KR20230149753A - Protein kinase inhibitor and use thereof - Google Patents

Abstract

Provided are compounds of formula 1 having protein kinase inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, and uses thereof.

Description

Protein kinase inhibitor and use thereof {Protein kinase inhibitor and use thereof}

The present disclosure relates to compounds of formula 1 having protein kinase inhibitory activity and their uses.

Protein kinase is an enzyme that catalyzes the phosphorylation of hydroxy groups located on tyrosine, serine, and threonine residues of proteins, and plays an important role in growth factor signal transduction that causes cell growth, differentiation, and proliferation. Mutation or overexpression of specific protein kinases can cause various diseases by disrupting the normal intracellular signaling system.

The protein kinases include Bruton's tyrosine kinase (BTK). BTK is an enzyme encoded by the BTK gene in humans. BTK is a kinase that plays an important role in B cell development. BTK plays an important role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor. BTK contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). When PIP3 binds to BTK, it induces BTK to phosphorylate phospholipase C. Phosphorylated phospholipase C hydrolyzes PIP2 and phosphatidylinositol to generate two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). These secondary messengers regulate the activity of downstream proteins during B cell signaling.

Ibrutinib is the first approved BTK inhibitor and is being used to treat leukemia (CLL) and lymphoma (MCL). However, ibrutinib is an irreversible inhibitor that covalently binds to C481 in BTK, so there is a problem in that it cannot treat patients with C481 mutation. Accordingly, reversible non-covalent BTK inhibitors are being developed. For example, International Publication No. WO2017/103611 discloses a reversible BTK inhibitor, its preparation method, and its use. Nevertheless, alternative BTK inhibitors are needed.

One aspect is to provide a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another aspect is to provide a pharmaceutical composition for use in treating a disease mediated by protein kinases, comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .

Another aspect is to provide a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect provides a method of treating a disease mediated by protein kinases in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. .

Another aspect is to provide a method of inhibiting the activity of a protein kinase comprising contacting the protein kinase with a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

One aspect provides a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

In Formula 1,

Cy is C _3-12 aryl, C _3-12 cycloalkyl or C _3-10 heteroaryl, and the C _3-12 aryl, C _3-12 cycloalkyl or C _3-10 heteroaryl is C _1-6 alkyl, C _1-6 alkoxy, halo, cyano, -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), C _{1- 6} alkylNR ₃ - (wherein R ₃ is hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl) and hydroxy;

A is a 5-membered ring having 2 or more N atoms or -CONH-;

X is CH or S;

Y is NH or O when X is CH, or CH when X is S;

Z ₁ is C;

R ₁ is C _1-6 alkyl (where C _1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC _1-6 alkyl (where C _1-6 alkyl may be substituted with one or more halo or hydroxy), may be substituted with halo or hydroxy), NR ₃ R ₄ C _1-6 alkyl (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl) , -NR ₃ R ₄ (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), NR ₃ R ₄ C _1-6 alkylcarbonyl (here R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, hydroxy, C _1-6 alkoxy, halo, C _3-6 cycloether, and C _3-10 heterocycloalkyl-(CH ₂ )n1 (n1 is an integer of 0 to 6), C _3-10 which may be substituted with one or more substituents selected from the group consisting of C _1-6 alkylcarbonyl. Oxoheterocycloalkyl, -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _{1 -6} alkyl), -OR ₃ where R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl), or -SR ₃ , where R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl;

Z ₂ is CH or N;

R ₂ is C _3-12 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 heterocycloalkyl, C ₃ formed by combining the N of L ₂ with carbon. _-10 heterocycloalkyl, C _3-10 heteroaryl, or C _3-12 aryl, and the C _3-12 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 heterocycloalkyl, C _3-10 heterocycloalkyl formed by combining the N of L ₂ with carbon, C _3-10 heteroaryl, or C _3-12 aryl is hydroxy, C _1-6 alkoxy, -NR ₃ R ₄ (where R ₃ and R ₄ are independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, halo, C _1-6 alkyl (where C _{1-6 6} alkyl may be substituted with one or more halo or hydroxy), C _1-6 alkylsulfonyl, C _1-6 alkylphosphonyl, aminosulfonyl, -CONH ₂ , or C _3-12 cycloalkyl (here C _3-12 cycloalkyl may be substituted with hydroxy or hydroxyC _1-6 alkyl) and may be substituted with one or more substituents selected from the group consisting of;

L ₁ and L ₂ are independently NH, N, O, or S;

n is an integer of 0 or 1.

In embodiments, Cy can be C _5-12 aryl, C _5-12 cycloalkyl, or C _3-6 heteroaryl.

In certain examples, Cy can be phenyl, cyclohexyl, pyrazolyl, or pyridyl.

In particular, Cy may be phenyl or pyridyl.

In particular, Cy is substituted with one or more substituents selected from the group consisting of C _1-6 alkyl, halo or -NR ₃ R ₄ (wherein R ₃ and R ₄ are each independently hydrogen or C _1-6 alkyl) It can be.

In embodiments, A can be a 5-membered heteroaryl having two or more N atoms. A may be a 5-membered ring having 2 to 4 N atoms, or 2 or 3 N atoms and 1 O atom, or -CONH-. In certain examples, A can have 2 to 4 N atoms, or can be a 5-membered heteroaryl with 2 or 3 N atoms and 1 O atom.

In certain examples, A can be imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-. When A is -CONH-, N may be bonding to Cy, and C may be bonding to Cy.

In particular, A may be imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.

More particularly, A may be tetrazolyl, oxadiazolyl, or -CONH-.

In embodiments, R ₁ is C _1-6 alkyl (wherein C _1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC _1-6 alkyl (wherein C _1-6 alkyl may be substituted with one or more halo or hydroxy), NR ₃ R ₄ C _1-6 alkyl (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl carbonyl), -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), NR ₃ R ₄ C _1-6 alkyl carbonyl (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, hydroxy, C _1-6 alkoxy, halo, C _{3- 6} C _3-10 heterocycloalkyl-(CH ₂ )n1 (n1 is an integer from 0 to 6), which may be substituted with one or more substituents selected from the group consisting of cycloether, and C _1-6 alkylcarbonyl; C _3-10 oxoheterocycloalkyl, -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or is hydroxyC _1-6 alkyl), -OR ₃ (wherein R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl) , or -SR ₃ wherein R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl.

In certain instances, R ₁ is C _1-6 alkyl (wherein C _1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC _1-6 alkyl (wherein C _1-6 alkyl may be substituted with one or more halo or hydroxy), NR ₃ R ₄ C _1-6 alkyl (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkyl carbonyl), -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), NR ₃ R ₄ C _1-6 alkyl carbonyl (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, hydroxy, halo, C _3-6 cycloether, and C morpholinyl, morpholinomethyl, piperazinyl, piperidinyl or pyrrolidinyl, which may be substituted with one or more substituents selected from the group consisting of _1-6 alkylcarbonyl; -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl) ; -OR ₃ where R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl); or -SR ₃ wherein R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl, or hydroxyC _1-6 alkyl.

In an embodiment, when R ₁ is C _3-10 heterocycloalkyl, one of the heteroatoms of C _3-10 heterocycloalkyl may be bonded to the carbon of Z 1 . One of the heteroatoms may be N, O, or S.

In embodiments, R ₂ is C _3-12 cycloalkyl, C _1-6 alkyl, C _3-10 heterocycloalkyl, C _3-10 heterocycloalkyl formed by combining the N of L ₂ with carbon, or C _{3- 12} Can be aryl. The C _3-12 cycloalkyl may be bicyclic or spiro.

In certain instances, R ₂ is C _4-7 cycloalkyl, C _1-6 alkyl, C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl formed by combining the N and carbon of L ₂ , or C _{5- 12} Can be aryl.

In particular, R ₂ is C _4-7 cycloalkyl, C _1-6 alkyl, C _4-7 heterocycloalkyl, C 4-7 heterocycloalkyl formed by combining N and carbon of L 2, or C _5-12 aryl, The C _4-7 cycloalkyl, C _1-6 alkyl, C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl formed by combining N and carbon of L ₂ , or C _5-12 aryl is hydroxy, It may be substituted with hydroxymethyl, cyano, -CONH ₂ , or aminosulfonyl.

In embodiments, L ₁ and L ₂ may be independently NH, N, or O.

For example, the compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

(1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia zol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(piperazine -1-yl)pyridin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((4-(4-isopropylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((4-(4-ethylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia zol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol;

N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-(4-(2-hydroxyethyl)piperazine -1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide;

(1R,4R)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole -2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia zol-2-yl))amino)pyrimidin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclohexan-1-ol;

(1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl ) amino) pyridin-2-yl) amino) cyclohexan-1-ol; and

(1R,4R)-4-((4-((4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia sol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol.

(1R,4R)-4-((4-(4-fluoropiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl ) thiazol-2-yl ) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-morpholinopyrimidin-4-yl)amino) Thiazole-5-carboxamide

(1R,4R)-4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl) thiazol -2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-(piperic din-1-yl) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyridin-2-yl)amino)cyclohexan-1-ol

N-(2-chloro-6-methylphenyl)-2-((6-(4-fluoropiperidin-1-yl)-2-(((1R,4R)-4-hydroxycyclohexyl)amino ) pyrimidin-4-yl) amino) thiazole-5-carboxamide

(1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -6-morpholinopyrimidin- 2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-(methylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino ) pyrimidin-2 -yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-(dimethylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino ) pyrimidin-2 -yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-thiomopoly Nopyrimidin-2-yl) amino) cyclohexan-1-ol

(1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclopentan-1-ol

(1R,3R)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclobutan-1-ol

6-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)spiro[3.3]heptan-2-ol

(1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclopentan-1-ol

(1S,4R)-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((5-(5-phenyl- 1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole -2-yl) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

1-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-4-yl)piperidin-4-ol

(1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-(2, 2,6,6-tetrafluoromorpholino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-((2-methoxyethyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

1-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one

1-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile

(1R,4R)-4-((4-methoxy-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyri midin-2-yl)amino)cyclohexan-1-ol

1-(4-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one

(1R,4R)-4-((4-(4-methoxypiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-(4-(dimethylamino)piperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol- 2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((4-(1H-imidazol-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)methyl)-3,4-dihydropyridin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)adamantane-1-ol

4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol

(S)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)propan-1-ol

4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia sol-2-yl) amino) pyrimidin-2-yl) amino) bicyclo [2.2.2] octan-1-ol

(S)-3-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)piperidine-1-carbonitrile

3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2 -yl)amino)piperidine -1-carbonitrile

4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.2]octan-1-ol

1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2- 1) Pyrrolidin-3-ol

4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Synthesis of amino)phenol

(1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2 -yl)piperidin-4-yl)methanol

(S)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)propan-1-ol

(R)-N-(2-chloro-6-methylphenyl)-2-((2-(3-hydroxypyrrolidin-1-yl)-6-morpholinopyrimidin-4-yl)amino) Thiazole-5-carboxamide

(1R,4R)-4-(methyl(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-)amino) Pyrimidin-2-yl)amino)cyclohexan-1-ol

(R)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)pyrrolidin-3-yl)methanol

(S)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)pyrrolidin-3-yl)methanol

(S)-1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)pyrrolidine-2-carboxamide

(R)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)propan-1-ol

4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.1]heptan-1-ol

4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)adamantan-1-ol

4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)adamantane-1-ol

(1R,4R)-1-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin -2-yl) amino) cyclohexan-1-ol

3-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)butan-1-ol

N-(2-chloro-6-methylphenyl)-2-((2-((5-hydroxyadamantan-2-yl)amino)-6-morpholinopyrimidin-4-yl)amino)thia Sol-5-carboxamide

3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[1.1.1]pentan-1-ol

3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)phenol

For example, the compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, but the scope of the present disclosure is not limited thereto:

The compound of Formula 1 may be substituted with a detectable label. The detectable label may be an optical label, an electrical label, a magnetic label, or an indirect label. An optical label is a substance that generates a detectable optical signal and may be a radioactive substance or a coloring substance such as a fluorescent substance. An indirect label refers to a substance that can generate a detectable label as a result of binding to a specific substance, such as an enzyme that converts a substrate into a coloring substance or its substrate, antibody, or antigen. The optical label may be an isotope of an element constituting the compound of Formula 1. Accordingly, the compound of Formula 1 may have one or more of the elements constituting it replaced with its isotope, for example, a radioactive isotope. Examples of these isotopes include ² H (which can be represented by D for deuterium), ³ H (which can be represented by T for tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, Includes ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, etc.

