS (m / z) 297.1 (M + H) &lt; + &gt;.

< Example  3 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Cyclobutyl ) Preparation of acetamide

The procedure of Preparation Example 3 was repeated to produce the target compound.

¹ H NMR (300 MHz, CDCl 3)? 8.68 (br s, 1H), 8.55 (s, 1H), 8.44 (M, 2H), 2.95-2.74 (m, 2H), 2.07 (s, 2H), 4.93 , 3H); LCMS (m / z) 338.1 (M + H) &lt; + &gt;.

< Example  4> 6-Methyl-N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

The procedure of Example 3 was repeated, except that 6-methylpicolinic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz, CDCl3} ) δ 8.86 (d, J = 8.4 Hz, 1H), 8.68 (s, 1H), 8.55 (d, J = 4.7 Hz, 1H), 8.51 (s, 1H), 8.03 ( (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.76 (t, J = 7.7 Hz, 2H), 7.33 (M, 1H), 6.43 (s, 1H), 4.94 (d, J = 3.7 Hz, 2H), 4.90 4.73 (m, 1 H), 4.80? 4.54 (m, 1 H), 3.29? 3.11 (m, 2H), 3.08? 2.89 (m, 2 H), 2.65 (s, 3 H); LCMS (m / z) 415.1 (M + H) &lt; + &gt;.

< Example  5> 6-Methyl-N - (( 1s, 3s ) -3- (6- (1- (methylsulfonyl) piperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide

Instead of using acetic acid in Step 2 of Example 3, 6-methylpicolinic acid was used and 1- (methylsulfonyl) piperidin-4-amine was used instead of 3-picolylamine , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.79 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 5.92 (d, J = 7.5 Hz, 1H), 4.85-4.74 2H), 2.94-2.30 (m, 2H), 2.82 (m, 2H), 3.84-3.75 (m, s, 3H), 2.63 (s, 3H), 2.27 - 2.22 (m, 2H), 1.80 - 1.67 (m, 2H); LCMS (m / z) 485.1 (M + H) &lt; + &gt;.

< Example  6 > N - (( 1s, 3s ) -3- (6- (3-fluorobenzyl Amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (3-fluorophenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl3} ) δ 8.79 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.74 ( 1H, J = 7.8 Hz, 1H), 7.33-7.27 (m, 2H), 7.17-7.08 (m, 2H), 6.99-6.93 ), 4.79-4.74 (m, 1H), 4.67-4.53 (m, 1H), 3.22-3.12 (m, 2H), 3.01-2.91 (m, 2H), 2.63 (s, 3H); LCMS (m / z) 432.1 (M + H) &lt; + &gt;.

< Example  7> tert - Butyl 2 - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutylcarbamoyl) pyrrolidine-1-carboxylate

The procedure of Example 3 was repeated except that 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid was used instead of acetic acid in Step 2 of Example 3 to obtain the desired compound Respectively.

¹ H NMR (300 MHz, CDCl 3)? 8.64 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.45 2H), 4.75-4.60 (m, 1H), 4.55-4.35 (m, 1H), 7.70 (s, 1H), 7.24 (dd, J = 7.8,4.8Hz, 1H) 1H), 4.35-4.15 (m, 1H), 3.08-3.01 (m, 2H), 2.88-2.10 (m, 6H), 2.01-1.86 (m, 2H), 1.43 (s, 9H); LCMS (m / z) 493.1 (M + H) &lt; + &gt;.

< Example  8 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cycle Butyl) pyrrolidine-2-carboxamide hydrochloride

The target compound was prepared by removing -Boc in Example 7 above.

^{1 H NMR (300 MHz, CDCl3} ) δ 9.09 (s, 1H), 8.87-8.80 (m, 2H), 8.75-8.48 (m, 2H), 8.14 (t, J = 7.2 Hz, 1H), 5.81-5.08 (m, 2H), 5.51 (s, 2H), 4.45-4.25 (m, 2H), 3.48-3.38 -2.02 (m, 4 H); LCMS (m / z) 393.1 (M + H) &lt; + &gt;.

<Example 9> 1- (methylsulfonyl) -N - ((1s, 3s ) -3- (6- ( pyridin-3-ylmethyl-amino) -9H- purin-9-yl) cyclobutyl) piperidin 4-carboxamide &lt; / RTI &gt;

The objective compound was prepared in a similar manner to Example 3, except that 1- (methylsulfonyl) piperidine-4-carboxylic acid was used instead of acetic acid in Step 2 of Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.66 (s, 1H), 8.53 (d, J = 4.0 Hz, 1H), 8.40 (s, 1H), 7.74 (s, 2H), 7.46 (d, J = 2H), 4.72-4.67 (m, 1H), 4.53-4.47 (m, 1H), 3.84-3.74 (m, m, 2H), 3.25-3.00 (m, 2H), 2.82-2.25 (m, 2H), 2.81 (s, 3H), 2.30-1.75 (m, 7H); LCMS (m / z) 485.1 (M + H) &lt; + &gt;.

< Example  10 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) morpholine-4-carboxamide

The procedure of Example 3 was repeated except that morpholine-4-carboxylic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

¹ H NMR (300 MHz, CDCl ₃ )? 8.68 (s, IH), 8.55 (d, J = 6.1 Hz, IH), 8.38 J = 6 Hz, 1H), 3.74 (t, J = 6 Hz, 4H), 3.43 (t, J = , 4H), 3.35-3.33 (m, 2H), 2.88-2.83 (m, 2H), 2.06 (s, 1H), 1.27 (t, J = 6.1 Hz, 2H); LCMS (m / z) 409.1 (M + H) &lt; + &gt;.

< Example  11 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) nicotinamide

The procedure of Example 3 was repeated except for using acetic acid instead of nicotinic acid in Step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz, Methanol} -d4) δ 9.02 (s, 1H), 8.70 (d, J = 6.1 Hz, 1H), 8.60 (s, 1H), 8.35 (m, 2H), 8.30 (d, J 1H), 7.41-7.48 (m, 1H), 4.90 (s, 1H), 4.54 (d, J = -4.52 (m, 1 H), 3.09-3.06 (m, 2 H), 2.89-2.85 (m, 2 H); LCMS (m / z) 401.1 (M + H) &lt; + &gt;.

< Example  12 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) Cyclobutyl ) Preparation of isonicotinamide

The procedure of Example 3 was repeated except that isonicotinic acid was used instead of acetic acid in step 2 of Example 3 to obtain the desired compound.

¹ H NMR (300 MHz, CDCl ₃ )? 8.71 (d, J = 3.1 Hz, 1H), 8.60 (s, 1H), 7.83 (d, J = 6.1 Hz, 1H), 7.42-7.48 (m, 1H), 4.92-4.89 (m, 1H), 4.52-4.50 (m, 1H), 3.33-3.30 , &Lt; / RTI &gt; 2H), 2.95-2.91 (m, 2H); LCMS (m / z) 401.1 (M + H) &lt; + &gt;.

< Example  13 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) pyrazine-2-carboxamide

The procedure of Example 3 was repeated except for using pyrazine-2-carboxylic acid instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz, Methanol} -d4) δ 9.27 (s, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.28 (s 1H), 7.90 (m, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.44-7.40 (m, 1H), 4.94-4.90 3.03-3.00 (m, 2H), 2.96-2.94 (m, 2H); LCMS (m / z) 402.1 (M + H) &lt; + &gt;.

< Example  14> 1- methyl -N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) pyrrolidine-2-carboxamide

The procedure of Example 3 was repeated, except that 1-methylpyrrolidine-2-carboxylic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz, Methanol} -d4) δ 8.61 (s, 1H), 8.44 (s, 1H) 8.30 (s, 1H), 8.24 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H) , 7.42 (t, J = 6.1Hz, 1H), 4.85-4.82 (m, 1H), 4.39-4.36 ), 2.82-2.80 (m, 2 H) 2.41 (s, 3 H); LCMS (m / z) 407.1 (M + H) &lt; + &gt;.

< Example  15> 2-phenyl-N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) acetamide

The procedure of Example 3 was repeated, except that 2-phenylacetic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the target compound.

^{1 H NMR (300 MHz, Methanol} -d4) δ 8.60 (s, 1H), 8.43 (d, J = 6.1 Hz, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 7.90 (d, J = 9.1 Hz, 1 H), 7.42-7.39 (m, 1 H), 7.38 (t, J = 6.1 Hz, 4H), 7.26-7.22 (m, 1H), 4.83-4.80 m, 1 H), 4.15-4.14 (m, 1 H), 3.33 (s, 2H), 3.03-3.00 (m, 2H), 2.78-2.75 (m, 2H); LCMS (m / z) 414.1 (M + H) &lt; + &gt;.

< Example  16> 2- Cyclohexyl -N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) acetamide

The objective compound was prepared in a similar manner to Example 3, except that 2-cyclohexyl acetic acid was used instead of acetic acid in the step 2 of Example 3.

^{1 H NMR (300 MHz, Methanol} -d4) δ 8.73 (s, 1H) 8.64 (s, 1H), 8.43 (d, J = 6.1 Hz, 1H), 8.29 (s, 1H), 8.20 (s, 1H) , 7.91 (d, J = 6.1 Hz, 1H), 7.42-7.40 (m, IH), 4.98-4.95 (m, IH), 4.26-4.24 (m, 2H), 1.87 (d, J = 9.1 Hz, 2H), 1.83-1.80 (m, 6H), 1.28 ); LCMS (m / z) 420.1 (M + H) &lt; + &gt;.

< Example  17 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) -tetrahydro-2H-pyran-4-carboxamide

The objective compound was prepared in a manner similar to that of Example 3 except that tetrahydro-2H-pyran-4-carboxylic acid was used instead of acetic acid in Step 2 of Example 3.

¹ H NMR (300 MHz, methanol-d4)? 8.61 (s, IH), 8.44 (s, IH), 8.30 ), 7.42 (q, J = 6.1 Hz, IH), 4.89-4.87 (m, IH), 4.33-4.29 (m, IH), 4.03-4.01 2H), 3.37 (t, J = 9.1 Hz, 2H), 2.99-2.96 (m, 2H), 2.69-2.67 -1.93 (m, 4H), 1.28-1.25 (m, 1 H); LCMS (m / z) 408.1 (M + H) &lt; + &gt;.

< Example  18 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated except for using benzoic acid instead of acetic acid in step 2 of Example 3 to prepare the target compound.

^{1 H NMR (300 MHz, MeOD} ) δ 8.62 (d, J = 1.7 Hz, 1H), 8.44 (dd, J = 4.9, 1.4 Hz, 1H), 8.30 (d, J = 10.8 Hz, 1H), 8.25 ( (m, 3H), 7.62-7.47 (m, 3H), 7.42 (dd, J = 7.8,4.9Hz, 1H), 4.94-4.90 m, 1 H), 3.19-3.04 (m, 2H), 2.95-2.81 (m, 2H).

< Example  19> 4-Methoxy-N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated except that 4-methoxybenzoic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the target compound.