The compounds of the present disclosure may be in the form of their pharmaceutically acceptable salts. Said salts include the usual acid addition salts used in the pharmaceutical field, for example salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid, and salts derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, Contains salts derived from organic acids such as citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid. do. The salts also include common metal salt forms, for example salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium. The acid addition salt or metal salt can be prepared according to conventional methods.

Compounds of the present disclosure may also be in the form of their solvates. “Solvate” means a complex or aggregate formed by one or more solute molecules, i.e. a compound of Formula 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more solvent molecules. Solvates may be complexes or aggregates formed with, for example, water, methanol, ethanol, isopropanol, acetic acid, or dimethyl sulfoxide (DMSO).

Compounds of the present disclosure may also be in the form of their stereoisomers. The stereoisomers include all stereoisomers such as enantiomers and diastereomers. The compound may be in stereoisomerically pure form or a mixture of one or more stereoisomers, for example a racemic mixture. Separation of specific stereoisomers can be performed by any of the conventional methods known in the art. Some examples of compounds of the present disclosure may have a greater BTK inhibitory effect of specific stereoisomers than their racemic mixtures. In this case, the dosage can be reduced by using a specific stereoisomer.

In relation to the compounds, compositions and methods of this disclosure, the following terms have the following meanings, unless otherwise indicated.

The term “alkyl” refers to a straight-chain or branched saturated hydrocarbon group. The alkyl may contain 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Alkyl is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, It may contain n-nonyl or n-decyl.

The term “alkenyl” refers to alkyl having at least one carbon-carbon double bond. where alkyl is as defined above. Alkenyl may be, for example, ethenyl or propenyl.

The term “alkynyl” refers to alkyl having at least one carbon-carbon triple bond. where alkyl is as defined above. Alkynyl may be, for example, ethynyl or 2-propynyl.

The term “alkoxy” refers to an (alkyl)O-group. where alkyl is as defined above.

The term “aryl” refers to an aromatic ring in which each ring-forming atom is a carbon atom. The ring may be monocyclic or polycyclic. The polycyclic ring may include one having a fused ring (e.g. naphthalene) or one having an unfused ring (e.g. biphenyl). The polycyclic ring may have, for example, 2, 3, or 4 rings. The aryl group is, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 5 to 20, 5 to 15, 5 to 12, 5 to 10. , or has 6 to 10 carbon ring atoms. Such aryl groups include, for example, phenyl, naphthalenyl (e.g., naphthalen-1-yl and naphthalen-2-yl), biphenyl, anthracenyl, and phenanthrenyl.

The term “cycloalkyl” refers to a non-aromatic carbon ring in which each ring-forming atom is a carbon atom. The cycloalkyl may be monocyclic or polycyclic. The polycyclic ring is one having, for example, 2, 3 or 4 fused rings. The cycloalkyl may include one fused to an aromatic ring. The cycloalkyl has, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 3 to 10, 3 to 7, 5 to 7, or 5 to 6 ring carbons. Contains atoms. Cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcanyl, and adamantyl. The “cycloalkyl” may include a spiro ring. The spiro ring may include a C7, C8, or C10 ring.

The term “heterocycloalkyl” refers to a carbon ring containing 1 to 4 ring-forming heteroatoms each selected from N, O, and S. Heterocycloalkyl may be one that does not have two adjacent O or S. Heterocycloalkyls include monocyclic or polycyclic structures, for example, structures having two, three or four fused rings. Examples of “heterocycloalkyl” include morpholinyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, oxadiazolyl , oxanyl, etc. The heterocycloalkyl is, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 3 to 10, 4 to 10, 3 to 7, 5 to 5. It contains 7 or 5 to 6 ring-forming atoms.

Cyclic groups (e.g., cycloaliphatic and heterocyclic) may be linearly fused, bridged, or spirocyclic. For example, cycloalkyls include adamantyl, bicyclo[1.1.1]fentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and spiro[4.4]. ]octanyl or spiro[5.5]undecanyl, and heterocycloalkyl may include 2-oxa-5-azabicyclo[2.2.1]heptane or cyclopenta[c]pyrrole.

The term “heteroaryl” refers to an aromatic carbon ring having 1 to 4 heteroatoms selected from N, O and S as ring members. Heteroaryl includes monocyclic or polycyclic structures. The polycyclic ring may have, for example, 2, 3, or 4 condensed rings. The heteroaryl contains, for example, 3 to 10, 5 to 10, 5 to 8, 5 to 7, 5, 6, or 7 ring atoms. The heteroaryl may contain 1, 2, or 3 heteroatoms. Heteroaryl is, for example, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, furanyl, benzoyl. Furanonyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl , isothiazolyl, benzothienyl, purinyl, benzimidazolyl, or indolinyl.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

Another aspect provides a pharmaceutical composition for use in treating a disease mediated by protein kinases, comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The disease may be caused by an increase in protein kinase activity.

The protein kinase may catalyze the reaction of adding a phosphate group to another protein. The protein kinase may be a serine/threonine-specific protein kinase, a tyrosine-specific protein kinase, or a serine/threonine and tyrosine protein kinase. The protein kinase may be a receptor or non-receptor protein kinase. Receptor protein kinases include, for example, PDGFR or VEGFR. The non-receptor protein kinase may be a member of an intracellular protein. The non-receptor protein kinase may be a member of the Syk, SRC, or Tec families.

cSRC is the prototypical member of the SRC family of tyrosine kinases, which includes Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk, and Yes.

Tec kinase may be a non-receptor tyrosine kinase expressed primarily in cells of hematological origin. The Tec family includes Tec, Btk, inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and myeloid expressed kinase (Bmx/Etk).

In the composition, Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of tyrosine kinases and is a key regulator of early B cell development, mature B cell activation, signaling and survival. B cell signaling through the B cell receptor (BCR) results in a wide range of biological outputs. Abnormal BCR-mediated signaling can lead to deregulated B cell proliferation and/or formation of pathogenic autoantibodies that lead to multiple autoimmune and/or inflammatory diseases. In humans, mutations in BTK can cause X-linked agammaglobulinaemia (XLA). The disease is associated with impaired maturation of B cells, reduced immunoglobulin production, T cell-independent immune responses, and marked attenuation of sustained calcium signaling upon BCR stimulation.

The protein kinase may be a cysteine-containing kinase. The protein kinase may have a cysteine residue near the ATP-binding site of the kinase. The cysteine residue may be in close spatial proximity near the ATP-binding site of the kinase. Protein kinases with cysteine residues near the ATP-binding site may be BTK, BMX, TEC, TXK, ITK, EGFR, ErbB, JAK3, BLK, etc.

In an embodiment, the protein kinase is ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX/ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B , EPHA, EPHB, FAK/PTK2, FER, FES/FPS, FGFR, FGR, FLT3, FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GSK3b, HCK, IGF1R, IR, IRAK1, IRR/INSRR, ITK, JAK2 , KHS/MAP4K5, LCK, LYN, PHKg, PLK4/SAK, PYK2, RET, ROS/ROS1, TIE2/TEK, TRK, TXK, TYK, YES/YES1, or a combination thereof.

The protein kinase may be BTK, especially C481 mutant BTK, for example C481S BTK.

Inhibition of protein kinase activity, such as BTK, may be useful in treating the following autoimmune and/or inflammatory diseases. Moreover, protein kinases, such as BTK, have been reported to play a role in apoptosis. Inhibition of protein kinase activity, such as BTK, may be useful in treating B-cell proliferative disorders or mast cell proliferative disorders. Inhibition of protein kinase activity, such as BTK, may be useful in treating cancers such as B cell lymphoma and leukemia. In the composition, the disease may be cancer, inflammatory disease, or autoimmune disease. The cancer may be a solid cancer or a hematological cancer. The blood cancer may be lymphoma, leukemia, multiple myeloma, plasma cell myeloma, or myelodysplastic syndrome.

The above lymphomas include mantle cell lymphoma (MCL) or non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL), and high-risk small lymphoma. High-risk small lymphocytic lymphoma, follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Burkitt's lymphoma ( Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma , precursor B-lymphoblastic lymphoma, splenic marginal zone lymphoma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravenous giant It may be intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. The leukemia may be chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or B cell prolymphocytic leukemia.

Solid cancers include brain tumor, head and neck cancer, lung cancer, breast cancer, thymoma, mesothelioma, esophageal cancer, colon cancer, liver cancer, stomach cancer, pancreas cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovarian cancer, cervical cancer, and endometrium. Includes cancer, sarcoma, malignant melanoma and skin cancer.

The inflammatory diseases and/or autoimmune diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, and asthma. , chronic graft vs host disease, multiple sclerosis, Sjogren's syndrome, Crohn's disease, Behcet's Disease, or Type 1 Diabetes. ) can be. The above diseases merely exemplify specific diseases to which the pharmaceutical composition of the present disclosure can be applied, and the scope of the present disclosure is not limited to the above diseases.

The disease may be resistant or refractory to an irreversible BTK inhibitor, such as ibrutinib.

The term “treatment” means treating a disease or medical condition, e.g., a BTK-related disease, in an individual, e.g., a mammal, including a human, and includes: (a) the disease or medical condition; Alleviation, i.e., causing elimination or recovery of a disease or medical condition in a patient; (b) inhibition of a disease or medical condition, i.e., slowing or halting the progression of a disease or medical condition in an individual; or (c) alleviating a disease or medical condition in an individual.

The amount of the compound of Formula 1 or its pharmaceutically acceptable salt can be appropriately selected by a person skilled in the art. The amount is 0.01 mg to 10,000 mg, 0.1 mg to 1,000 mg, 1 mg to 100 mg, 0.01 mg to 1,000 mg, 0.01 mg to 100 mg, 0.01 mg to 10 mg, or 0. It may be .01 mg to 1 mg.