^{1 H NMR (300 MHz, MeOD} ) δ 8.62 (d, J = 1.7 Hz, 1H), 8.44 (dd, J = 4.9, 1.5 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 1H), 7.95-7.83 (m, 3H), 7.41 (dd, J = 7.8,4.9Hz, 1H), 7.07-6.998 3.88 (s, 3H), 3.15-3.01 (m, 2H), 2.93-2.79 (m, 2H).

< Example  20 > N - (( 1s, 3s ) -3- (6- (3- Chlorophenylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

The procedure of Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 3-chlorobenzeneamine was used instead of 3-picolylamine. To give the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.80 (d, J = 8.1 Hz, 1H), 8.62 (s, 1H), 8.07 (t, J = 2.0 Hz, 1H), 8.02 (s, 2H), 8.00 (s, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.1, 1.2 Hz, 1H) 2H), 2.64 (s, 3H), 2.63 (s, 3H) ; LCMS (m / z) 434.1 (M + H) &lt; + &gt;.

< Example  21 > N - (( 1s, 3s ) -3- (6- (3-fluorophenyl Amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 3-fluorobenzeneamine was used instead of 3-picolylamine. The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.80 (d, J = 8.1 Hz, 1H), 8.62 (s, 1H), 8.07 (t, J = 2.0 Hz, 1H), 8.02 (s, 2H), 8.00 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.1 Hz, 1.2 Hz, 1H) (M, 2H), 2.64 (m, 2H), 3.06-2.96 (m, 2H) , 3H).

< Example  22 > N - (( 1s, 3s ) -3- (6- (4-methoxy Phenylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 4-methoxybenzenamine was used instead of 3-picolylamine. The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.80 (d, J = 8.4 Hz, 1H), 8.62 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.96 (s, 1H), 7.74 (t, J = 7.8 Hz, IH), 7.67 (s, 2H), 7.64 (s, IH), 7.30 1H), 4.89-4.78 (m, 1H), 4.67-4.53 (m, 1H), 3.82 (s, 3H) 3.23-3.14 (m, 2H), 3.06-2.96 (m, 2H).

<Example 23> 2,6-Dichloro -N - Preparation of ((1s, 3s) -3- ( 6- ( pyridin-3-ylmethyl-amino) -9H- purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated, except that 2,6-dichlorobenzoic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.61 (s, 1H), 8.48 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.71 (m, 2H), 3.30-3.13 (m, 2H), 4.83 (s, , &Lt; / RTI &gt; 2H), 3.00-2.80 (m, 2H).

Preparation of ((1s, 3s) -3- ( 6- ( pyridin-3-ylmethyl-amino) -9H- purin-9-yl) cyclobutyl) benzamide <Example 24> 2,3-dichloro -N

The procedure of Example 3 was repeated except that 2,3-dichlorobenzoic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.61 (s, 1H), 8.48 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.71 (m, 2H), 3.30-3.13 (m, 2H), 4.83 (s, , &Lt; / RTI &gt; 2H), 3.00-2.80 (m, 2H).

< Example  25> 2,6- Difluoro -N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated, except that 2,6-dichlorobenzoic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.61 (s, 1H), 8.48 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.71 (m, 2H), 3.30-3.13 (m, 2H), 4.83 (s, , &Lt; / RTI &gt; 2H), 3.00-2.80 (m, 2H)

< Example  26> 4- Chloro -2- Methoxy -N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) benzamide

The objective compound was prepared in a manner similar to that of Example 3 except that 4-chloro-2-methoxybenzoic acid was used instead of acetic acid in the step 2 of Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.61 (s, 1H), 8.48 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 8.15 (m, 1H), 7.10 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.76 (d, J = 2H), 4.84-4.72 (m, 1H), 4.64-4.50 (m, 1H), 7.02 (d, J = 1.5 Hz, 1H), 4.04 (s, 3H), 3.25-3.07 (m, 2H), 3.03-2.90 (m, 2H).

< Example  27> 1r, 3r ) -Methyl 3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutanecarboxylate

The target compound was prepared in the same manner as in Example 3 except that the step 1 of Example 3 was not carried out and only the terminal carboxyl group was changed to a methoxycarbonyl group.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.66 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 7.74-7.72 (m, 2H), 7.23-7.21 (m, 1H), 3H), 3.15-3.14 (m, IH), 3.08-3.06 (m, 2H), 2.87 (m, IH) -2.85 (m, 2H).

< Example  28> 1r, 3r ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutanecarboxylic acid

The procedure of Example 3 was repeated except that the step 1 of Example 3 was not carried out to produce the desired compound.

^{1 H NMR (300 MHz MeOD-} d 4) δ 8.91 (s, 1H), 8.73 (s, 1H), 8.59 (d, J = 6.0 Hz, 1H), 8.31 (s, 1H), 7.98-7.97 (m 2H), 3.64 (s, 2H), 3.09-3.07 (m, J = 6.0 Hz, 2H) ), 2.87-2.85 (m, 2H).

< Example  29> N-Phenyl-3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutanecarboxamide

The procedure of Example 3 was repeated except that the step 1 of Example 3 was not performed and only the terminal carboxyl group was converted into a phenylcarbamoyl group to give the target compound.

^{1 H NMR (300 MHz Methanol-} d 4) δ 8.62 (s, 1H), 8.43 (s, 1H), 8.26 (d, J = 6.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 1H), (T, J = 6.0 Hz, 1H), 7.60 (d, J = 6.0 Hz, 2H), 7.42 (t, J = 9.0 Hz, 1H), 3.33 (br s, 1H), 3.10 (q, J = 9.0 Hz, 2H), 2.91 (q, J = 9.0 Hz, 2H).

<Example 30> 6-Methyl -N - ((1s, 3s) -3- (6- ( naphthalen-1-ylmethyl-amino) -9H- purin-9-yl) cyclobutyl) the production of choline amide

Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and naphthalen-1-ylmethanamine was used instead of 3-picolylamine. The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.86 (d, J = 8.1 Hz, 1H), 8.55 (s, 1H), 8.15-.05 (m, 1H), 8.01 (d, J = 7.8 Hz, 1H ), 7.90-7.70 (m, 4H), 7.58-7.38 (m, 4H), 7.30 (d, J = 7.8 Hz, 1H) 6.35 (bs, 1H), 5.29 (s, 2H), 4.84-4.70 (M, 2H), 2.64 (s, 3H).

< Example  31 > N - (( 1s, 3s ) -3- (6- (4-cyano Benzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 4- (aminomethyl) benzonitrile was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl3} ) δ 8.81 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H), 7.74 ( (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.49 2H), 3.05-2.90 (m, 2H), 2.62 (s, 2H) 3H).

<Example 32> N - ((1R, 3s) -3- (6 - ((S) -2- hydroxy-1-phenyl-ethylamino) -9H- purin-9-yl) cyclobutyl) -6 Preparation of methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (R) -2-amino-2-phenylethanol was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.78 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.73 (m, 1H), 4.64-4.86 (m, 1H), 5.51 (bs, , 4.13-4.02 (m, 2H), 3.70-3.55 (m, 1H), 3.20-3.05 (m, 2H), 3.00-2.85 (m, 2H), 2.62 (s, 3H).

<Example 33> N - ((1S, 3s) -3- (6 - ((R) -2- hydroxy-2-phenyl-ethylamino) -9H- purin-9-yl) cyclobutyl) -6 Preparation of methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (S) -2-amino-1-phenylethanol was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.78 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.73 (m, 1H), 4.64-4.86 (m, 1H), 5.51 (bs, , 4.13-4.02 (m, 2H), 3.70-3.55 (m, 1H), 3.20-3.05 (m, 2H), 3.00-2.85 (m, 2H), 2.62 (s, 3H).

< Example  34 > N- (1- ( Methylsulfonyl ) Piperidin-4-yl) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutanecarboxamide

The procedure of Example 3 was repeated except that the terminal carboxyl group was changed to the 1- (methylsulfonyl) piperidin-4-ylcarbamoyl group without carrying out the step 1 of Example 3, .

^{1 H NMR (300 MHz Methanol-} d 4) δ 8.51 (br s, 1H), 8.41-8.40 (m, 1H), 8.30-8.20 (m, 2H), 7.98-7.87 (m, 1H), 7.42-7.40 (m, 1H), 5.24-5.20 (m, 1H), 3.98-3.50 (m, 4H), 3.02-2.80 (m, 7H), 2.12-1.98 .

< Example  35> 1-Methyl-N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) -1H-pyrazole-5-carboxamide

The objective compound was prepared in a manner similar to that of Example 3 except that 1-methyl-1H-pyrazole-5-carboxylic acid was used instead of acetic acid in the Step 2 of Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.61 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.90 (d, 1H), 7.50 (m, 2H), 6.86 (s, IH), 4.88 (m, IH), 4.14 (s, 3H), 3.05 (m, 2H), 2.88 (m, 2H).

< Example  36> 6-Methyl-N - (( 1s, 3s ) -3- (6- (pyridin-2- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

The procedure of Example 3 was repeated, except that 6-methylpicolinic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz Methanol d} -4) δ 8.53 (d, J = 6.0 Hz, 1H), 8.34 (s, 1H), 7.80-7.78 (m, 3H), 7.46 (d, J = 12.0 Hz, 2H ), 7.32 (d, J = 8.0 Hz, 1H), 4.96-4.94 (m, 2H), 4.61 (t, J = 8 Hz, , &Lt; / RTI &gt; 2.66 (s, 3H).

< Example  37> 6- methyl -N - (( 1s, 3s ) -3- (6- (2- Methylbenzylamino ) -9H-purin-9-yl) Cyclobutyl ) Preparation of picolinamide

The procedure of Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and o-tolylmethanamine was used instead of 3-picolylamine. To give the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, 8.4 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.78-7.70 (m, 1H), 7.38-7.28 (m, 2H), 7.24-7.14 (m, 3H), 6.24 (bs, 2H), 2.63 (s, 3H), 2.38 (s, 3H)

< Example  38 > N - (( 1s, 3s ) -3- (6- (2- Methoxybenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (2-methoxyphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, 8.4 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.78-7.70 (m, 1H), 7.38-7.28 (m, 2H), 7.24-7.14 (m, 3H), 6.24 (bs, 2H), 2.63 (s, 3H), 2.32 (s, 3H)

< Example  39 > N - (( 1s, 3s ) -3- (6- (2- Chlorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (2-chlorophenyl) methanamine was used instead of 3-picolylamine. 3, the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, 8.4 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.78-7.70 (m, 1H), 7.38-7.28 (m, 2H), 7.24-7.14 (m, 3H), 6.24 (bs, (m, 1 H), 3.26-3.10 (m, 2 H), 2.63 (s, 3 H)

< Example  40 > N - (( 1s, 3s ) -3- (6- (2- Fluorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (2-fluorophenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, 8.4 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.78-7.70 (m, 1H), 7.38-7.28 (m, 2H), 7.24-7.14 (m, 3H), 6.24 (bs, (m, 1 H), 3.26-3.10 (m, 2 H), 2.63 (s, 3 H).

< Example  41> 6- methyl -N - (( 1s, 3s ) -3- (6- (3- ( Trifluoromethyl ) Benzylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

(3- (trifluoromethyl) phenyl) methaneamine was used instead of 3-picolylamine in place of acetic acid in the step 2 of Example 3, using 6-methylpicolinic acid instead of 3-picolylamine , The target compound was prepared.