In the above compositions, “pharmaceutically acceptable carrier” refers to a substance, generally an inert substance, used in combination with the active ingredient to aid in the application of the active ingredient. The carrier includes conventional pharmaceutically acceptable excipients, additives or diluents. The carrier includes, for example, fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, thickeners, coloring agents, emulsifiers, and suspending agents. It may contain one or more selected from topical agents, stabilizers, and isotonic agents.

The composition of the present disclosure may be in an oral dosage form, or a parenteral dosage form, including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. Accordingly, the composition of the present disclosure may be formulated in various forms such as tablets, capsules, aqueous solutions, or suspensions. In the case of oral tablets, excipients such as lactose and corn starch and lubricants such as magnesium stearate can usually be added. For capsules for oral administration, lactose and/or dried corn starch may be used as diluents. When an aqueous suspension for oral use is required, the active ingredient may be combined with an emulsifying and/or suspending agent. If necessary, specific sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared, and the pH of the solution can be suitably adjusted and buffered. For intravenous administration, the total concentration of solutes can be adjusted to render the formulation isotonic. The composition according to the present disclosure may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline solution at physiological pH. The solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.

The compound of Formula 1 defined in the present disclosure may exhibit an effect of inhibiting protein kinase activity. “Inhibition” herein includes reducing the kinase activity of a protein kinase. The protein kinase may be BTK. The protein kinase may be C481 mutant BTK, for example C481S BTK.

The pharmaceutical composition can be combined with one or more other therapeutic agents to treat diseases associated with protein kinases. Other therapeutic agents include chemotherapy agents, anti-inflammatory agents, immunosuppressants, and anticancer agents. Examples of other therapeutic agents include anti-angiogenic agents, MALT1, MCL-1 or IDH1 inhibitors, TLR9 inhibitors, Bcl-2, JAK2, ALK or Hsp90 inhibitors, CYP3A4 inhibitors, BET inhibitors, and immune checkpoint inhibitors. checkpoint inhibitor), anti-CD20 treatment, HDAC inhibitor, PIM inhibitor, and mTOR inhibitor. Combination treatment may produce synergistic effects. The drug for combination treatment can be administered in combination with the protein kinase inhibitor in a single dose or sequential dosage form, or can be administered simultaneously or sequentially in separate dosage forms. The protein kinase may be BTK.

Another aspect provides the use of a compound of formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as defined above, in the treatment of diseases associated with protein kinases.

Another aspect provides the use of a compound of formula (1) as defined above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases associated with protein kinases.

Another aspect provides a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect provides a method of treating a protein kinase-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In the above method, the administration route can be appropriately selected by a person skilled in the art depending on the patient's condition. The administration may be oral, parenteral, or topical. The subject may be a mammal, such as a human, cow, pig, horse, or cat.

In the above method, “therapeutically effective amount” means an amount sufficient to produce a therapeutic effect when administered to an individual in need of treatment. As described above, the dosage may vary depending on various factors such as the patient's condition, route of administration, and the judgment of the attending physician. Effective doses can be estimated from dose-response curves obtained from in vitro experiments or animal model tests. The proportion and concentration of compounds present in the administered composition may be determined depending on the chemical nature, route of administration, therapeutic dosage, etc. The dosage may be administered to the individual in an effective amount of about 1 μg/kg to about 1 g/kg per day, or about 0.1 mg/kg to about 500 mg/kg per day. The dosage may vary depending on the individual's age, weight, sensitivity, or symptoms.

In the method, the disease may be one described for the pharmaceutical composition. The above diseases merely exemplify specific diseases to which the method of the present disclosure can be applied, and the scope of the present disclosure is not limited to the above diseases.

Additionally, a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in combination with one or more other therapeutic agents for treating diseases associated with protein kinases, such as BTK. .

Another aspect is activating Bruton's Tyrosine Kinase (BTK) comprising contacting a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof with a protein kinase, such as Bruton's Tyrosine Kinase (BTK). Provides a way to hinder it.

The contacting step may be performed ex vivo or in vitro. The contacting step may include incubation in a medium containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a protein kinase, such as Bruton's tyrosine kinase (BTK). The medium may be a liquid, for example water, or an organic solvent. The contacting step may include administering the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual and allowing it to come into contact with a protein kinase, for example, Bruton's tyrosine kinase (BTK), within the individual.

The BTK may be C481 mutant BTK, for example, C481S BTK.

In an embodiment, a compound of Formula 1 according to one aspect may be prepared according to Scheme 1 below.

[Scheme 1]

In Scheme 1, Hal represents halogen. In Scheme 1, Cy, R ₁ , R ₂ , L ₁ , L ₂ , A, X, Y, Z and n are as defined in Formula 1.

In step (1-1), the compound of Formula 1-IIa can be prepared by reacting the compound of Formula 1-IV with the compound of Formula V. This reaction can be carried out in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide in a polar organic solvent such as dioxane.

In step (1-2), a compound of formula (1-IIb) can be prepared in which the halogen group of the compound of formula (1-IIa) is replaced with an amino group. This reaction can be carried out in the presence of potassium carbonate, copper oxide, N,N'-dimethylethylenediamine, and aqueous ammonia in an organic solvent, such as a glycol solvent, especially ethylene glycol.

In step (1-3), the compound of formula I can be prepared by reacting the compound of formula 1-IIb obtained in step (1-2) with the compound of formula III. This reaction can be performed using the same reagent or solvent as step (1-1).

In an embodiment, among the compounds of Formula 1 according to one aspect, the compound in which Z ₂ is N may be prepared according to Scheme 2 below.

[Scheme 2]

In step (2-1), a compound of formula 2-IIb can be prepared by reacting formula 2-IV with compound V. This reaction is carried out in a polar aprotic organic solvent in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof. For example, it can be carried out in tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, N,N-dimethylsulfoxide, dichloromethane, or combinations thereof.

In step (2-2), a compound of formula (2-IIa) can be prepared in which the halogen group of the compound of formula 2-IIb is replaced with an R ₁ group. Polar aprotic organic solvents in the presence of bases such as diisopropylethylamine, triethylamine, pyridine, sodium hydrochloride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof. For example, it may be carried out in tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, N,N-dimethylsulfoxide, or combinations thereof.

In step (2-3), a compound of Formula I can be prepared by reacting a compound of Formula 2-IIa with a compound of Formula 2-III. This reaction can be carried out in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide in a polar organic solvent such as dioxane.

According to one aspect, the compound of Formula 1, its stereoisomer or its pharmaceutically acceptable salt can be used to treat diseases mediated by protein kinases, such as BTK.

Pharmaceutical compositions according to other aspects can be used to treat diseases mediated by protein kinases, such as BTK.

According to a method for treating a disease mediated by a protein kinase, such as BTK, according to another aspect, a disease mediated by a protein kinase, such as BTK, can be efficiently treated in an individual.

According to a method for inhibiting the activity of a protein kinase, for example, BTK, according to another aspect, the activity of a protein kinase, for example, BTK, can be efficiently inhibited.

The BTK may be C481 mutant BTK, for example, C481S BTK.

Hereinafter, the present disclosure will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present disclosure is not limited by these examples.

Example 1. (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of sol-2-yl)) amino) pyridin-2-yl) amino) cyclohexan-1-ol

Step 1) Synthesis of 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole

2-Bromo-5-formylthiazole (0.50 g, 2.60 mmol) and benzhydrazide (0.35 g, 2.60 mmol) were dissolved in 26 ml of ethanol and heated to reflux for 1 hour. When the reaction is completed, the solvent is distilled under reduced pressure. The obtained residue was dissolved in 13 ml of dimethyl sulfoxide, and then potassium carbonate (1.08 g, 7.80 mmol) and iodine (0.79 g, 3.12 mmol) were added. This solution is stirred at 100°C for 1 hour. When the reaction is completed, it is extracted using ethyl acetate, washed with water, dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.72 g, 90%).

Step 2) Synthesis of 1-(2,6-dibromopyridin-4-yl)-4-methylpiperazine

2,6-dibromo-4-nitropyridine (5.00 g, 17.80 mmol) and sodium hydride (0.71 g, 17.80 mmol) dispersed 60% in mineral oil were mixed with 18 ml of dried dimethylformamide under nitrogen at 0°C. Dissolve in and stir for 30 minutes. Afterwards, 1-methyl piperazine (1.97 ml, 1.80 mmol) was added and stirred at room temperature for an additional 16 hours. When the reaction is complete, the reaction is terminated using distilled water. The reaction mixture was extracted with ethyl acetate, washed with water, the resulting organic layer was dried with magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (2.11 g, 35%).

Step 3) Synthesis of (1R,4R)-4-((6-bromo-4-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol

1-(2,6-dibromopyridin-4-yl)-4-methylpiperazine (2.11 g, 6.30 mmol), trans-4-aminocyclohexanol (0.87 g, 7.56 mmol) obtained in step 2 above. , tris(dibenzylindeneacetone)dipalladium (0.58 g, 0.63 mmol), xantphos (0.36 g, 0.63 mmol), sodium-tert-butoxide (0.91 g, 9.45 mmol), and anhydrous 1,4-dioxane 31. After dissolving in ml, stir at room temperature for 16 hours. When the reaction is completed, it is extracted with ethyl acetate, washed with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (1.10 g, 47%).

Step 4) Synthesis of (1R,4R)-4-((6-amino-4-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((6-bromo-4-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol (0.55 g , 1.49 mmol), cupric acetylacetone (0.04 g, 0.15 mmol), and cesium carbonate (0.97 g, 2.98 mmol) were placed in a microwave vial and a nitrogen environment was created. Then, acetylacetone (0.10 ml, 0.60 mmol), ammonia solution (2.53 ml, 22.35 mmol), and 7 ml of anhydrous dimethylformamide were sequentially added, the lid of the microwave vial was closed, and the mixture was stirred at 90°C overnight. When the reaction is complete, the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the resulting organic layer is dried over magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (0.23 g, 51%).

Step 5) (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- Synthesis of 1) thiazol-2-yl)) amino) pyridin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((6-amino-4-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol (0.23 g , 0.75 mmol), 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.28 g, 0.90 mmol) obtained in Step 1, Tris (dibenzylindene Acetone) Dipalladium (0.07 g, 0.08 mmol), xanthos (0.04 g, 0.08 mmol) and sodium-tert-butoxide (0.11 g, 1.13 mmol) are dissolved in 4 ml of 1,4-dioxane. The reaction mixture is stirred at 80° C. for 2 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.08 g, 21%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.29 (s, 1H), 8.19 (s, 1H), 8.11-8.08 (m, 2H), 7.63-7.61 (m, 3H), 6.21 (d) , 1H, J= 8.0 Hz), 5.82 (d, 1H, J= 1.2 Hz), 5.61 (s, 1H), 4.66 (d, 1H, J= 8.0 Hz), 4.05-3.85 (m, 1H), 3.50 (s, 1H), 3.21 (s, 1H), 3.21 (s, 4H), 2.67 (s, 3H), 2.42 (s, 2H), 2.06 (d, 2H, J= 8.0 Hz), 1.90 (d, 2H, J= 12.0 Hz), 1.52-1.44 (m, 2H), 1.28-1.19 (m, 2H).