^{1 H NMR (300 MHz, MeOD} ) δ 8.34 (d, J = 10.7 Hz, 2H), 8.01 - 7.79 (m, 2H), 7.74 - 7.63 (m, 2H), 7.60 - 7.46 (m, 2H), 4.93 (d, J = 7.9 Hz, 2H), 4.72-4.54 (m, 2H), 3.71-3.52 (m, 1H), 3.25-2.91 (m, 4H), 2.66 (s, 3H).

< Example  42 > N - (( 1s, 3s ) -3- (6- (3- Chlorobenzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (3-chlorophenyl) methanamine was used instead of 3-picolylamine. 3, the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.80 (d, J = 8.1 Hz, 1H), 8.62 (s, 1H), 8.07 (t, J = 2.0 Hz, 1H), 8.02 (s, 2H), 8.00 (s, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.1, 1.2 Hz, 1H) 2H), 3.06-2.96 (m, &lt; RTI ID = 0.0 &gt; 1H), &lt; 2H), 2.64 (s, 3H); LCMS (m / z) 448.1 (M + H) &lt; + &gt;.

< Example  43 > N - (( 1s, 3s ) -3- (6- (4- ( Dimethylamino )benzyl Amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in step 2 of Example 3, 6-methylpicolinic acid was used and 4- (aminomethyl) -N, N-dimethylbenzenamine was used instead of 3-picolylamine , The target compound was prepared.

^{1 H NMR (300 MHz, Methanol} d-4) δ 8.36 (s, 1H), 8.29 (s, 1H), 7.88-7.86 (m, 2.5H), 7.47 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 4.72 (s, 2H), 4.63-4.62 (m, 3H), 3.63-3.61 3.54 (m, 3H), 3.37-3. 35 (m, 2H), 3.33 (s, 3H). 3.05 (s, 3 H).

< Example  44> 6-Methyl-N - (( 1s, 3s ) -3- (6- (pyridin-4- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and pyridin-4-ylmethanamine was used instead of 3-picolylamine. The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.81 (br s, 1H), 8.49 (s, 1H), 8.43 (d, J = 8.0 Hz, 2H), 8.05-8.03 (m, 2H), 7.63-7.61 (m, 2H), 4.63 (s, 1H), 3.18-3.16 (m, 2H) m, 2H), 3.04-3.02 (m, 2H), 2.37 (s, 3H).

< Example  45> 6- methyl -N - (( 1s, 3s ) -3- (6- (4- ( Trifluoromethyl ) Benzylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

(4- (trifluoromethyl) phenyl) methanamine was used instead of 3-picolylamine in place of acetic acid in the step 2 of Example 3, using 6-methylpicolinic acid instead of 3- , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (s, 1H), 8.51 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.95 (s, 1H), 7.77-7.75 (m, (Br s, 1 H), 5.82 (br s, 1 H), 4.82 (d, J = 6.0 Hz, (M, 2H), 2.66 (s, 2H), 3.66 (s, 2H) s, 3H).

< Example  46> 6-Methyl-N - (( 1s, 3s ) -3- (6- (4- (trifluoromethyl) Oromethoxy )benzyl Amino ) -9H-purin-9-yl) cyclobutyl) picolinamide

(4- (trifluoromethoxy) phenyl) methanamine was used instead of 3-picolylamine in place of acetic acid in the step 2 of Example 3 , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.74 (s, 1H) , 7.74 (t, J = 6.0 Hz, 1H), 7.43 (d, J = 6.0 Hz, 1H), 7.32 (m, 2H), 2.96 (m, 2H), 4.92 (br s, -2.94 (m, 2 H), 2.66 (s, 3 H).

< Example  47 > N - (( 1s, 3s ) -3- (6- (4-methoxy Benzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (4-methoxyphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.88 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H), 8.10-7.80 (m, 3H), 7.23-7.20 (m, 3H), 6.80- 2H), 6.23 (brs, 1H), 4.80-4.60 (m, 4H), 3.80 (s, 3H), 3.20-2.80 (m, 4H), 2.30 (s, 3H).

< Example  48> 6-Methyl-N - (( 1s, 3s ) -3- (6- (4-Sulfamoyl Benzylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 4- (aminomethyl) benzenesulfonamide was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.83 (d, J = 9.0 Hz, 1H), 8.48 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.87 (s, 1H), 7.79 (d, J = 6.0 Hz, 2H), 7.74 (t, J = 6.0 Hz, 1H), 7.50 J = 6.0 Hz, 1H), 4.61 (q, J = 9.0 Hz, 1H), 3.04-3.02 (m, 2H), 2.98-2.96 (m, 2H), 2.65 (s, 3H).

< Example  49 > N - (( 1s, 3s ) -3- (6- (cyclohexyl Methyl amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Similar to Example 3, except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and cyclohexylmethanamine was used instead of 3-picolylamine To give the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.81 (br s, 1H), 8.52 (s, 1H), 8.12-8.10 (m, 1H), 7.80 (s, 1H), 7.77-7.70 (m, 1H) , 7.27 (s, IH), 5.93 (br s, IH), 4.82-4.79 (m, IH), 4.60-4.58 (m, 3.20-3.12 (m, 2H), 3.08-2.87 (m, 2H), 2.62 (s, 3H), 1.88-0.82 (m, 9H); LCMS (m / z) 420.1 (M + H) &lt; + &gt;.

< Example  50 > N - (( 1s, 3s ) -3- (6 - ((2,3- Dihydrobenzo [b] [1,4] dioxin -2 days) Methyl amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in the step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and (2,3-dihydrobenzo [b] [1,4] Dioxin-2-yl) methanamine, the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.82-8.80 (m, 1H), 8.4 (s, 1H), 8.00-7.80 (m, 3H), 7.27-7.26 (m, 1H), 6.80-6.78 (m , 4H), 6.32 (br s, 1 H), 4.80-3.80 (m, 5H), 3.56-2.80 (m, 8H), 2.50 (s, 3H).

<Example 51> 3,5-dimethyl -N - Preparation of ((1s, 3s) -3- ( 6- ( pyridin-3-ylmethyl-amino) -9H- purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated except that 3,5-dimethylbenzoic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.69 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 6.0 Hz, 1H), 7.77 (s, 1H) , 7.53 (s, 2H), 7.19 (s, IH), 6.32 (br s, IH), 4.94 (br s, 2H), 4.75-4.73 m, 2H), 2.93-2.91 (m, J = 3.0 Hz, 2H).

<Example 52> 3,4-dimethyl -N - Preparation of ((1s, 3s) -3- ( 6- ( pyridin-3-ylmethyl-amino) -9H- purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated except that 3,4-dimethylbenzoic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.69 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 6Hz, 1H), 7.77 (s, 2H), 2H), 7.74 (m, J = 9 Hz, 2H), 7.27 (s, 3.67 (s, 1H), 3.25 (m, J = 3 Hz, 2H), 2.93 (m, J = 3 Hz, 2H).

< Example  53> 3- ( Dimethylamino ) -N - (( 1s, 3s ) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide

The procedure of Example 3 was repeated, except that 3- (dimethylamino) benzoic acid was used instead of acetic acid in step 2 of Example 3 to obtain the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.69 (s, 1H), 8.56 (d, J = 3.0 Hz, 1H), 8.46 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H) 7.31 (d, J = 6.0 Hz, 2H), 7.15 (d, J = 6.0 Hz, 1H), 6.88-6.86 , 4.93 (br s, 2H), 4.76-4.74 (m, 3H), 3.67 (s, 2H), 3.22-3.20 (m, 2H), 3.04 (s, 6H), 2.96-2.

< Example  54 > N - (( 1s, 3s ) -3- (6- (4-fluorobenzyl Amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3 and 4- (fluorophenyl) phenylmethanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.81 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.49 2H), 3.05-2.90 (m, 2H), 2.62 (m, IH), 4.85-4.75 (m, s, 3H); LCMS (m / z) 432.1 (M + H) &lt; + &gt;.

< Example  55 > N - (( 1r, 3r ) -3- (6- (4- Bromobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 4- (bromophenyl) phenylmethanamine was used instead of 3-picolylamine and 6-methylpicolinic acid was used instead of acetic acid in the step 2 of Example 3, The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.46 (m, 2H), 7.33-7.28 (m, 3H), 4.86 (s, 2H), 4.84-4.75 ), 3.23-3.14 (m, 2H), 3.02-2.92 (m, 2H), 2.65 (s, 3H)

< Example  56 > N - (( 1r, 3r ) -3- (6- (3- Bromobenzylamino ) -9H-purin-9-yl) Cyclo Butyl) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3 and 3- (bromophenyl) phenylmethanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.84 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.85 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.40 (d, J = 1H), 6.42 (br s, IH), 4.88 (s, 2H), 4.85-4.73 (m, IH), 4.67-4.53 m, 2 H), 2.64 (s, 3 H); LCMS (m / z) 493.1 (M + H) &lt; + &gt;.

< Example  57> N - (( 1r, 3r ) -3- (6- (2,4- Dimethoxybenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (2,4-dimethoxyphenyl) methanamine was used instead of 3-picolylamine , &Lt; / RTI &gt; Example 3, the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, J = 7.8 Hz, 1H), 8.48 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 6.46 2H), 3.85-2.40 (m, 2H), 3.85 (s, 3H) 2.64 (s, 3 H)

< Example  58 > N - (( 1r, 3r ) -3- (6- (3,4- Dimethoxybenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (3,4-dimethoxyphenyl) methanamine was used instead of 3-picolylamine , &Lt; / RTI &gt; Example 3, the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.84 (d, J = 8.1 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.75 (t, J = 7.5 Hz, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 6.94 (s, 3H), 3.86 (s, 3H), 3.22-3.12 (m, 2H), 4.84-4.74 , 2H), 3.01-2.91 (m, 2H), 2.64 (s, 3H).

< Example  59> N - (( 1r, 3r ) -3- (6- (3-hydroxy-4- Methoxybenzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and 5- (aminomethyl) -2-methoxyphenol was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.80 (d, J = 8.2 Hz, 1H), 8.50 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.77 (t, J = 7.8 Hz (D, J = 8.2 Hz, 1H), 7.65 (s, 1H), 7.32 (d, J = 7.8 Hz), 7.00 ), 6.78 (bs, IH), 4.84 (s, 2H), 4.87-4.79 (m, IH), 4.68-4.53 2.90 - 2.75 (m, 2 H), 2.67 (s, 3 H).

< Example  60 > N - (( 1r, 3r ) -3- (6- (4-hydroxy-3- Methoxybenzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and 4- (aminomethyl) -2-methoxyphenol was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.81 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.77 (t, J = 7.8 Hz J = 6.0 Hz, 1H), 6.90 (s, 2H), 6.64 (s, 1H) (s, 3H), 3.22-3.13 (m, 2H), 2.92-2.83 (m, IH) (m, 2 H), 2.67 (s, 3 H)

< Example  61 > N - (( 1r, 3r ) -3- (6- (3- Fluorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methoxypicolinamide &lt; / RTI &gt;

Except that 6-methoxypicolinic acid was used instead of acetic acid in step 2 of Example 3, and (3-fluorophenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.40 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.77 (m, 2H), 7.33-6.91 (m, (M, 2H), 4.86 (s, 3H), 3.45 (s, 3H) , 3.08-2.98 (m, 2H).

< Example  62> 6- Methoxy -N - (( 1r, 3r ) -3- (6- (4- Methoxybenzylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Except that 6-methoxypicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (4-methoxyphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

¹ H NMR (300 MHz, CDCl ₃ )? 8.41 (s, IH), 8.35 (d, J = 8.4 Hz, IH), 7.84 1H), 7.31 (d, J = 7.31 Hz, 2H), 6.94-6.86 (m, 3H), 6.13 (bs, 3H), 3.79 (s, 3H), 3.19-3.09 (m, 2H), 3.08-2.94 (m, 2H).

< Example  63> 6- Chloro -N - (( 1r, 3r ) -3- (6- (3-fluorobenzyl Amino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Except that 6-chloropicolinic acid was used instead of acetic acid in step 2 of Example 3, and (3-fluorophenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 9.17 (d, J = 8.1 Hz, 1H), 8.65 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.73-7.52 (m, 2H), 4.84-4.76 (m, IH), 4.71-4.60 (m, IH), 5.97 (t, J = , 3.25-3.15 (m, 2H), 3.03-2.93 (m, 2H); LCMS (m / z) 452.1 (M + H) &lt; + &gt;.

< Example  64> 6- methyl -N - (( 1s, 3s ) -3- (6- (2- Phenylacetamido ) -9H-purin-9-yl) Cyclobutyl ) Preparation of picolinamide

The procedure of Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 2-phenylacetamide was used instead of 3-picolylamine. To give the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.82 (s, 1H), 8.70 (d, J = 6.0 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J = 3.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63-7.59 (m, 1H), 7.45-7.43 (q, J = 6.0 Hz, 1H), 4.58 (q, J = 6.0 Hz, 1H), 3.20-3.18 (m, 2H), 3.03-3.01 (m, 2H), 2.62 (s,

< Example  65> 6-Methyl-N - (( 1s, 3s ) -3- (6- (4-phenoxy Benzylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (4-phenoxyphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.88 (s, 1H), 8.72 (br s, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H J = 6.0 Hz, 1H), 7.91 (s, 1H), 7.77 (t, J = 6.0 Hz, 1H), 7.28-7.26 J = 9.0 Hz, 1H), 3.66 (d, J = 9.0 Hz, 2H), 3.20-3.18 (m, 2H), 4.62 , 2H), 3.01-2.99 (m, 2H), 2.66 (s, 3H).

< Example  66 > N - (( 1s, 3s ) -3- (6- (4- (4- Fluorophenoxy ) Benzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and (4- (4-fluorophenoxy) phenyl) methanamine was used instead of 3- The procedure of Example 3 was repeated except for using the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (s, 1H), 8.70 (br s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H ), 7.98 (s, 1H), 7.75-7.74 (m, 1H), 7.28-7.26 (m, 2H), 6.99-6.97 2H), 4.65-4.63 (m, J = 9.0 Hz, 1H), 3.21-3.20 (m, 2H), 3.02-3.00 (m, 2H), 2.66 (s, 3H).

<Example 67> N - ((1s, 3s) -3- (6- (3,5- dichloro-4-methoxybenzyl-amino) -9H- purin-9-yl) cyclobutyl) -6-methylpiperidin Preparation of choline amide

Instead of using acetic acid in the step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and (3,5-dichloro-4-methoxyphenyl) methanamine was used instead of 3- The procedure of Example 3 was repeated except for using the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.34 (s, 1H), 8.05 (br s, 0.5H), 8.02 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.77 (s, J = 6.0 Hz, 1H), 4.13 (s, 2H), 4.92 (s, 2H) ), 3.24 (q, J = 9 Hz, 2H), 3.15 (m, 2H), 2.62 (s, 3H).

< Example  68 > N - (( 1s, 3s ) -3- (6- (3- Bromo -4- Methoxybenzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in the step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and (3-bromo-4-methoxyphenyl) methanamine was used instead of 3- , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.86 (d, J = 9.0 Hz, 1H), 8.51 (s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 7.76 (m, 3H), 4.61 (q, J = 9 Hz, 1H), 3.89 (d, J = (s, 3H), 3.17 (q, J = 9.0 Hz, 2H), 3.00 (q, J = 9.0 Hz, 2H), 2.66 (s,

< Example  69 > N - (( 1s, 3s ) -3- (6- (4- ( Benzyloxy ) Benzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (4-benzylphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (d, J = 8.7 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H) 7.84 (s, 1H), 7.74 ( 1H, J = 7.8 Hz, 1H), 7.43-7.30 (m, 8H), 6.94 (d, J = 8.7 Hz, 2H), 6.16 (bs, 2H), 2.64 (s, 3H), 3.63-3.30 (m, 2H)

< Example  70 > N - (( 1s, 3s ) -3- (6- (4-iso Propoxybenzylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (4-isopropoxy) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.87 (d, J = 7.6 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.7 Hz, 3H), 6.09 (bs, 1H), 4.81 (s, 2H), 4.80-4.73 2H), 3.64 (m, 2H), 2.64 (s, 3H), 1.33 (m, 1H), 4.67-4.56 s, 3H), 1.31 (s, 3H).

< Example  (6- Methyl pyridine Yl) (3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) azetidin-1-yl) methanone

The procedure of Example 3 was repeated except that the step 1 of Example 3 was not performed and only the terminal carboxyl group was converted into the 6-methylpicolinoyl group, to thereby prepare the target compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.66 (s, 1H), 8.52 (d, J = 4.6 Hz, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.97 (d, J = 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 4.6 Hz, 1H), 6.44 (bs, 1H), 5.54-5.45 (m, 1H), 5.17-5.11 (m, 1H), 4.91 (s, 2H), 4.85-4.78

<Example 72> Preparation (3- (6- (3-Chloro-benzylamino) -9H- purin-9-yl) azetidin-1-yl) (6-methylpyridin-2-yl) methanone

Except that the terminal carboxyl group was converted to the 6-methylpicolinoyl group and the 3-picolylamine was replaced with (3-chlorophenyl) methanamine instead of 3-picolylamine in step 2, And the procedure of Example 3 was repeated to produce the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.43 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.40 (s, 1H), 7.28 (s, 8H) , 6.33 (bs, IH), 5.54-5.48 (m, IH), 5.43-5.36 (m, IH), 5.19-5.14 (m, IH), 4.91 (s, 2H), 4.88-4.81 , 4.72-4.66 (m, 1 H), 2.56 (s, 3 H).

<Example 73> Preparation (3- (6- (3-Bromo-benzyl-amino) -9H- purin-9-yl) azetidin-1-yl) (6-methylpyridin-2-yl) methanone

(3-bromophenyl) methanamine was used instead of 3-picolylamine in Step 2 to obtain the desired compound , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.41 (s, 1H), 8.04 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.53 (m, 2H), 6.23 (bs, 1H), 5.55-5.46 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H) 2H), 4.88-4.79 (m, 1H), 4.72-4.64 (m, 1H), 2.54 (m, s, 3H).

< Example  74 > N - (( 1s, 3s ) -3- (6- (3,4- Difluorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3 and (3,4-difluorophenyl) methanamine was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

¹ H NMR (300 MHz, CDCl ₃ )? 8.85 (s, IH), 8.71 (d, J = 9.1 Hz, IH), 8.51 (s, IH), 8.35 1H), 7.99 (s, 1H), 7.80-7.76 (m, 1H), 7.30-7.26 (m, 1H), 7.15-7.12 4.90 (m, 2H), 4.62-4.58 (m, 1H), 3.20-3.17 (m, 2H), 2.30-2.80 (m, 2H), 2.66 (s, 3H); LCMS (m / z) 450.1 (M + H) &lt; + &gt;.

< Example  75 > N - (( 1s, 3s ) -3- (6- (3,4- Dichlorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (3,4-dichlorophenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.85 (s, 1H), 8.71 (d, J = 9.1 Hz, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 2H), 6.44 (br s, 1H), 4.98-4.87 (m, 2H) m, 2H), 4.70-4.60 (m, 1H), 3.25-3.21 (m, 2H), 3.10-3.02 (m, 2H), 2.66 (s, 3H); LCMS (m / z) 483.1 (M + H) &lt; + &gt;.

<Example 76> tert - butyl-4- (9 - ((1s, 3s) -3- (6- methyl-picoline amido) cyclobutyl) -9H- purin-6-ylamino) piperidin-1 Preparation of carboxylate

Instead of using acetic acid in Step 2 of Example 3, 6-methylpicolinic acid was used and tert-butyl 4-aminopiperidine-1-carboxylate was used instead of 3-picolylamine , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.86 (s, 1H), 8.47 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.76 (s, 1H), 7.73-7.70 (m, (M, 1H), 7.31-7.30 (m, IH), 5.70 (br s, IH), 4.80-4.79 2H), 1.49 (s, 9H), 1.27 (s, 2H), 3.16-3.14 (m, 2H), 2.96-2.94 1H).

< Example  77> tert - Butyl 4 - ((9 - (( 1s, 3s ) -3- (6- Methylpicolinamide ) Cyclobutyl ) -9H-purin-6-ylamino) methyl) piperidine-1-carboxylate

Instead of using acetic acid in the step 2 of Example 3, 6-methylpicolinic acid was used and instead of 3-picolylamine, tert-butyl 4- (aminoethyl) piperidine-1-carboxyl The procedure of Example 3 was followed except that the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.84 (d, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.90-7.80 (m, 1H), 7.76 (s, 1H), 7.73-7.72 ( (br s, 2H), 3.61 (m, IH), 7.31-7.30 (m, IH), 5.89 (s, 3H), 2.06-2.04 (m, 3H), 1.47 (m, 2H), 3.16-3.14 (m, 2H), 2.96-2.94 (s, 9H), 1.27 - 1.25 (m, 3H).

< Example  78> 6- methyl -N - (( 1s, 3s ) -3- (6- (Piperidin-4- Amino ) -9H-purin-9-yl) cyclobutyl) picolinamide Of the hydrochloride  Produce

Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3 and piperidin-4-amine was used instead of 3-picolylamine. The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 9.09 (s, 1H), 9.84 (s, 1H), 8.42 (s, 1H), 7.91-7.90 (m, 2H), 7.50-7.49 (m, 1H), 2H), 2.87 (m, 3H), 2.51 (s, 2H), 4.90-4.89 (m, 1.5H), 4.52-4.50 3H), 2.09 (m, 2H), 1.86 (m, 3H).

< Example  79> 6- methyl -N - (( 1s, 3s ) -3- (6- (Piperidin-4- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide Of the hydrochloride  Produce

Except that 6-methylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and piperidin-4-ylmethanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 9.05 (s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H), 4.87-4.85 ( 2H), 2.89-2.87 (m, 4H), 2.62 (s, 1H), 2.51 (m, s, 3H), 1.91 - 1.89 (m, 3H), 1.39 - 1.38 (m, 1H).