Example 2. (1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(piperazine Synthesis of -1-yl)pyridin-2-yl)amino)cyclohexan-1-ol

Step 1) Synthesis of tert-butyl 4-(2,6-dibromopyridin-4-yl)piperazine-1-carboxylate

In step 2 of Example 1, the target compound (1.20 g, 16%) was reacted in the same manner, except that tert-butyl piperazine-1-carboxylate (3.31 g, 17.80 mmol) was used instead of 1-methyl piperazine. ) was obtained.

Step 2) Synthesis of tert-butyl 4-(2-bromo-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)piperazine-1-carboxylate

tert-butyl 4-(2,6-dibromopyridin-4-yl)piperazine-1-carboxylate (1.20 g, 2.85 mmol) synthesized in Step 1 above was subjected to the same method as Step 3 of Example 1. By reacting, the target compound (0.71 g, 55%) was obtained.

Step 3) Synthesis of tert-butyl 4-(2-amino-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)piperazine-1-carboxylate

tert-butyl 4-(2-bromo-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)piperazine-1-carboxylate synthesized in step 2 (0.71 g, 1.56 mmol) was reacted in the same manner as step 4 of Example 1 to obtain the target compound (0.55 g, 90%).

Step 4) tert-Butyl 4-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole- Synthesis of 2-yl)thiazol-2-yl)amino)pyridin-4-yl)piperazine-1-carboxylate

tert-butyl 4-(2-amino-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)piperazine-1-carboxylate ( 0.50 g, 1.28 mmol) was reacted in the same manner as step 5 of Example 1 to obtain the target compound (0.27 g, 34%).

Step 5) (1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4- Synthesis of (piperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol

tert-butyl 4-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxa) synthesized in step 4 Dissolve diazol-2-yl)thiazol-2-yl)amino)pyridin-4-yl)piperazine-1-carboxylate (0.02 g, 0.03 mmol) in 0.06 ml of dichloromethane and 0.06 ml of methanol. After doing so, slowly add 4.0M hydrochloric acid (0.08 ml, 0.32 mmol). The reaction mixture was stirred at room temperature for 16 hours. When the reaction is completed, the reaction mixture is neutralized using an aqueous sodium carbonate solution. After extraction using dichloromethane, washing with water, the obtained organic layer was dried with sodium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.01 g, 60%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.31 (d, 1H, J= 8.0 Hz), 5.84 (s, 1H), 5.63 (s, 1H), 4.68 (d, 1H, J= 4.0 Hz), 3.96-3.93 (m, 1H), 3.57 (s, 1H), 3.51-3.46 (m, 2H), 3.19 (s, 4H), 2.08 (d, 2H, J= 12.0 Hz), 1.90 (d, 2H, J= 8.0 Hz), 1.53-1.42 (m, 2H), 1.30-1.22 (m, 2H).

Example 3. (1R,4R)-4-((4-(4-isopropylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) Synthesis of thiazol-2-yl)) amino) pyridin-2-yl) amino) cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-(4-isopropylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl synthesized in step 5 of Example 2 )Amino)-4-(piperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol (0.03 g, 0.06 mmol) and potassium carbonate (0.02 g, 0.12 mmol) were dissolved in 0.2 ml of aceto. After dissolving in nitrile, stir at room temperature for 30 minutes. Afterwards, 2-iodopropane (0.02 ml, 0.17 mmol) was slowly added to the reaction solution and refluxed for 20 hours. When the reaction is completed, it is cooled to room temperature, extracted using ethyl acetate, washed with water, the obtained organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.02 g, 74%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.27 (s, 1H), 8.19 (s, 1H), 8.11-8.08 (m, 2H), 7.63-7.62 (m, 3H), 6.21 (s) , 1H), 5.83 (s, 1H), 5.60 (s, 1H), 4.66 (d, 1H, J= 4.0 Hz), 4.04-4.02 (m, 1H), 3.92-3.90 (m, 2H), 3.17- 3.16 (m, 4H), 2.07 (d, 2H, J= 12.0 Hz), 1.91-1.90 (m, 2H), 1.52-1.44 (m, 2H), 1.28-1.23 (m, 2H), 1.19 (s, 6H).

Example 4. (1R,4R)-4-((4-(4-ethylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of sol-2-yl)) amino) pyridin-2-yl) amino) cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-(4-ethylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- Synthesis of 1) thiazol-2-yl)) amino) pyridin-2-yl) amino) cyclohexan-1-ol

The target compound (3.00 mg, 14%) was obtained by reacting in the same manner, except that iodoethane (0.01 ml, 0.11 mmol) was used instead of 2-iodopropane in Step 1 of Example 3.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.25 (s, 1H), 8.18 (s, 1H), 8.11-8.08 (m, 2H), 7.63-7.62 (m, 3H), 6.17 (d) , 1H, J= 8.0 Hz), 5.82 (s, 1H), 5.59 (s, 1H), 4.65 (d, 1H, J= 4.0 Hz), 3.92-3.90 (m, 1H), 3.51-3.48 (m, 1H), 2.51 (s, 4H), 2.50-2.45 (s, 4H), 2.38-2.33 (m, 2H), 2.07 (d, 2H, J= 12.0 Hz), 1.90-1.88 (m, 2H), 1.52 -1.41 (m, 2H), 1.27-1.22 (m, 2H), 1.03 (t, 3H, J= 8.0 Hz).

Example 5. N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-(4-(2-hydroxyethyl)piperazine Synthesis of -1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide

Step 1) Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate

Ethyl 2-aminothiazole-5-carboxylate (3.60 g, 20.93 mmol) and di-tert-butyl dicarboate (13.70 g, 62.79 mmol) were mixed with isopropanol solvent and stirred at 50°C for 24 hours. When the reaction was completed, the solvent was concentrated under reduced pressure to obtain the target compound (5.30 g, 93%).

Step 2) Synthesis of 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid

Ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (4.50 g, 16.52 mmol) obtained in Step 1 and sodium hydroxide (2.64 g, 66.08 mmol) were mixed in a mixed solvent of THF and water. After that, it was heated and refluxed for 12 hours. When the reaction was completed, 1N hydrochloric acid solution was added to crystallize, and the resulting crystals were filtered to obtain the target compound (2.90 g, 99%).

Step 3) Synthesis of tert-butyl (5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)carbamate

2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid (0.23 g, 1.00 mmol) obtained in step 2 was dissolved in the solvent tetrahydrofuran and then added to 2M oxalyl chloride dichloromethane solution (1.00 ml). , 2.00 mmol) is added slowly. Add 3 drops of N,N-dimethylformamide to this solution and stir at room temperature for 4 hours. This solution was distilled under reduced pressure, dichloromethane was added to the obtained residue, the temperature was lowered to 0°C, and 2-chloro-6-methylaniline (0.21 g, 1.50 mmol) and diisopropylethylamine (0.70 ml, 4.00 mmol) were added. After adding slowly, raise the temperature to room temperature and stir for 24 hours. When the reaction is completed, the extract is extracted using dichloromethane, washed with 1N aqueous hydrochloric acid solution and water, the obtained organic layer is dried over magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.14 g, 40%).

Step 4) Synthesis of 5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine

The temperature of the tert-butyl (5-(phenylcarbamoyl)thiazol-2-yl)carbamate (0.07 g, 0.19 mmol) and dichloromethane solution obtained in step 3 was lowered to 0°C and added to trifluoroacetic acid (1.00 ml). , 2.47 mmol) is added. This solution was stirred for 2 hours and the solvent was distilled under reduced pressure. The obtained residue is neutralized using an aqueous sodium bicarbonate solution and extracted using dichloromethane. The organic solvent was dried using magnesium sulfate and filtered under reduced pressure to obtain the target compound (0.02 g, 30%).

Step 5) Synthesis of (1R,4R)-4-((4,6-dichloropyrimidin-2-yl)amino)cyclohexan-1-ol

2,4,6-Trichloropyrimidine (12.00 g, 65.42 mmol), trans-4-aminocyclohexanol (8.29 g, 71.97 mmol) and triethylamine (13.68 ml, 98.13 mmol) were dissolved in 130 ml of dichloromethane. After dissolving in , it reacts at room temperature. When the reaction is completed, it is extracted with ethyl acetate, washed with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (4.80 g, 28%).

Step 6) (1R,4R)-4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexane-1- synthesis of all

(1R,4R)-4-((4,6-dichloropyrimidin-2-yl)amino)cyclohexan-1-ol (0.5 g, 1.91 mmol) and cesium carbonate (1.24 g, 3.82 mmol) was dissolved in 4 ml of acetonitrile, 1-(2-hydroxyethyl)piperazine (0.35 ml, 2.87 mmol) was slowly added, and stirred at 90°C overnight. When the reaction was completed, the solution was blown away, and the obtained residue was purified using column chromatography to obtain the target compound (0.57 g, 84%).

Step 7) N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-(4-(2-hydroxyethyl ) Piperazin-1-yl) pyrimidin-4-yl) amino) thiazole-5-carboxamide synthesis

5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.09 g, 0.34 mmol) synthesized in step 4 and (1R,4R) obtained in step 6 -4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.28 mmol) , palladium acetate (0.01 g, 0.03 mmol), xanthos (0.03 mg, 0.06 mmol) and cesium carbonate (0.27 mg, 0.84 mmol) were dissolved in 3 ml of 1,4-dioxane and stirred in a microwave at 160°C for 1 hour. . When the reaction was completed, the solution was blown away, and the obtained residue was purified using column chromatography to obtain the target compound (0.08 g, 47%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.19 (s, 1H), 9.82 (s, 1H), 8.21 (s, 1H), 7.40-7.38 (m, 2H), 7.29-7.23 (m , 3H), 6.42 (s, 1H), 5.54 (s, 1H), 4.48 (s, 1H), 3.80-7.73 (m, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 2.45 ( s, 4H), 2.24 (s, 3H), 2.93 (s, 3H), 1.77 (s, 3H), 1.25 (s, 6H).

Example 6. (1R,4R)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole Synthesis of -2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

Step 1) Synthesis of 5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine

2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.50 g, 1.62 mmol) obtained in Step 1 of Example 1 and 28-30 in a microwave vial. % Aqueous ammonia (1.85 ml, 16.20 mmol) was dissolved in 3 ml of ethanol and stirred at 150°C for 16 hours. When the reaction was completed, the solution was blown away, and the obtained residue was purified using column chromatography to obtain the target compound (0.23 g, 57%).