< Example  80> N- ((1 R, 3R) -3- (6- (3-bromo Benzylamino ) -9H-purin-9-yl) cyclobutyl) benzo [d] thiazol-2-amine

(3-bromophenyl) methanamine was used instead of 3-picolylamine and benzo [d] thiazol-2-ol was used in place of acetic acid in step 2 of Example 3 , The target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.45 (s, 1H), 7.83 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.5 (d, J = 12.2 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.35-7.28 (m, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.10 1H), 6.47 (s, 2H), 4.87 (s, 2H), 4.82-4.71 (m, 1H), 4.39-4.29 , 2H).

< Example  81> 6- methyl -N - (( 1s, 3s ) -3- (6- (1- Methylpiperidine -4- Amino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3 and 1-methylpiperidin-4-amine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.85 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 9.6 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.89 (d, J = (D, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.32 (m, 3H), 2.37 (s, 3H), 2.37-1.20 (m, 8H).

< Example  82 > N - (( 1s, 3s ) -3- (6 - (( 1r, 4r )-4- Hydroxycyclohexylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in the step 2 of Example 3 and (1r, 4r) -4-aminocyclohexanol was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.46 (s, 1H), 8.05 (s, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.76 (s, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 10.5 Hz, IH), 4.81-4.62 (m, IH), 4.59 (m, 2H), 2.13-2.09 (m, 4H), 1.14-1. 13 (m, 1H).

<Example 83> tert - butyl-3- (9 - ((1s, 3s) -3- (6- methyl-picoline amido) cyclobutyl) -9H- purin-6-ylamino) pyrrolidin-1 Preparation of carboxylate

Instead of using acetic acid in Step 2 of Example 3, 6-methylpicolinic acid was used and tert-butyl 3-aminopyrrolidine-1-carboxylate was used instead of 3-picolylamine , The target compound was prepared.

¹ H NMR 300 MHz CDCl ₃ δ 8.86 (br s, 1H), 8.84 (s, 1H), 8.49 (d, J = 9.3 Hz, 1H), 7.92 ), 7.34 (d, J = 7.5 Hz, IH), 5.98 (s, IH), 4.84-4.81 (m, IH), 4.78-4.63 (m, IH), 3.82-3.80 2H), 1.45 (br s, 2H), 1.45 (m, 2H), 3.52 (m, 2H), 3.21-3.19 (s, 9 H).

< Example  84> 6-Methyl-N - (( 1s, 3s ) -3- (6- (Pyrrolidin-3- Amino ) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride

The compound prepared in Example 83 was prepared in analogy to Example 83, except that the acid treatment was further carried out to remove the -Boc group.

^{1 H NMR 300 MHz Methanol d-} 4 8.65 (s, 1H), 8.51 (s, 1H), 8.08 (s, 2H), 7.64-7.60 (m, 1), 4.99-4.90 (m, 1H), 4.61- (M, 1H), 3.57 (m, 1H), 3.54-3.35 (m, 4H), 3.10-2.98 (m, 3H), 2.60 1H).

< Example  85 > N - (( 1s, 3s ) -3- (6- (1- Acetyl piperidine -4- Amino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in the step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and 1- (4-aminopiperidin-1-yl) ethanone , The target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.84-8.80 (m, 1H), 8.48 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.71 (t, J = 4.8 (M, 2H), 4.15-4.13 (m, IH), 7.33 (d, J = 8.1 Hz, (m, 2H), 3.66 (s, 3H), 3.51 (s, 1H), 3.20-2.89 (m, 9H), 2.66 (s, 3H).

< Example  86> 6- methyl -N - (( 1s, 3s ) -3- (6- (1- (2- Phenylacetyl ) Piperidin-4- Amino ) -9H-purin-9-yl) cyclobutyl) picolinamide

Methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3 and 1- (4-aminopiperidin-1-yl) -2 -Phenylethanone, the target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.82 (d, J = 8.4 Hz, 1H), 8.45 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 4.8 Hz, 1H) , 7.38-7.29 (m, 5H), 5.68 (br s, 1 H), 4.83-4.77 (m, ), 2.65 (s, 3H), 2.06 (m, 1H), 0.96-0.87 (m, 5H).

< Example  87 > N - (( 1s, 3s ) -3- (6 - (( 1s, 4s )-4- Acetamidocyclohexylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and N - ((1s, 4s) -4-aminocyclohexyl) Amide, the target compound was prepared.

¹ H NMR 300 MHz CDCl ₃ δ 8.88-8.85 (d, J = 8.7 Hz, 1H), 8.47 (s, 1H), 8.04-8.02 (Br s, 1H), 4.88-4.81 (m, 1H), 4.75 (d, J = 7.8 Hz, 2H), 2.66 (s, 3H), 1.91 (s, 3H) (s, 3H), 1.84-1.27 (m, 8H).

< Example  88 > N - (( 1s, 3s ) -3- (6 - (( 1r, 4r )-4- Acetamidocyclohexylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Instead of using acetic acid in the step 2 of Example 3, 6-methylpicolinic acid was used instead of 3-picolylamine and N - ((1r, 4r) -4-aminocyclohexyl) Amide, the target compound was prepared.

¹ H NMR 300 MHz CDCl ₃ δ 8.87 (d, J = 8.7 Hz, 1H), 8.47 (s, 1H), 8.04-8.02 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.68 2H), 3.12-3.16 (m, 2H), 2.95 (s, 1H), 2.25-2.21 ), 2.00 (s, 3H), 1.44-1. 39 (m, 4H).

< Example  89> N2- (4-methoxybenzyl) -N6 - (( 1s, 3s ) -3- (6- (4- Methoxybenzylamino ) -9H-purin-9-yl) cyclobutyl) pyridine-2,6-dicarboxamide

(4-methoxybenzylcarbamoyl) picolinic acid was used in place of acetic acid in Step 2 of Example 3, and instead of 3-picolylamine, (4-methoxyphenyl) methane Amine, the target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.99 (d, J = 9.0 Hz, 1H), 8.78 (br s, 1H), 8.41-8.31 (m, 3H), 8.02 (t, J = 7.8 Hz, 1H), 7.50 (br s, 1 H), 4.78 (br s, 2H), 7.69 - 4.60 (m, 3H), 7.23-7.21 (m, 3H) 3H), 3.76 (s, 3H), 3.00-2.96 (m, 2H), 2.85-2.81 (m, 2H).

< Example  90 > N - (( 1s, 3s ) -3- (6- (3- Chlorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-cyanophenolamide &lt; / RTI &gt;

Except that 6-cyanopicolinic acid was used instead of acetic acid in step 2 of Example 3, and (3-chlorophenyl) methanamine was used instead of 3-picolylamine. 3, the target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.99 (d, J = 9.0 Hz, 1H), 8.71 (s, 1H), 8.42-8.38 (m, 2H), 8.30 (s, 1H), 8.08-8.05 (m, 1H 2H), 4.74-4.68 (m, 2H), 7.86 (s, 1H), 7.79 (s, , 3.08 (t, J = 10.8 Hz, 4H).

< Example  91 > N - (( 1s, 3s ) -3- (6- (4-methoxy Benzylamino ) -9H-purin-9-yl) cyclobutyl) -6-phenylpicolinamide

Except that 6-phenylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (4-methoxyphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.78 (d, J = 8.1 Hz, 1H), 8.44 (s, 1H), 8.20-8.20 (m, 1H), 8.10-8.09 (m, 1H), 7.97- 1H), 7.90 (m, 3H), 7.54-7.51 (m, 3H), 7.35 (d, J = 8.7 Hz, 2H) (m, 3H), 4.69-4.61 (m, 1H), 3.82 (s, 3H), 3.21-3.18 (m, 2H), 3.11-3.05 (m, 2H); LCMS (m / z) 506.1 (M + H) &lt; + &gt;.

< Example  92 > N - (( 1s, 3s ) -3- (6- (3- Chlorobenzylamino ) -9H-purin-9-yl) cyclobutyl) -6-phenylpicolinamide

Except that 6-phenylpicolinic acid was used instead of acetic acid in Step 2 of Example 3 and (3-chlorophenyl) methanamine was used in place of 3-picolylamine. 3, the target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.79 (br s, 1H), 8.42 (s, 1H), 8.20-8.18 (m, 1H), 8.09-8.07 (m, 2H), 7.92-7.90 (m, 3H), 2H), 7.56-7.54 (m, 3H), 7.40 (s, IH), 6.45 (s, IH), 4.90-4.83 (m, 3H), 4.66-4.63 3.09-3.02 (m, 2H).

< Example  93> 6-Phenyl-N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) picolinamide

The procedure of Example 3 was repeated, except that 6-phenylpicolinic acid was used instead of acetic acid in the step 2 of Example 3 to obtain the desired compound.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.79 (br s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.20-8.18 (m, 1H), 8.09-8.07 ( (m, 2H), 7.93-7.93 (m, 3H), 7.77-7.75 (m, 1H), 7.56-7.54 m, 1H), 4.66-4.63 (m, 1H), 3.25-3.16 (m, 2H), 3.10-3.01 (m, 2H).

< Example  94> 6-Ethyl-N - (( 1s, 3s ) -3- (6- (4- Methoxybenzylamino ) -9H-purin-9-yl) Cyclobutyl ) Preparation of picolinamide

Except that 6-ethylpicolinic acid was used instead of acetic acid in step 2 of Example 3, and (4-methoxyphenyl) methanamine was used instead of 3-picolylamine. The target compound was prepared in a similar manner to Example 3.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.81-8.77 (m, 1H), 8.50 (s, 1H), 8.06-8.04 (m, 1H), 7.90 (s, 1H), 7.80-7.79 (m, 1H), 7.33 (M, 2H), 5.97 (s, 1H), 4.80-4.79 (m, 3H), 4.69-4.56 , 2.99-2.92 (m, 4H), 1.42-1.38 (m, 3H).

< Example  95 > N - (( 1s, 3s ) -3- (6- (3- Chlorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-ethylpicolinamide &lt; / RTI &gt;

Except that 6-ethylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and (3-chlorophenyl) methanamine was used instead of 3-picolylamine. 3, the target compound was prepared.

¹ H NMR 300 MHz CDCl ₃ (m, 2H), 6.32 (s, 1H), 7.90-7.76 (m, (M, 3H), 4.90-4.82 (m, 3H), 4.65-4.59 (m, 1H), 3.17 (s, 2H), 3.02-2.91 (m, 4H), 1.39-1.37

< Example  96 > N - (( 1s, 3s ) -3- (6- (4- Methoxybenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6- (trifluoromethyl) picolinamide &lt; / RTI &gt;

Except that 6- (trifluoromethyl) picolinic acid was used instead of acetic acid in step 2 of Example 3, and (4-methoxyphenyl) methanamine was used instead of 3-picolylamine , The target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.86 (d, J = 7.8 Hz, 1H), 8.52 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.07 (t, J = 7.8 Hz, 1H) , 7.87 (d, J = 8.7 Hz, IH), 7.82 (s, IH), 7.34 (d, J = 8.7 Hz, 2H), 6.89 , 4.86-4.78 (m, 3H), 4.69-4.66 (m, 1H), 3.81 (s, 3H), 3.23-3.18 (m, 2H), 3.03-3.02 (m, 2H).

< Example  97> N - (( 1s, 3s ) -3- (6- (3- Chlorobenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -6- (trifluoromethyl) picolinamide &lt; / RTI &gt;

(Trifluoromethyl) picolinic acid was used in place of acetic acid in the step 2 of Example 3, and (3-chlorophenyl) methanamine was used in place of 3-picolylamine , The target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.84 (d, J = 8.1Hz, 1H), 8.51 (s, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.07 (t, J = 7.8 Hz, 1H) 2H), 4.84-4.78 (m, 1H), 4.66-4.63 (m, 1H), 7.86-7.81 (m, 3H), 7.48-7.41 , 3.22-3.16 (m, 2H), 3.09-3.03 (m, 2H).

< Example  98 > N - (( 1s, 3s ) -3- (6- (4- Methoxybenzylamino ) -9H-purin-9-yl) Cyclobutyl ) -2-methylthiazole-4-carboxamide &lt; / RTI &gt;

Except that 2-methylthiazole-4-carboxylic acid was used instead of acetic acid in step 2 of Example 3, and (4-methoxyphenyl) methanamine was used instead of 3-picolylamine And the procedure of Example 3 was repeated to produce the desired compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.58 (br s, 1H), 8.53 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.33-7.28 (m, 2H), 6.89 2H), 6.28 (s, 1H), 4.83-4.62 (m, 4H), 3.80 (m, 3H), 3.23-3.13 (s, 3 H); LCMS (m / z) 450.1 (M + H) &lt; + &gt;.

< Example  99 > N - (( 1s, 3s ) -3- (6- (3- Chlorobenzylamino ) -9H-purin-9-yl) cyclobutyl) -2-methylthiazole-4-carboxamide

Except that 2-methylthiazole-4-carboxylic acid was used instead of acetic acid in step 2 of Example 3, and (3-chlorophenyl) methanamine was used instead of 3-picolylamine , &Lt; / RTI &gt; Example 3, the target compound was prepared.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.63-8.52 (m, 2H), 7.98 (s, 1H), 7.76 (s, 1H), 7.38-7.21 (m, 3H), 6.54 (s, 1H), 2H), 2.82 (s, 3H); 4.90 (s, 2H), 4.82-4.76 (m, 1H), 4.71-4.55 (m, 1H), 3.23-3.09 (m, 2H), 2.93-2.84 (m, LCMS (m / z) 454.1 (M + H) &lt; + &gt;.

< Example  100 > N - (( 1s, 3s ) -3- (6- (pyridin-3- Ylmethylamino ) -9H-purin-9-yl) cyclobutyl) -6- (trifluoromethyl) picolinamide

The procedure of Example 3 was repeated except that 6- (trifluoromethyl) picolinic acid was used instead of acetic acid in the step 2 of Example 3, to thereby prepare the target compound.

¹ H NMR 300 MHz CDCl ₃ δ 8.93 (s, 1H), 8.92-8.88 (m, 1H), 8.65-8.49 (m, 3H), 7.75 (s, 2H), 7.75-7.73 (M, 2H), 3.17-7.34 (m, 1H), 6.26 (s, 3.04 (m, 2H).

< Example  101> 6- methyl -N - (( 1s, 3s ) -3- (6- (pyridin-4- Amino ) -9H-purin-9-yl) Cyclobutyl ) Preparation of picolinamide

The procedure of Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and pyridin-4-amine was used instead of 3-picolylamine. To give the desired compound.

^{1 H NMR 300 MHz CDCl3 δ 9.43} (d, J = 8.41 Hz, 1H) 8.88 (s, 1H), 8.70 (br s, 1H), 8.41 (s, 1H), 8.06-8.04 (m, 1H), 7.81 (D, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 5.00-4.97 m, 1 H), 4.63-4.58 (m, 1 H), 3.24-3.22 (m, 2 H), 3.13-3.09 (m,

< Example  102 > N - (( 1s, 3s ) -3- (6- (3- Methoxyphenylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 3-methoxybenzeneamine was used instead of 3-picolylamine. The target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.81 (br s, 1H), 8.64 (s, 1H), 8.06-8.03 (m, 2H), 7.77-7.74 (m, 2H), 7.64 (s, 1H), 7.35- (S, 3H), 3.23-3.20 (m, 2H), 3.08 (m, 2H) -3.01 (m, 2 H), 2.67 (s, 3 H).

< Example  103> N - (( 1s, 3s ) -3- (6- (3- Chlorophenylamino ) -9H-purin-9-yl) Cyclobutyl ) -6-methylpicolinamide &lt; / RTI &gt;

The procedure of Example 3 was repeated except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3, and 3-chlorobenzeneamine was used instead of 3-picolylamine. To give the desired compound.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.83 (br s, 1H), 8.66 (s, 1H), 8.11 (s, 1H), 8.06-8.05 (m, 2H), 7.65-7.63 (m, 2H), 7.62 ( (d, J = 8.0 Hz, 1H), 7.28-8.28 (d, J = 8.0 Hz, 2H), 7.08-7.07 (m, 1H), 4.92-4.81 , 3.23-3.08 (m, 2H), 3.03-2.99 (m, 2H), 2.67 (s, 3H).

< Example  104> N - (( 1s, 3s ) -3- (6- (3,4- Dimethoxyphenylamino ) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide

Except that 6-methylpicolinic acid was used instead of acetic acid in Step 2 of Example 3 and 3,4-dimethoxybenzeneamine was used instead of 3-picolylamine, 3, the target compound was prepared.

_{^{1 H NMR 300 MHz CDCl 3 δ}} 8.81 (d, J = 8.1 Hz, 1H), 8.59 (s, 1H), 8.05-8.01 (m, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.65 ( 1H), 7.50 (s, 1H), 7.28-7.24 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 4.88-4.82 , 3.95 (s, 3H), 3.91 (s, 3H), 3.22-3.17 (m, 2H), 3.01-2.97 (m, 2H), 2.66 (s, 3H).

The structural formulas of the compounds prepared in Examples 1 to 104 are shown in Table 2 below.

Example constitutional formula Example constitutional formula One

53

2

54

3

55

4

56

5

57

6

58

7

59

8

60

9

61

10

62

11

63

12

64

13

65

14

66

15

67

16

68

17

69

18

70

19

71

20

72

21

73

22

74

23

75

24

76

25

77

26

78

27

79

28

80

29

81

30

82

31

83

32

84

33

85

34

86

35

87

36

88

37

89

38

90

39

91

40

92

41

93

42

94

43

95

44

96

45

97

46

98

47

99

48

100

49

101

50

102

51

103

52

104

< Experimental Example  1> CDK ( cyclin  dependent kinase ) Inhibition activity evaluation

In order to evaluate the inhibitory activity against the CDK enzyme of the compound according to the present invention, the following experiment was conducted.

Specifically, the experimental method was carried out according to the method provided by Perkinel Elmer. The reaction was started by adding ATP to the mixture in which the CDK 2 or CDK 5 and the substrate peptide (ULight-4E-BP) and the compound of Example 1-104 were present, and after 1 hour, a solution containing EDTA was added to stop the reaction , The phosphorylated peptide was obtained by using an antibody recognizing a phosphorylated peptide having europium (Eu). After 1 hour, the sample was excited with 320 or 340 nm light using an Envision reader, and 665 nm emission light was measured. The results are shown in Table 3 below. On the other hand, the IC ₅₀ was converted by using a grip pad prism, and as a comparative example, Dinaciclib was used.