Step 2) (1R,4R)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4- Synthesis of oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.08 g, 0.34 mmol) synthesized in Step 1 and Step 6 of Example 5 (1R,4R)-4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.28 mmol), palladium acetate (0.01 g, 0.03 mmol), xanthos (0.03 g, 0.06 mmol) and cesium carbonate (0.27 g, 0.84 mmol) were dissolved in 3 ml of 1,4-dioxane and heated at 160°C in a microwave. Stir for 1 hour. When the reaction was completed, the solution was blown away, and the obtained residue was purified using column chromatography to obtain the target compound (0.01 g, 8%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.50 (s, 1H), 8.23 (s, 1H), 8.11-8.09 (m, 3H), 7.64-7.61 (m, 5H), 6.58 (d) , 1H, J= 8.0 Hz), 5.57 (s, 1H), 4.68 (s, 1H), 4.51-4.47 (m, 2H), 3.88 (s, 1H), 3.53 (s, 4H), 3.46 (s, 4H), 3.16 (d, 1H, J= 4.0 Hz), 2.47-2.42 (m, 7H), 2.01-1.99 (m, 2H), 1.91-1.88 (m, 4H), 1.82 (s, 1H), 1.52 -1.43 (m, 2H), 1.37-1.31 (m, 2H), 1.23-1.16 (m, 2H).

Example 7. (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of sol-2-yl)) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) Synthesis of (1R,4R)-4-((4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol

The target compound (0.60 g, 96%) was reacted in the same manner, except that 1-methylpiperazine (0.32 ml, 2.86 mmol) was used instead of 1-(2-hydroxyethyl)piperazine in step 6 of Example 5. ) was obtained.

Step 2) (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- Synthesis of 1) thiazol-2-yl)) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.31 mmol) and 5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.09 g, 0.37 mmol) synthesized in step 1 of Example 6. By reacting in the same manner as step 7 of Example 5, the target compound (0.04 g, 23%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.49 (s, 1H), 8.22 (s, 1H), 8.10-8.09 (m, H), 7.63-7.62 (m, 4H), 6.55 (d) , 1H, J= 8.0 Hz), 5.58 (s, 1H), 4.66 (s, 1H), 3.89 (s, 1H), 3.46 (s, 5H), 2.37 (s, 4H), 2.22 (s, 3H) , 2.01 (s, 2H), 1.90 (s, 4H), 1.46 (s, 2H), 1.36-1.21 (m, 8H).

Example 8. (1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of -6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino) cyclohexan-1-ol

Step 1) Synthesis of 4-fluorobenzohydrazide

Sodium methyl 4-fluorobenzoate (0.5 g, 3.24 mmol) and hydrazine monohydrate (1.73 ml, 16.2 mmol) were dissolved in 6.5 ml of methanol and stirred at 70°C for 3 hours. When the reaction was completed, it was cooled to room temperature, and the obtained residue was purified using column chromatography to obtain the target compound (0.5 g, 100%).

Step 2) Synthesis of 2-(2-bromothiazol-5-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole

4-Fluorobenzohydrazide (0.5 g, 3.24 mmol) obtained in Step 1 was reacted in the same manner as Step 1 of Example 1 to obtain the target compound (0.32 g, 30%).

Step 3) Synthesis of 5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-amine

2-(2-bromothiazol-5-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (0.30 g, 0.92 mmol) obtained in step 2 was prepared in Example 6. By reacting in the same manner as in Step 1, the target compound (0.07 g, 27%) was obtained.

Step 4) (1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl )Amino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol synthesis

5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.07 g, 0.25 mmol) synthesized in step 3 and Example 5 (1R,4R)-4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexane synthesized in step 6 of -1-ol (0.08 g, 0.21 mmol) was reacted in the same manner as step 7 of Example 5 to obtain the target compound (0.03 g, 20%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.25 (s, 1H), 8.18 (s, 1H), 8.11-8.08 (m, 2H), 7.63-7.62 (m, 3H), 6.17 (d) , 1H, J= 8.0 Hz), 5.82 (s, 1H), 5.59 (s, 1H), 4.65 (d, 1H, J= 4.0 Hz), 3.92-3.90 (m, 1H), 3.51-3.48 (m, 1H), 2.51 (s, 4H), 2.50-2.45 (s, 4H), 2.38-2.33 (m, 2H), 2.07 (d, 2H, J= 12.0 Hz), 1.90-1.88 (m, 2H), 1.52 -1.41 (m, 2H), 1.27-1.22 (m, 2H), 1.03 (t, 3H, J= 8.0 Hz).

Example 9. (1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyrimidin-2-yl)amino)cyclohexan-1-ol

Step 1) Synthesis of (1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclohexan-1-ol

The target compound (0.34 g, 94%) was obtained by reacting in the same manner, except that morpholine (0.15 ml, 1.71 mmol) was used instead of 1-(2-hydroxyethyl)piperazine in step 6 of Example 5. .

Step 2) (1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl) amino) cyclohexan-1-ol synthesis

(1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclohexan-1-ol (0.08 g, 0.26 mmol) synthesized in step 1 and Example 5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.07 g, 0.03 mmol) synthesized in step 1 of 6 was prepared in the same manner as step 7 of Example 5. By reacting with this method, the target compound (0.02 g, 15%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.55 (s, 1H), 8.26 (s, 1H), 8.11-8.10 (m, 2H), 7.63 (s, 5H), 6.60 (d, 1H) , J= 8.0 Hz), 5.57 (s, 1H), 4.68 (s, 1H), 3.90 (s, 1H, 3.65 (s, 4H), 3.53 (s, 4H), 2.10-1.84 (m, 4H), 1.52-1.24 (m, 4H).

Example 10. (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl ) Amino) pyridin-2-yl) amino) cyclohexan-1-ol synthesis

Step 1) Synthesis of N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide

2-Bromo-5-formylthiazole (0.10 g, 0.52 mmol) and p-toluenesulfonyl hydrazide (0.18 g, 0.98 mmol) are added to a microwave vial and mixed with ethanol solvent. 1M hydrochloric acid (0.02 ml, 0.02 mmol) was slowly added to this solution and stirred in a microwave at 80°C for 1 hour. When the reaction is complete, cool to room temperature, stir for an additional 3 hours, and blow off the solution. The obtained residue was purified using column chromatography to obtain the target compound (0.15 g, 80%).

Step 2) Synthesis of 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole

3 ml of N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (0.50 g, 1.39 mmol) and aniline (0.13 ml, 1.46 mmol) obtained in step 1 above. Dissolve it in a mixed solvent of tetrahydrofuran and 1 ml of pyridine and stir at room temperature for 30 minutes. Isoamyl nitrite (0.24 ml, 1.81 mmol) was added to this solution and stirred at room temperature for an additional 25 hours. When the reaction is completed, the extract is extracted using ethyl acetate, washed with water, the resulting organic layer is dried over magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.17 g, 56%).

Step 3) (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol- Synthesis of 2-yl) amino) pyridin-2-yl) amino) cyclohexan-1-ol

2-Bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (0.7 g, 2.3 mmol) synthesized in step 2 and (1R,4R synthesized in step 4 of Example 1 )-4-((6-amino-4-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)cyclohexan-1-ol (0.58 g, 1.9 mmol) was mixed with tris(dibenzyline) Denacetone) Dipalladium (0.18 g, 0.2 mmol), xanthos (0.12 g, 0.2 mmol), and sodium-tert-butoxide (0.27 g, 2.85 mmol) were dissolved in 5 ml of 1,4-dioxane. The reaction mixture is stirred at 80° C. for 2 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.16 g, 16%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.65-7.62 (t, 2H) , 7.59-7.56 (t, 1H), 6.18-6.17 (d, 2H), 5.79 (s, 1H), 5.56 (s, 1H), 4.77 (s, 1H), 4.11-4.10 (m, 1H), 3.52 (m, 1H), 3.16 (d, 2H), 3.12 (s, 4H), 2.39 (s, 4H), 2.20 (s, 3H), 2.08-2.06 (d, 2H), 1.93-1.91 (d, 2H) ), 1.62-1.55 (m, 2H).

Example 11. (1R,4R)-4-((4-((4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of sol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) Synthesis of 4-((6-chloro-2-(((1R,4R)-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)amino)cyclohexan-1-ol

The target compound (0.20 g, 51 mmol) was reacted in the same manner, except that 4-aminocyclohexanol (0.20 g, 1.71 mmol) was used instead of 1-(2-hydroxyethyl)piperazine in Step 6 of Example 5. %) was obtained.

Step 2) (1R,4R)-4-((4-((4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- Synthesis of 1) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

4-((6-chloro-2-(((1R,4R)-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)amino)cyclohexan-1-ol (0.08 g, 0.24 mmol) and 4-((6-chloro-2-(((1R,4R)-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)amino synthesized in step 1 of Example 6 ) Cyclohexan-1-ol (0.07 g, 0.28 mmol) was reacted in the same manner as step 7 of Example 5 to obtain the target compound (0.02 g, 13%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.38 (s, 1H), 8.20 (s, 1H), 8.10-8.09 (m, 2H), 7.63 (s, 3H), 6.62 (s, 1H) , 6.37 (s, 1H), 5.37 (s, 1H), 4.66 (s, 1H), 4.54 (s, 1H), 3.88 (s, 1H), 3.76 (s, 1H), 3.45 (s, 2H), 1.99 (s, 2H), 1.90-1.83 (m, 8H), 1.78-1.45 (m, 2H), 1.37-1.30 (m, 2H), 1.24-1.19 (m, 6H).

Example 12. (1R,4R)-4-((4-(4-fluoropiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

Step 1) 2,4-dichloro-6-(4-fluoropiperidin-1-yl)pyrimidine

2,4,6-Trichloropyrimidine (12.00 g, 65.42 mmol) was dissolved in 130 ml of dichloromethane, then 4-fluoropiperidine (7.64 mL, 71.91 mmol) and TEA (13.68 ml, 98.13 mmol). Add slowly at 0°C. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (4.80 g, 28%).

Step 2) (1R,4R)-4-((4-chloro-6-(4-fluoropiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,4-dichloro-6-(4-fluoropiperidin-1-yl)pyrimidine (0.30 g, 1.14 mmol) and cesium carbonate (0.74 g, 2.28 mmol) obtained in step 1 were mixed with 2.0 ml of aceto. After dissolving in nitrile, stir at room temperature for 30 minutes. Afterwards, 4-fluoropiperidine is slowly added and reacted in the microwave at 9°C for three hours. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (250 mg, 68%).

Step 3) (1R,4R)-4-((4-(4-fluoropiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-(4-fluoropiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol synthesized in step 2 above. (0.10 g, 0.31 mmol), 5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine synthesized in step 1 of Example 7 synthesis (0.08 g, 0.37 mmol), palladium acetate (0.01 g, 0.03 mmol), xanthos (0.04 g, 0.06 mmol), and cesium carbonate (0.30 g, 0.92 mmol) were dissolved in 3.0 ml of 1,4-dioxane, then microwaved at 16°C for 1 hour. Reaction. When the reaction was completed, extraction was performed using ethyl acetate, washing with water, the obtained organic layer was dried with magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7 mg, 4 %) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.49 (s, 1H), 8.22 (s, 1H), 8.09 (t, 2H, J= 4.0 Hz), 7.63 (d, 3H, J= 2.0 Hz), 6.60 (d, 1H, J= 2.0 Hz), 5.76 (s, 2H), 5.62 (s, 1H), 4.94 (s, 1H), 4.84 (s, 1H), 4.68 (s, 1H), 3.89 (s, 1H0, 3.65 (s, 2H), 3.47 (s, 2H), 3.17 (d, 2H, J= 2.0 Hz), 2.08 (s, 1H), 2.01 (s, 1H), 1.91-1.89 ( m, 3H), 1.67 (s, 2H), 1.48-1.46 (m, 2H), 1.35-1.32 (m, 2H).