CDK5 / p35 (h)
Enzyme activity%
Or IC ₅₀ CDK2 / cyclin A (h)
Enzyme activity%
Or IC ₅₀ Example CDK5 / p35 (h)
Enzyme activity%
Or IC ₅₀ CDK2 / cyclin A (h)
Enzyme activity%
Or IC ₅₀ Comparative Example 25 nM 22 nM 53 97 (@ 25 nM) 99 (@ 25 nM) One 102 (@ 50 nM)
105 (@ 500 nM) 107 (@ 50 nM)
98 (@ 500 nM) 54 26 (@ 25 nM)
0.01318 uM 59 (@ 25 nM)
0.009328 uM 2 101 (@ 50 nM)
89 (@ 500 nM) 97 (@ 50 nM)
83 (@ 500 nM) 55 20 (@ 25 nM) 36 (@ 25 nM) 3 89 (@ 50 nM)
55 (@ 500 nM) 103 (@ 50 nM)
83 (@ 500 nM) 56 8 (@ 25 nM)
0.001299 19 (@ 25 nM)
0.002698 uM 4 14 (@ 50 nM)
4 (@ 500 nM)
10.2 nM (IC ₅₀ ) 29 (@ 50 nM)
4 (@ 500 nM)
15.5 nM (IC50) 57 58 (@ 25 nM) 78 (@ 25 nM) 5 52 (@ 25 nM)
18 (@ 100 nM) 38 (@ 25 nM)
10 (@ 100 nM) 58 47 (@ 25 nM) 77 (@ 25 nM) 6 31 (@ 25 nM)
10 (@ 100 nM)
0.006116 uM 46 (@ 25 nM)
18 (@ 100 nM)
0.01167 uM 59 13 (@ 25 nM) 20 (@ 25 nM) 7 99 (@ 25 nM)
85 (@ 100 nM) 92 (@ 25 nM)
58 (@ 100 nM) 60 31 (@ 25 nM) 58 (@ 25 nM) 8 99 (@ 25 nM)
99 (@ 100 nM) 98 (@ 25 nM)
103 (@ 100 nM) 61 40 (@ 25 nM) 62 (@ 25 nM) 9 103 (@ 25 nM)
96 (@ 100 nM) 100 (@ 25 nM)
86 (@ 100 nM) 62 64 (@ 25 nM) 86 (@ 25 nM) 10 95 (@ 25 nM)
65 (@ 100 nM) 95 (@ 25 nM)
67 (@ 100 nM) 63 10 (@ 25 nM)
0.026 uM 18 (@ 25 nM)
0.02935uM 11 103 (@ 25 nM)
91 (@ 100 nM) 101 (@ 25 nM)
93 (@ 100 nM) 64 100 (@ 25 nM) 111 (@ 25 nM) 12 106 (@ 25 nM)
92 (@ 100 nM) 96 (@ 25 nM)
93 (@ 100 nM) 65 61 (@ 25 nM) 81 (@ 25 nM) 13 84 (@ 25 nM)
50 (@ 100 nM) 94 (@ 25 nM)
63 (@ 100 nM) 66 76 (@ 25 nM) 96 (@ 25 nM) 14 104 (@ 25 nM)
85 (@ 100 nM) 95 (@ 25 nM)
76 (@ 100 nM) 67 38 (@ 25 nM) 57 (@ 25 nM) 15 48 (@ 25 nM)
19 (@ 100 nM) 43 (@ 25 nM)
17 (@ 100 nM) 68 10 (@ 25 nM) 13 (@ 25 nM) 16 97 (@ 25 nM)
81 (@ 100 nM) 93 (@ 25 nM)
67 (@ 100 nM) 69 29 (@ 25 nM) 50 (@ 25 nM) 17 106 (@ 25 nM)
80 (@ 100 nM) 92 (@ 25 nM)
72 (@ 100 nM) 70 21 (@ 25 nM) 35 (@ 25 nM) 18 72 (@ 25 nM)
40 (@ 100 nM) 68 (@ 25 nM)
38 (@ 100 nM) 71 89 (@ 25 nM) 101 (@ 25 nM) 19 86 (@ 25 nM)
56 (@ 100 nM) 86 (@ 25 nM)
53 (@ 100 nM) 72 97 (@ 25 nM) 103 (@ 25 nM) 20 40 (@ 25 nM) 63 (@ 25 nM) 73 98 (@ 25 nM) 99 (@ 25 nM) 21 53 (@ 25 nM) 62 (@ 25 nM) 74 0.01273 uM 0.03071 uM 22 37 (@ 25 nM) 46 (@ 25 nM) 75 0.03403 uM 0.1135 uM 23 36 (@ 25 nM) 18 (@ 25 nM) 76 0.06298 uM 0.09151 uM 24 88 (@ 25 nM) 81 (@ 25 nM) 77 0.09042 uM 0.1019 uM 25 43 (@ 25 nM) 22 (@ 25 nM) 78 0.2106 uM 0.4001 uM 26 65 (@ 25 nM) 64 (@ 25 nM) 79 0.07067 uM 0.04341 uM 27 97 (@ 25 nM) 97 (@ 25 nM) 80 > 3 uM 0.2275 uM 28 107 (@ 25 nM) 104 (@ 25 nM) 81 > 3 uM 29 108 (@ 25 nM) 105 (@ 25 nM) 82 1 uM 30 66 (@ 25 nM) 84 (@ 25 nM) 83 1.413 uM 31 51 (@ 25 nM) 65 (@ 25 nM) 84 > 3 uM 32 103 (@ 25 nM) 100 (@ 25 nM) 85 0.4543 uM 0.5524 uM 33 116 (@ 25 nM) 107 (@ 25 nM) 86 0.1497 uM 0.2423 uM 34 107 (@ 25 nM) 104 (@ 25 nM) 87 0.2054 uM 0.1109 uM 35 95 (@ 25 nM) 88 (@ 25 nM) 88 0.2053 uM 0.1503 uM 36 46 (@ 25 nM) 61 (@ 25 nM) 89 > 3 uM 37 74 (@ 25 nM) 95 (@ 25 nM) 90 > 3 uM 38 77 (@ 25 nM) 92 (@ 25 nM) 91 0.4409 uM 1.113 uM 39 41 (@ 25 nM) 60 (@ 25 nM) 92 > 0.3 8.673 uM 40 45 (@ 25 nM) 68 (@ 25 nM) 93 0.03112 uM 0.03362 uM 41 28 (@ 25 nM) 55 (@ 25 nM) 94 0.02234 uM 0.03862 uM 42 13 (@ 25 nM)
0.002285 uM 28 (@ 25 nM)
0.005422 uM 95 0.04911 uM 0.03008 uM 43 47 (@ 25 nM) 69 (@ 25 nM) 96 0.06514 uM 0.09432 uM 44 82 (@ 25 nM) 104 (@ 25 nM) 97 0.09 uM 0.1057 uM 45 42 (@ 25 nM) 62 (@ 25 nM) 98 0.06335 uM 0.05308 uM 46 45 (@ 25 nM) 72 (@ 25 nM) 99 0.1839 uM 0.1959 uM 47 19 (@ 25 nM) 43 (@ 25 nM) 100 0.02316 uM 0.01223 uM 48 37 (@ 25 nM) 64 (@ 25 nM) 101 > 3 uM > 1 uM 49 25 (@ 25 nM)
0.03 uM 36 (@ 25 nM)
0.03277 uM 102 0.06693 uM > 0.001 uM 50 39 (@ 25 nM) 51 (@ 25 nM) 103 0.3965 uM > 0.1 uM 51 71 (@ 25 nM) 87 (@ 25 nM) 104 0.09355 uM 0.03379 uM 52 70 (@ 25 nM) 89 (@ 25 nM)

(In Table 3,

A (@ B nM) indicates that the maintenance enzyme activity rate is A% when the amount of compound administered is B nM; And

The result value written in the form of C uM or C nM represents the IC ₅₀ value)

As can be seen in Table 3 above, the novel CDK inhibitor compounds according to the present invention can inhibit CDK activity to a greater or similar level than the comparative control dynasicyl lip.

Accordingly, the novel CDK inhibitory compound according to the present invention exhibits excellent inhibitory activity at a nanomolar concentration in CDK 2 and CDK 5, and is useful as a pharmaceutical composition for the prophylaxis or treatment of CDK-related diseases, preferably cancer or neurodegenerative diseases Can be used.

Claims (10)

Claims 1. A compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is substituted or unsubstituted C _3-10 cycloalkyl, substituted or unsubstituted C _3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, Substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted C _5-10 heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, substituted or unsubstituted C _3-10 cycloalkyl C _1-10 alkyl, N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _3-10 heterocycloalkyl C _1-10 alkyl, Substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or substituted or unsubstituted C _5-10 heteroaryl C _{1 -10} heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S _{Lt; /} RTI &gt;
Wherein said substituted C _3-10 cycloalkyl, substituted C _3-10 heterocycloalkyl, substituted C _6-10 aryl, substituted C _5-10 heteroaryl, substituted C _3-10 cyclo alkyl C _1-10 alkyl, substituted C _3-10 heterocycloalkyl C _1-10 alkyl, substituted C _6-10 aryl C _1-10 alkyl and substituted C _5-10 heteroaryl C _1-10 alkyl is optionally substituted Or unsubstituted C _1-10 linear or branched alkyl, substituted or unsubstituted C _1-10 linear or branched alkoxy, halogen, cyano, hydroxy, phenyl, C _1-2 alkylphenyl, substituted Substituted or unsubstituted C _1-2 alkylamino, substituted or unsubstituted C _1-2 alkylamino, sulfonyl, C ₁ -C ₆ alkyl, _-2 shed some light substituted with alkylsulfonyl, C _1-2 alkyl sulfonyl, aminosulfonyl, one or more substituents selected from the group consisting of C _1-2 alkyl, aminosulfonyl and di-C _1-2 alkylamino-sulfonyl , Or is cycloalkyl, fused with a ring selected from heterocycloalkyl, aryl, and the group consisting of C _5-10 heteroaryl C _6-10 of the C _3-10 (fused) a C _3-10,
Wherein said substituted C _1-10 straight or branched chain alkyl, substituted C _1-10 straight chain or branched chain alkoxy, substituted benzyl, substituted C _1-2 alkylamino, substituted di C _{1- 2} alkylamino is substituted with one or more substituents selected from the group consisting of -CF ₃ , hydroxy, oxo, cyano, and halogen;

R ³ is selected from the group consisting of hydroxy, triisopropylsilyloxy (-OTIPS), straight or branched chain C _1-10 alkoxy, carboxy, C _1-2 alkylcarboxy, -NH-CO-R ⁴ , -NH-R ^{4 , -CO-NH-R 4,} -CO-R 4, -NH-CO-R 4 -CO-NH-R 5, -CO-NH-R 4 -CO-NH-R 5, -NH-CO- R ⁴ -NH-CO-R ⁵ , or -CO-NH-R ⁴ -NH-CO-R ⁵ ,
Wherein R ⁴ and R ⁵ are each independently a substituted or unsubstituted C _3-10 cycloalkyl, a substituted or unsubstituted alkylene group containing at least one heteroatom selected from the group consisting of N, O, and S, heterocycloalkyl, substituted or unsubstituted aryl of _6-10 ring C of _3-10 C, N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S, or unsubstituted C _5-10 ring a heteroaryl group, a substituted or unsubstituted C _3-10 cycloalkyl C _1-10 alkyl, N, O, and a substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of a C _3-10 ring S heterocycloalkyl C _1-10 alkyl, substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or N, O, and substituted and containing one or more heteroatoms selected from the group consisting of S or unsubstituted _Gt; C10 &lt; / RTI &gt; heteroaryl Ci- ₁₀ alkyl,
Wherein said substituted C _3-10 cycloalkyl, substituted C _3-10 heterocycloalkyl, substituted C _6-10 aryl, substituted C _5-10 heteroaryl, substituted C _3-10 cycloalkyl C _1-10 alkyl, substituted C _3-10 heterocycloalkyl C _1-10 alkyl, substituted C _6-10 aryl C _1-10 alkyl and substituted C _5-10 heteroaryl C _1-10 alkyl is Substituted or unsubstituted C _1-10 straight-chain or branched alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, halogen, cyano, hydroxy, phenyl, C _1-2 alkylphenyl, Substituted or unsubstituted benzyl, substituted or unsubstituted benzyl, tert-butyloxycarbonyl (-Boc), amino, substituted or unsubstituted C _1-2 alkylamino, substituted or unsubstituted C _1-2 alkylamino, substituted with _1-2 alkylsulfonyl, C _1-2 alkyl sulfonyl, aminosulfonyl, C _1-2 alkylamino, di C _1-2 sulfonyl, and one or more substituents selected from the group consisting of alkyl aminosulfonyl Or, or it is a fusion (fused) with one of the ring is selected from heterocycloalkyl, aryl, and the group consisting of C _5-10 heteroaryl group of C _6-10 cycloalkyl, C _3-10 of C _3-10,
Wherein said substituted C _1-10 straight chain or branched chain alkyl, substituted C _1-10 straight chain or branched chain alkoxy, substituted benzyl, substituted C _1-2 alkylamino, substituted di C _{1 -2} alkylamino is substituted with one or more substituents selected from the group consisting of -CF ₃ , hydroxy, oxo, cyano, and halogen; And

And A is a carbon or nitrogen atom.
delete The method according to claim 1,
R ¹ is

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A stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ³ is -OH, -COOH, -COOCH ₃ ,

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or

A stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Any one compound selected from the following group of compounds, its stereoisomer or pharmaceutically acceptable salt thereof:
(1) (lr, 3r) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanol;
(2) (ls, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanol;
(3) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide;
(4) 6-Methyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(5S) -3- (6- (1- (methylsulfonyl) piperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) Picolinamide;
(6) N - ((1s, 3s) -3- (6- (3-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(7S) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutylcarbamoyl) pyrrolidine- Rate;
(8) N - ((1 s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) pyrrolidine-2-carboxamide;
(9) 1- (Methylsulfonyl) -N - ((1S, 3S) -3- (6- (pyridin- 3- ylmethylamino) -9H- purin-9- yl) cyclobutyl) piperidin- 4-carboxamide;
(10) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) morpholine-4-carboxamide;
(11) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) nicotinamide;
(12) N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) isonicotinamide;
(13) N - ((1s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) pyrazine-2-carboxamide;
(14) Synthesis of 1-methyl-N - ((ls, 3s) -3- (6- (pyridin- 3- ylmethylamino) -9H- purin- amides;
(15) 2-Phenyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide;
(16) 2-Cyclohexyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) acetamide;
(17) Synthesis of N - ((1 s, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H- purin-9-yl) cyclobutyl) -tetrahydro- amides;
(18) N - ((1 s, 3s) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(19) 4-Methoxy-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(20) N - ((1s, 3s) -3- (6- (3-chlorophenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(21) N - ((1s, 3s) -3- (6- (3-fluorophenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(22) N - ((1 s, 3s) -3- (6- (4-methoxyphenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(23) 2,6-Dichloro-N - ((ls, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(24) 2,3-Dichloro-N - ((ls, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(25) 2,6-Difluoro-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(26) 4-Chloro-2-methoxy-N - ((ls, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(27) (lr, 3r) -Methyl 3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxylate;
(28) (lr, 3r) -3- (6- (Pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxylic acid;
(29) N-phenyl-3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxamide;
(30) 6-Methyl-N - ((1s, 3s) -3- (6- (naphthalen-1-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(31) N - ((1 s, 3s) -3- (6- (4-cyanobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(32) N - ((1 R, 3S) -3- (6 - ((S) -2-hydroxy- 1 -phenylethylamino) -9H- purin-9-yl) cyclobutyl) Choline amide;
(33) N - ((1S, 3S) -3- (6 - ((R) -2-hydroxy-2- phenylethylamino) -9H- purin-9-yl) cyclobutyl) Choline amide;
(34) Synthesis of N- (1- (methylsulfonyl) piperidin-4-yl) -3- (6- (pyridin- 3- ylmethylamino) -9H-purin-9-yl) cyclobutanecarboxamide ;
(35) 1-Methyl-N - ((ls, 3s) -3- (6- (pyridin- 3- ylmethylamino) -9H- purin- Carboxamide;
(36) 6-Methyl-N - ((ls, 3s) -3- (6- (pyridin-2-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(37) 6-Methyl-N - ((ls, 3s) -3- (6- (2-methylbenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(38) N - ((1 s, 3s) -3- (6- (2-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(39) N - ((1s, 3s) -3- (6- (2-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(40) N - ((1s, 3s) -3- (6- (2-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(41) 6-Methyl-N - ((1s, 3s) -3- (6- (3- (trifluoromethyl) benzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(42) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(43) N - ((1 s, 3s) -3- (6- (4- (Dimethylamino) benzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(44) 6-Methyl-N - ((ls, 3s) -3- (6- (pyridin-4-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(45) 6-Methyl-N - ((lS, 3s) -3- (6- (4- (trifluoromethyl) benzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(46) 6-Methyl-N - ((1s, 3s) -3- (6- (4- (trifluoromethoxy) benzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(47) N - ((1 s, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(48) 6-Methyl-N - ((ls, 3s) -3- (6- (4-sulfamoylbenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(49) N - ((1s, 3s) -3- (6- (Cyclohexylmethylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(50) N - ((1 S, 3S) -3- (6 - ((2,3-dihydrobenzo [b] [1,4] dioxin- 2- yl) methylamino) -9H- -Yl) cyclobutyl) -6-methylpicolinamide;
(51) 3,5-Dimethyl-N - ((ls, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(52) 3,4-Dimethyl-N - ((ls, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(53) 3- (dimethylamino) -N - ((1s, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9-yl) cyclobutyl) benzamide;
(54) N - ((1s, 3s) -3- (6- (4-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(55) N - ((lr, 3r) -3- (6- (4-bromobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(56) N - ((lr, 3r) -3- (6- (3-bromobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(57) N - ((1 r, 3r) -3- (6- (2,4-dimethoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(58) N - ((lr, 3r) -3- (6- (3,4-Dimethoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(59) N - ((lr, 3r) -3- (6- (3-hydroxy-4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(60) N - ((lr, 3r) -3- (6- (4-hydroxy-3-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(61) N - ((lr, 3r) -3- (6- (3-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6- methoxypicolinamide;
(62) 6-Methoxy-N - ((lr, 3r) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(63) 6-Chloro-N - ((lr, 3r) -3- (6- (3-fluorobenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(64) 6-Methyl-N - ((ls, 3s) -3- (6- (2-phenylacetamido) -9H-purin-9-yl) cyclobutyl) picolinamide;
(65) 6-Methyl-N - ((1s, 3s) -3- (6- (4-phenoxybenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(66) N - ((1 s, 3s) -3- (6- (4- (4-fluorophenoxy) benzylamino) -9H- purin-9-yl) cyclobutyl) -6-methylpicolinamide ;
(67) N - ((1 s, 3s) -3- (6- (3,5-Dichloro-4-methoxybenzylamino) -9H- purin-9- yl) cyclobutyl) -6- methylpicolinamide ;
(68) N - ((1s, 3s) -3- (6- (3-Bromo-4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(69) N - ((1s, 3s) -3- (6- (4- (Benzyloxy) benzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(70) N - ((1s, 3s) -3- (6- (4-Isopropoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(71) (6-Methylpyridin-2-yl) (3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) azetidin-1-yl) methanone;
(72) (3- (6- (3-Chlorobenzylamino) -9H-purin-9-yl) azetidin-1-yl) (6-methylpyridin-2-yl) methanone;
(73) (3- (6- (3-Bromobenzylamino) -9H-purin-9-yl) azetidin-1-yl) (6-methylpyridin-2-yl) methanone;
(74) N - ((1s, 3s) -3- (6- (3,4-Difluorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(75) N - ((1s, 3s) -3- (6- (3,4-Dichlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(76) tert -Butyl 4- (9- (ls, 3s) -3- (6-methylpicolinamido) cyclobutyl) -9H-purin-6-ylamino) piperidine- ;
(77) tert-Butyl 4 - ((9 - ((1 s, 3s) -3- (6-methylpicolinamido) cyclobutyl) -9H- purin- - carboxylate;
(78) 6-Methyl-N - ((ls, 3s) -3- (6- (piperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride;
(79) 6-Methyl-N - ((ls, 3s) -3- (6- (piperidin-4-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride;
(80) N - ((lr, 3r) -3- (6- (3-bromobenzylamino) -9H-purin-9-yl) cyclobutyl) benzo [d] thiazol-2-amine;
(81) 6-Methyl-N - ((ls, 3s) -3- (6- (l -methylpiperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(82) N - ((1 s, 3s) -3- (6 - ((1 r, 4r) -4- hydroxycyclohexylamino) -9H- purin- 9- yl) cyclobutyl) -6- amides;
(83) tert -Butyl 3- (9 - ((ls, 3s) -3- (6-methylpicolinamido) cyclobutyl) -9H- purin-6-ylamino) pyrrolidine- ;
(84) 6-Methyl-N - ((ls, 3s) -3- (6- (pyrrolidin-3-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide hydrochloride;
(85) N - ((1 s, 3s) -3- (6- (1-Acetylpiperidin-4-ylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(86) 6-Methyl-N - ((ls, 3s) -3- (6- (1- (2-phenylacetyl) piperidin- 4- ylamino) -9H- purin- ) Picolinamide;
(87) N - ((1 s, 3s) -3- (6 - ((1 s, 4s) -4- acetamidocyclohexylamino) -9H- purin- Choline amide;
-9H-purin-9-yl) cyclobutyl) -6-methylpiperazin-1-ylmethoxy) - N - ((1S, 3S) -3- (6- ( Choline amide;
(89) N2- (4S, 3S) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) , 6-dicarboxamide;
(90) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-cyanopicolinamide;
(91) N - ((1s, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6-phenylpicolinamide;
(92) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-phenylpicolinamide;
(93) 6-Phenyl-N - ((1s, 3s) -3- (6- (pyridin-3-ylmethylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(94) 6-Ethyl-N - ((ls, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(95) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6-ethylpicolinamide;
(96) N - ((ls, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -6- (trifluoromethyl) picolinamide;
(97) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -6- (trifluoromethyl) picolinamide;
(98) N - ((ls, 3s) -3- (6- (4-methoxybenzylamino) -9H-purin-9-yl) cyclobutyl) -2-methylthiazole-4-carboxamide;
(99) N - ((1s, 3s) -3- (6- (3-chlorobenzylamino) -9H-purin-9-yl) cyclobutyl) -2-methylthiazole-4-carboxamide;
(100) N - ((1 s, 3s) -3- (6- (pyridin-3- ylmethylamino) -9H-purin-9- yl) cyclobutyl) -6- (trifluoromethyl) picolinamide ;
(101) 6-Methyl-N - ((ls, 3s) -3- (6- (pyridin-4-ylamino) -9H-purin-9-yl) cyclobutyl) picolinamide;
(102) N - ((1s, 3s) -3- (6- (3-methoxyphenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide;
(103) N - ((1s, 3s) -3- (6- (3-chlorophenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide; And
(104) N - ((1 s, 3s) -3- (6- (3,4-Dimethoxyphenylamino) -9H-purin-9-yl) cyclobutyl) -6-methylpicolinamide.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with 6-chloropurine to prepare a compound represented by the formula (3) (step 1);
Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2); And
A process for producing a compound represented by the formula (1) by reacting a compound represented by the formula (4) and R ¹ -NH ₂ represented by the formula (5) Preparation of the indicated compounds:
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
A, R ¹ and R ³ are as defined in formula I of claim 1;
B is -OTIPS or -NHBoc.
A pharmaceutical composition for the prophylaxis or treatment of CDK (cyclin dependent kinase) -related disease comprising the compound of any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient,
Wherein the CDK-related disease is cancer or neurodegenerative disease.
8. The method of claim 7,
The pharmaceutical composition according to any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which inhibits cyclin dependent kinase (CDK) to prevent or treat cancer or a neurodegenerative disease.
9. The method of claim 8,
The cancer may be selected from the group consisting of a cancer selected from the group consisting of a cancer selected from the group consisting of a caudal myxoma, an intrahepatic bile duct cancer, a hepatoblastoma, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a myelodysplastic syndrome, a glioblastoma, a oral cancer, a larynx cancer, a bacterial sarcoma, an acute lymphocytic leukemia, Cholangiocarcinoma, cholangiocarcinoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Barter's bulge, ovarian cancer, ovarian cancer, ovarian cancer cell, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, Cancer, bladder cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Malignant melanoma, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovarian cancer, vulvar cancer, ureter cancer, urethral cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, Cancer of the uterus, uterine cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, uterine cancer, breast cancer, sarcoma, penile cancer, Cancer of the lungs, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, neuroendocrine tumor, pancreatic cancer, salivary cancer, Kaposi sarcoma, Paget's disease, Skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma; And
Such neurodegenerative diseases include, but are not limited to, alcoholism, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, HIV-associated dementia, Alzheimer's disease, Alzheimer's disease, Lewy body dementia, tauopathy, progressive supranuclear palsy, corticobasal degeneration, Argyrophilic Grain Disease, peak disease, amyotrophic lateral sclerosis (ALS) ), C-type Niemann-Pick Type C (NPC) and epilepsia, multiple sclerosis (MS), muscular atrophy (MD) and hereditary frontotemporal dementia &Lt; / RTI &gt;
A health functional food for preventing or ameliorating a CDK (cyclin dependent kinase) -related disease containing the compound of any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient,
Wherein said CDK-related disease is cancer or neurodegenerative disease.