Example 13. N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-morpholinopyrimidin-4-yl)amino) Thiazole-5-carboxamide

Step 1) N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-morpholinopyrimidin-4-yl )Amino)thiazole-5-carboxamide

(1R,4R)-4- synthesized in step 1 of the synthesis of Example 9 with 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (0.10 g, 0.37 mmol) ((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclohexan-1-ol (0.07 g, 0.31 mmol) was reacted in the same manner as step 3 of Example 12 to obtain the target compound (18) mg, 10%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.23 (s, 1H), 9.82 (s, 1H), 8.21 (s, 1H), 7.39-7.38 (m, 1H), 7.28-7.23 (m , 2H), 6.45 (d, 1H, J= 2.0 Hz), 5.53 (s, 1H), 4.47 (s, 1H), 3.80 (s, 1H), 3.64 (s, 4H), 3.40 (s, 4H) , 2.24 (s, 3H), 1.98 (s, 2H), 1.94 (s, 2H), 1.32-1.26 (m, 4H).

Example 14. (1R,4R)-4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl) thiazol -2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) (2S,6R)-4-(2,6-dichloropyrimidin-4-yl)-2,6-dimethylmorpholine

2,4,6-Trichloropyrimidine (1.00 g, 5.45 mmol) was dissolved in 76 ml of dichloromethane, then cis-2,6-dimethylmorpholine (0.74 ml, 6.00 mmol) and DIPEA (3.13 ml, 18 mmol) is added slowly. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.06 g, 74%).

Step 2) (1R,4R)-4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(2S,6R)-4-(2,6-dichloropyrimidin-4-yl)-2,6-dimethylmorpholine (1.00 g, 4.27 mmol) obtained in step 1 was dissolved in 4 ml of 1-propanol. do. Then, trans-4-aminocyclohexanol (0.74 g, 6.40 mmol) and DIPEA (2.23 ml, 12.81 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.03 mg, 77%).

Step 3) (1R,4R)-4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxa diazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(2S,6R)-4-(2,6-dichloropyrimidin-4-yl)-2,6-dimethylmorpholine (0.14 g, 0.57 mmol) obtained in step 1 above was synthesized in step 3 of Example 12. By reacting in the same way, the target compound (10 mg, 4%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.46 (s, 1H), 8.22 (s, 1H), 8.09 (t, 2H, J= 4.0 Hz), 7.62 (d, 3H, J= 2.0 Hz), 6.61 (d, 1H, J= 2.0 Hz), 5.57 (s, 1H), 4.68 (s, 1H), 4.03-4.00 (m, 2H), 3.88 (s, 1H), 3.55 (s, 4H) ), 3.46 (s, 2H), 2.36 (s, 2H), 2.02-1.98 (m, 2H), 1.90-1.88 (m, 2H), 1.47-1.45 (m, 2H), 1.33-1.31 (m, 2H) ), 1.26-1.16 (m, 7H).

Example 15. (1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-(piperic din-1-yl) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) 2,4-dichloro-6-(piperidin-1-yl)pyrimidine

The target compound (1.00 g, 79%) was obtained in the same manner as in Step 1 of Example 14, except that piperidine (0.59 ml, 6.00 mmol) was used instead of 2,6-dimethylmorpholine.

Step 2) (1R,4R)-4-((4-chloro-6-(piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,4-Dichloro-6-(piperidin-1-yl)pyrimidine (1.00 g, 4.31 mmol) obtained in Step 1 was reacted as in Step 2 of Example 14 to obtain the target compound (1.04 g, 68%). ) was obtained.

Step 3) (1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6- (piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-(piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.20 g, 0.56 mmol) and reacted in the same manner as step 3 of Example 12 to obtain the target compound (10 mg, 3%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.43 (s, 1H), 8.22 (s, 1H). 8.09 (t, 2H, J= 4.0 Hz), 7.62 (d, 3H, J= 2.0 Hz), 6.50 (d, 1H, J= 2.0 Hz), 5.58 (s, 1H), 4.68 (s, 1H), 3.89 (s, 1H), 3.48 (s, 6H), 2.01 (s, 1H), 2.01-1.89 (m, 2H), 1.61-1.60 (m, 2H), 1.49 (s, 7H), 1.34-1.29 ( m, 2H).

Example 16. (1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Pyridin-2-yl) amino) cyclohexan-1-ol

Step 1) 4-(2,6-dibromopyridin-4-yl)morpholine

2,6-Dibromo-4-nitropyridine (0.10 g, 0.36 mmol) and potassium carbonate (0.15 g, 1.07 mmol) were dissolved in 1 ml of dimethylformamide and stirred for 30 minutes. Afterwards, morpholine (0.03 ml, 0.36 mmol) was slowly added and stirred at room temperature for an additional 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (80 mg, 70%).

Step 2) (1R,4R)-4-((6-bromo-4-morpholinopyridin-2-yl)amino)cyclohexan-1-ol

4-(2,6-dibromopyridin-4-yl)morpholine (0.50 g, 1.55 mmol) obtained in Step 1 above was added to the target compound (100 mg, 18%) in the same manner as Step 3 of Example 1. got it

Step 3) (1R,4R)-4-((6-amino-4-morpholinopyridin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((6-bromo-4-morpholinopyridin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.28 mmol) obtained in step 2 was prepared in Example 1. By reacting in the same manner as step 4, the target compound (80 mg, 97%) was obtained.

Step 4) (1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) amino) pyridin-2-yl ) amino) cyclohexan-1-ol

(1R,4R)-4-((6-amino-4-morpholinopyridin-2-yl)amino)cyclohexan-1-ol (0.08 g, 0.28 mmol) and 2-(2) obtained in step 3 above. The target compound (5 mg, 3%) was obtained using -bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.10 g, 0.34 mmol).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.29 (s, 1H), 8.19 (s, 1H), 8.11-8.09 (m, 4H), 7.65-7.62 (m, 6H), 6.20 (d) , 1H, J= 4.0 Hz), 5.82 (s, 1H), 5.63 (s, 1H), 4.65 (s, 1H), 3.90 (s, 1H), 3.70 (d, 4H, J= 4.0 Hz), 3.10 (d, 4H, = 4.0 Hz), 2.06 (d, 2H, J= 4.0 Hz), 1.99 (s, 1H), 1.89 (d, 2H, J= 4.0 Hz), 1.49-1.47 (m, 2H), 1.27-1.16 (m, 2H).

Example 17. N-(2-chloro-6-methylphenyl)-2-((6-(4-fluoropiperidin-1-yl)-2-(((1R,4R)-4-hydroxycyclohexyl)amino )pyrimidin-4-yl)amino)thiazole-5-carboxamide

Step 1) N-(2-chloro-6-methylphenyl)-2-((6-(4-fluoropiperidin-1-yl)-2-(((1R,4R)-4-hydroxycyclo hexyl) amino) pyrimidin-4-yl) amino) thiazole-5-carboxamide

(1R,4R)-4-((4-chloro-6-(4-fluoropiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexane-1 obtained in step 2 of Example 12 -ol (0.10 g, 0.31 mmol) and 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (0.09 g, 0.34 mmol) were prepared in the same manner as in Example 12, Step 3. By reaction, the target compound (6 mg, 3%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.17 (s, 1H), 9.81 (s, 1H), 8.21 (s, 1H), 7.40-7.37 (m, 2H), 7.33 (s, 1H) ), 7.28-7.23 (m, 3H), 6.44 (s, 1H), 4.93 (s, 1H), 4.83 (s, 1H), 4.48 (s, 1H), 3.81 (s, 1H), 3.64 (s, 4H), 3.45 (s, 3H), 2.23 (s, 4H), 1.98-1.77 (m, 6H), 1.32-1.23 (m, 4H).

Example 18. (1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -6-morpholinopyrimidin- 2-yl) amino) cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl )Amino)-6-morpholinopyrimidin- 2-yl)amino)cyclohexan-1-ol

Example 9 (1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclohexan-1-ol (0.06 g, 0.21 mmol) synthesized in step 1 of the synthesis ) and 5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.06 g, 0.23 mmol) obtained in step 3 of Example 8 was reacted in the same manner as step 3 of Example 12 to obtain the target compound (16 mg, 14%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.54 (s, 1H), 8.23 (s, 1H), 8.17-8.14 (m, 2H), 7.48-7.44 (m, 2H), 6.60 (d) , 1H, J= 4.0 Hz), 5.56 (s, 1H), 4.73 (s, 1H), 3.90 (s, 1H), 3.64 (s, 4H), 3.47 (s, 4H), 2.02-2.01 (m, 2H, 1.90 (s, 3H), 1.47-1.45 (m, 2H), 1.37-1.32 (m, 3H).

Example 19. (1R,4R)-4-((4-(methylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino ) pyrimidin-2 -yl) amino) cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-chloro-6-(methylamino)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,6-Dichloro-N-methylpyrimidin-4-amine (0.50 g, 2.81 mmol) was reacted in the same manner as Example 14 Step 2 to obtain the target compound (360 mg, 50%).

Step 2) (1R,4R)-4-((4-(methylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin-2 -yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-(methylamino)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.20 g, 0.78 mmol) obtained in step 1 was used as Example 12 React in the same manner as step 3 to obtain the target compound (130 mg, 36%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.40 (s, 1H), 8.20 (s, 1H), 8.09 (d, 2H, J= 2.0 Hz), 7.62 (d, 3H, J= 2.0 Hz), 6.69 (s, 1H), 6.43 (s, 1H), 5.38 (s, 1H), 4.66 (s, 1H), 4.05-4.01 (m, 1H), 3.46 (s, 1H), 2.71 (s) , 3H), 1.99-1.88 (m, 2H), 1.47-1.45 (m, 2H), 1.34-1.30 (m, 2H), 1.19-1.16 (m, 2H).

Example 20. (1R,4R)-4-((4-(dimethylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino ) pyrimidin-2 -yl) amino) cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-chloro-6-(dimethylamino)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,6-Dichloro-N,N-dimethylpyrimidin-4-amine (0.30 g, 1.56 mmol) was reacted in the same manner as step 2 of Example 14 to obtain the target compound (186 mg, 44%).

Step 2) (1R,4R)-4-((4-(dimethylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin-2 -yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-(dimethylamino)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.37 mmol) obtained in step 1 was used as an example By reacting in the same manner as step 3 in 12, the target compound (104 mg, 59%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.45 (s, 1H), 8.21 (s, 1H), 8.10 (d, 2H, J= 2.0 Hz), 7.63 (d, 3H, J= 2.0 Hz), 6.47 (d, 1H, J= 4.0 Hz), 5.49 (s, 1H), 4.67 (s, 1H), 3.90 (s, 1H0, 3.46 (s, 1H), 2.97 (s, 7H), 2.00 (m, 2H), 1.89 (d, 2H, J= 4.0 Hz), 1.46 (d, 2H, J= 4.0 Hz), 1.35-1.33 (m, 2H).

Example 21. (1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-thiomopoly Nopyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) 4-(2,6-dichloropyrimidin-4-yl)thiomorpholine

Dissolve 2,4,6-trichloropyrimidine (7.00 g, 38.17 mmol) in 76 ml of dichloromethane and then slowly add thiomorpholine (3.79 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol). . Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (8.60 g, 67%).

Step 2) (1R,4R)-4-((4-chloro-6-thiomopolinopyrimidin-2-yl)amino)cyclohexan-1-ol

4-(2,6-dichloropyrimidin-4-yl)thiomorpholine (1.06 g, 4.27 mmol) obtained in step 1 above is dissolved in 4 ml of 1-propanol. Then, trans-4-aminocyclohexanol (0.74 g, 6.40 mmol) and DIPEA (2.23 ml, 12.81 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.07 mg, 77%).

Step 3) (1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6- Thiomopolinopyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-thiomopolinopyrimidin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.31 mmol) synthesized in step 2 above. The target compound (97 mg, 59%) was obtained by reacting in the same manner as step 3 of Example 12 synthesis.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.45 (s, 1H), 8.21 (s, 1H), 8.10 (m, 2H), 7.63 (m, 3H), 6.47 (d, 1H, J = 4.0 Hz), 5.49 (s, 1H), 4.67 (s, 1H), 3.90 (s, 1H), 3.46 (s, 1H), 3.01-3.28 (m, 4H), 2.80-2.75 (m, 4H) , 2.00 (m, 2H), 1.89 (d, 2H, J= 4.0 Hz), 1.46 (d, 2H, J= 4.0 Hz), 1.35-1.33 (m, 2H).

Example 22. (1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyrimidin-2-yl)amino)cyclopentan-1-ol

Step 1) Synthesis of 4-(2,6-dichloropyrimidin-4-yl)morpholine

2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, and then morpholine (3.46 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) were slowly added. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (8.60 g, 67%).

Step 2) Synthesis of (1R,3R)-3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclopentan-1-ol

4-(2,6-dichloropyrimidin-4-yl)morpholine (0.20 g, 0.85 mmol) obtained in Step 1 above and trans-3- instead of trans-4-aminocyclohexanol in Step 2 of Example 14. The target compound (0.20 g, 79.2%) was obtained using the same method, except that aminocyclopentanol hydrochloride (137.6 mg, 1.0 mmol) was used.

Step 3) (1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl ) Amino) cyclopentan-1-ol synthesis

(1R,3R)-3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclopentan-1-ol (0.10 g, 0.33 mmol) obtained in step 2 was prepared in Example 12. By reacting in the same manner as step 3, the target compound (17.6 mg, 10.5%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.37 (s, 1H), 8.22 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.31 (d) , 1H, J = 4.0 Hz), 5.84 (s, 1H), 5.63-5.61 (m, 1H), 3.96-3.93 (m, 1H), 3.51-3.46 (m, 2H), 3.19 (s, 4H), 2.08 (d, 2H, J = 4.0 Hz), 1.90 (d, 2H, J = 4.0 Hz), 1.53-1.42 (m, 2H), 1.30-1.22 (m, 2H).

Example 23. (1R,3R)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyrimidin-2-yl)amino)cyclobutan-1-ol

Step 1) Synthesis of (1 R ,3 R )-3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclobutan-1-ol

4-(2,6-dichloropyrimidin-4-yl)morpholine (0.20 g, 0.85 mmol) obtained in step 1 of synthesis of Example 22 and trans-4-aminocyclohexanol in step 2 of Example 14 The target compound (0.18 g, 77.6%) was obtained using the same method, except that trans-3-aminocyclobutanol (87.0 mg, 1.0 mmol) was used.

Step 2) (1R,3R)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl ) Amino) cyclobutan-1-ol synthesis

(1 R ,3 R )-3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclobutan-1-ol (65.0 mg, 0.20 mmol) obtained in step 1 above. By reacting in the same manner as Step 3 of Example 12, the target compound (33.7 mg, 34.2%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.54 (s, 1H), 8.21 (s, 1H), 8.11-8.09 (m, 2H), 7.64-7.63 (m, 3H), 7.13 (d) , 1H, J = 4.0 Hz), 5.59 (s, 1H), 4.78 (s, 1H), 4.44-4.38 (m, 2H), 3.66-3.65 (d, 4H, J = 4.0 Hz), 3.45-3.44 ( d, 4H, J = 4.0 Hz), 2.30 (s, 2H), 1.98 (s, 1H), 1.94 (s, 1H).

Example 24. 6-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)spiro[3.3]heptan-2-ol synthesis

Step 1) Synthesis of 6-((4-chloro-6-morpholinopyrimidin-2-yl)amino)spiro[3.3]heptan-2-ol

4-(2,6-dichloropyrimidin-4-yl)morpholine (0.20 g, 0.85 mmol) obtained in step 1 of synthesis of Example 22 and trans-4-aminocyclohexanol in step 2 of Example 14 The target compound (0.23 g, 82.4%) was obtained using the same method, except that 6-aminospiro[3,3]heptan-2-ol hydrochloride (0.16 g, 1.0 mmol) was used.

Step 2) 6-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- Synthesis of 2-yl)amino)spiro[3.3]heptan-2-ol

6-((4-chloro-6-morpholinopyrimidin-2-yl)amino)spiro[3.3]heptan-2-ol (65.0 mg, 0.20 mmol) obtained in Step 1 above was added to Step 3 of Example 12. By reacting in the same manner, the target compound (27.8 mg, 26.1%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.53 (s, 1H), 8.22 (s, 1H), 8.10 (m, 2H), 7.65-7.63 (m, 3H), 7.03-7.02 (d) , 1H, J = 4.0 Hz), 5.56 (s, 1H), 4.92-4.91 (d, 1H, J = 4.0 Hz), 4.52 (m, 1H), 4.01-3.96 (m, 1H), 3.65 (s, 4H), 3.43-3.-42 (d, 4H, J = 4.0 Hz), 2.30 (m, 2H), 2.18-2.14 (m, 1H), 2.07-2.05 (d, 2H, J = 4.0 Hz), 1.96-1.95 (d, 2H, J = 4.0 Hz), 1.85-1.81 (t, 1H, J = 4.0 Hz).

Example 25. (1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyrimidin-2-yl)amino)cyclopentan-1-ol

Step 1) Synthesis of (1S,3S)-3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclopentan-1-ol

4-(2,6-dichloropyrimidin-4-yl)morpholine (0.50 g, 2.14 mmol) obtained in step 1 of synthesis of Example 22 and trans-4-aminocyclohexanol in step 2 of Example 14. The target compound (0.47 g, 73.9%) was obtained using the same method, except that (1S,3S)-3-aminocyclopentanol hydrochloride (0.36 g, 2.60 mmol) was used.

Step 2) (1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl ) Amino) cyclopentan-1-ol synthesis

(1S,3S)-3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclopentan-1-ol (0.45 g, 1.50 mmol) obtained in Step 1 was added to Example 12. By reacting in the same manner as step 3, the target compound (126 mg, 16.6%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.54 (s, 1H), 8.21 (s, 1H), 8.10-8.09 (m, 2H), 7.63-7.62 (m, 4H), 6.78-6.77 (d, 1H, J = 8.0 Hz), 5.57 (s, 1H), 4.52 (s, 2H), 4.25 (s, 1H), 3.66 (s, 4H), 3.44 (s, 4H), 2.51-2.50 ( m, 2H), 1.97-1.74 (m, 2H).

Example 26. (1S,4 R )-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((5-(5-phenyl-1,3, Synthesis of 4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

Step 1) Synthesis of (1S,4S)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

2,4, except that (1s,4s)-2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (81.4 mg, 0.60 mmol) was used instead of morpholine in step 1 of Example 22. The target compound (0.12 g, 95.4%) was obtained using the same method as 6-trichloropyrimidine (0.10 g, 0.50 mmol).

Step 2) (1S,4 R )-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-chloropyrimidine-2 Synthesis of -yl)amino)cyclohexane-1ol

(1S,4S)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (1.00 g, 3.81 mmol) obtained in step 1 above. The target compound (1.06 g, 74%) was obtained in the same manner as Step 2 of Example 14.

Step 3) (1S,4 R )-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((5-( Synthesis of 5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1S,4 R )-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-chloropyrimidine obtained in step 2 above. -2-yl) amino) cyclohexan-1ol (0.6 g, 1.85 mmol) was reacted in the same manner as step 3 of Example 12 to obtain the target compound (131.2 mg, 13.3%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.48 (s, 1H), 8.22 (s, 1H), 8.10-8.08 (t, 1H, J = 4.0 Hz), 8.64 (m, 3H), 7.02 (s, 1H), 6.58-6.56 (d, 1H, J = 4.0 Hz), 5.33 (s, 1H), 4.66 (s 1H), 3.89 (s, 1H), 3.76-7.74 (d, 1H, J = 4.0 Hz), 3.65-3.63 (d, 1H, J = 4.0 Hz), 3.46 (s, 1H), 2.23 (s, 1H), 2.01-1.84 (m, 8H), 1.48-1.46 (d, 2H, J = 4.0 Hz), 1.34-1.32 (m, 2H), 1.24-1.21 (m, 2H).

Example 27. (One R ,4 R )-4-((4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl ) Synthesis of thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) Synthesis of 2-(2,6-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrole

2,4,6-trichloropyrimidine (0.50 g, 2.70 mmol), except that octahydrocyclopenta[c]pyrrole hydrochloride (0.50 g, 3.20 mmol) was used instead of morpholine in Step 1 of Example 22. The target compound (0.30 g, 39.2%) was obtained using the same method.

Step 2) (1 R ,4 R )-4-((4-chloro-6-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidin-2-yl)amino)cyclohexane- Synthesis of 1-ol

2-(2,6-dichloropyrimidin-4-yl)octahydrocyclopenta[c]pyrrole (0.27 g, 1.0 mmol) obtained in Step 1 above was reacted with the target compound (0.30 mmol) in the same manner as in Step 2 of Example 14. g, 84.9%) was obtained.

Step 3) (1 R ,4 R )-4-((4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-((5-(5-phenyl-1,3, Synthesis of 4-oxadiazol-2-yl) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1 R ,4 R )-4-((4-chloro-6-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidin-2-yl)amino)cyclo obtained in step 2 above Hexan-1-ol (0.28 g, 0.80 mmol) was reacted in the same manner as Step 3 of Example 12 to obtain the target compound (160.0 mg, 36.7%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.45 (s, 1H), 8.21 (s, 1H), 8.10-8.09 (m, 2H), 7.62 (m, 3H), 6.46-6.44 (d) , 1H, J = 7.5 Hz), 5.35 (s, 1H), 4.67 (s, 1H), 3.89 (s, 1H), 3.53 (s, 2H), 3.46 (s, 1H), 3.13-3.12 (d, 2H, J = 7.5 Hz), 2.70 (s, 2H), 1.99 (s, 2H), 1.90-1.88 (d, 2H, J = 7.5 Hz), 1.80-1.78 (m, 2H), 1.72-1.67 (m , 1H), 1.60-1.54 (m, 1H), 1.45 (s, 4H), 1.37-1.33 (m, 2H).

Example 28. 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine-4 -1) Synthesis of piperidin-4-ol

Step 1) Synthesis of 1-(2,6-dichloropyrimidin-4-yl)piperidin-4-ol

In Step 1 of Example 22, the same method as 2,4,6-trichloropyrimidine (0.30 g, 1.60 mmol) was used, except that 4-piperidiol (0.50 g, 3.20 mmol) was used instead of morpholine. The target compound (0.24 g, 61.7%) was obtained.

Step 2) Synthesis of 1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperidin-4-ol

1-(2,6-dichloropyrimidin-4-yl)piperidin-4-ol (0.24 g, 1.0 mmol) obtained in Step 1 above was mixed with the target compound (0.26 g) in the same manner as in Step 2 of Example 14. , 83.3%) was obtained.

Step 3) 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)amino)pyrimidin-4-yl)piperidin-4-ol

1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperidin-4-ol (0.26 g , 0.80 mmol) was reacted in the same manner as Step 3 of Example 12 to obtain the target compound (25.5 mg, 6.0%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.45 (s, 1H), 8.22 (s, 1H), 8.10-8.08 (m, 2H), 7.63-7.62 (d, 3H, J = 2.0 Hz ), 6.54-6.53 (d, 1H, J = 2.0 Hz), 5.59 (s, 1H), 4.73 (s, 1H), 4.72 (s, 1H), 3.92-3.90 (d, 2H, J = 2.0 Hz) , 2.70 (s, 2H), 1.99 (s, 2H), 1.90-1.88 (m, 2H), 1.80-1.78 (m, 2H), 1.72-1.67 (m, 1H), 1.60-1.54 (m, 1H) , 1.45 (s, 4H), 1.37-1.33 (m, 2H).

Example 29. (1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-(2, 2,6,6-tetrafluoromorpholino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) 4-(2,6-dichloropyrimidin-4-yl)-2,2,6,6-tetrafluoromorpholine

The target compound (430 mg, 26%) was obtained.

Step 2) (1R,4R)-4-((4-chloro-6-(2,2,6,6-tetrafluoromorpholino)pyrimidin-2-yl)amino)cyclohexan-1-ol

4-(2,6-dichloropyrimidin-4-yl)-2,2,6,6-tetrafluoromorpholine (0.43 g, 1.41 mmol) obtained in Step 1 above was used in the same manner as Step 2 of Example 14. By reacting with this method, the target compound (320 mg, 59%) was obtained.

Step 3) (1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6- (2,2,6,6-tetrafluoromorpholino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-(2,2,6,6-tetrafluoromorpholino)pyrimidin-2-yl)amino)cyclohexane-1- obtained in step 2 above. All (0.32 g, 0.83 mmol) was reacted in the same manner as Step 3 of Example 12 to obtain the target compound (180 mg, 37%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.73 (s, 1H), 8.25 (d, 1H, J= 4.0 Hz), 8.09 (t, 2H, J= 2.0 Hz), 7.63 (s, 3H), 6.97 (d, 1H, J= 4.0 Hz), 5.70 (s, 1H), 4.70 (s, 1H), 4.30 (s, 4H), 4.04-4.02 (m, 1H), 3.48 (s, 1H) ), 2.08-2.04 (m, 2H), 1.98-1.90 (m, 2H), 1.50-1.47 (m, 2H), 1.44-1.30 (m, 2H).

Example 30. (1R,4R)-4-((4-((2-methoxyethyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) 2,6-dichloro-N-(2-methoxyethyl)pyrimidin-4-amine

The target compound (630 mg, 52%) was obtained using the same method except that 2-methoxyethylamine (0.52 ml, 6.00 mmol) was used instead of 2,6-dimethylmorpholine in Step 1 of Example 22. .

Step 2) (1R,4R)-4-((4-chloro-6-((2-methoxyethyl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,6-Dichloro-N-(2-methoxyethyl)pyrimidin-4-amine (0.73 g, 3.29 mmol) obtained in Step 1 was reacted in the same manner as Step 2 of Example 14 to obtain the target compound (580 mg, 59%) was obtained.

Step 3) (1R,4R)-4-((4-((2-methoxyethyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl ) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-((2-methoxyethyl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.58 g, 1.93 mmol) was reacted in the same manner as Step 3 of Example 12 to obtain the target compound (210 mg, 21%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.40 (s, 1H), 8.20 (s, 1H), 8.09 (t, 2H, J=4 Hz), 7.62 (d, 3H, J= 2.0 Hz), 6.85 (s, 1H), 6.43 (d, 1H, J= 4.0 Hz), 5.43 (s, 1H), 4.66 (s, 1H), 3.89 (s, 1H), 3.40 (s, 6H), 3.26 (s, 4H), 1.99 (d, 2H, J= 2.0 Hz), 1.89 (d, 2H, J= 4.0 Hz), 1.47-1.45 (m, 2H), 1.37-1.18 (m, 2H).

Example 31. 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine-4 -1) Synthesis of -5-methylpyrrolidin-2-one

Step 1) Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methylpyrrolidin-2-one

2,4,6-trichloropyrimidine (0.15 g, 0.82 mmol), except that 5-methylpyrrolidin-2-one (0.10 g, 0.98 mmol) was used instead of morpholine in Step 1 of Example 22. The target compound (0.18 g, 89.2%) was obtained using the same method.

Step 2) 1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one synthesis

1-(2,6-dichloropyrimidin-4-yl)-5-methylpyrrolidin-2-one (0.20 g, 0.80 mmol) obtained in Step 1 above was used for the purpose in the same manner as Step 2 of Example 14. Compound (0.15 g, 58.9.3%) was obtained.

Step 3) 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one

1-(6-chloro-2-(((1R,4R)-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one ( 0.15 g, 0.50 mmol) was reacted in the same manner as step 3 of Example 12 to obtain the target compound (7.7 mg, 2.9%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.82 (s, 1H), 8.27 (s, 1H), 8.11-8.09 (m, 2H), 7.64-7.62 (m, 3H), 7.25 (s) , 1H), 7.03-7.01 (d, 1H, J = 2.0 Hz), 4.70 (s, 1H), 3.94 (s, 1H), 3.48 (s, 1H), 2.78-2.75 (m, 1H), 2.44- 238 (m, 2H), 2.04 (s, 1H), 1.91 (s, 3H), 1.70-1.69 (m, 1H), 1.50-1.40 (m, 2H), 1.38-1.30 (m, 5H), 1.26- 1.24 (m, 2H).

Example 32. 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine-4 -1) Synthesis of piperidine-4-carbonitrile

Step 1) Synthesis of 1-(2,6-dichloropyrimidin-4-yl)piperidine-4-carbonitrile

2,4,6-trichloropyrimidine (0.30 g, 1.60 mmol), except that piperidine-4-carbonitrile hydrochloride (0.30 g, 1.90 mmol) was used instead of morpholine in Step 1 of Example 22. The target compound (0.35 g, 85.4%) was obtained using the same method.

Step 2) Synthesis of 1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile

1-(2,6-dichloropyrimidin-4-yl)piperidine-4-carbonitrile (0.30 g, 0.60 mmol) obtained in Step 1 above was reacted with the target compound (0.19 g, 47.9%) was obtained.

Step 3) 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -1)thiazol-2-yl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile

1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile (0.20 g, 0.60 mmol) was reacted in the same manner as Step 3 of Example 12 to obtain the target compound (9.2 mg, 2.8%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.51 (s, 1H), 8.23 (s, 1H), 8.10-8.08 (m, 2H), 7.63-7.62 (m, 3H), 7.63-7.62 (m, 1H), 6.63-6.62 (d, 1H, J = 2.0 Hz), 5.59 (s, 1H), 4.68 (s, 1H), 4.56 (s, 1H), 4.56-4.55 (d, 2H, J = 2.0 Hz), 3.89-3.73 (m, 1H), 3.13-3.11 (m, 1H), 2.01 (s, 2H), 1.82-1.80 (d, 2H, J = 2.0 Hz), 1.47-1.19 (m, 6H)).

Example 33. (1R,4R)-4-((4-methoxy-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine -2-yl)amino)cyclohexan-1-ol

Step 1) (1R,4R)-4-((6-chloro-4-methoxypyridin-2-yl)amino)cyclohexan-1-ol

2,6-Dibromo-4-methoxypyridine (0.50 g, 1.87 mmol) was reacted in the same manner as step 2 of Example 14 to obtain the target compound (280 mg, 50%).

Step 2) (1R,4R)-4-((4-methoxy-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Amino) pyridin-2-yl) Amino) cyclohexan-1-ol

(1R,4R)-4-((6-chloro-4-methoxypyridin-2-yl)amino)cyclohexan-1-ol (0.28 g, 0.93 mmol) obtained in step 1 above was added to the step of Example 12. By reacting in the same manner as in 3, the target compound (27 mg, 6%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.42 (s, 1H), 8.21 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.52 (d) , 1H, J= 4.0 Hz), 5.83 (d, 1H, J= 2.0 Hz), 5.68 (d, 1H, J= 2.0 Hz), 4.66 (d, 1H, J= 2.0 Hz), 3.94-3.93 (m , 1H), 3.71 (d, 3H, J= 4.0 Hz), 3.52-3.48 (m, 1H), 2.08-2.06 (m, 2H), 1.91-1.89 (m, 2H), 1.29-1.27 (m, 2H) ), 1.24-1.22 (m, 2H).

Example 34. 1-(4-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine-4 Synthesis of -1) piperazine-1-yl) ethane-1-one

Step 1) Synthesis of 1-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)ethan-1-one

In Step 1 of Example 22, the same method as 2,4,6-trichloropyrimidine (0.15 g, 0.80 mmol) was used, except that 1-acetylpiperazine (0.12 g, 1.00 mmol) was used instead of morpholine. The target compound (0.17 g, 77.7%) was obtained.

Step 2) 1-(4-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperazin-1-yl)ethane- Synthesis of 1-ones

1-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)ethan-1-one (0.39 g, 1.40 mmol) obtained in step 1 was added to step 2 of Example 14. The target compound (0.44 g, 88.9%) was obtained in the same manner.

Step 3) 1-(4-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadia Synthesis of sol-2-yl)thiazol-2-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one

1-(4-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperazin-1-yl) obtained in step 2 above. Ethane-1-one (0.40 g, 1.10 mmol) was reacted in the same manner as Step 3 of Example 12 to obtain the target compound (70.6 mg, 11.4%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.54 (s, 1H), 8.23 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.64-6.63 (d, 1H, J = 2.0 Hz), 5.59 (s, 1H), 4.68 (s, 1H), 3.89 (s, 1H), 3.51 (s, 6H), 3.47 (s, 3H), 2.04 (s, 4H), 1.91-1.89 (m, 2H), 1.48-1.46 (m, 2H), 1.36-1.32 (m, 2H).

Example 35. (One R ,4 R )-4-((4-(4-methoxypiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2 Synthesis of -yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

Step 1) Synthesis of 2,4-dichloro-6-(4-methoxypiperidin-1-yl)pyrimidine

Same method as 2,4,6-trichloropyrimidine (0.30 g, 1.60 mmol) except that 4-methoxy piperidine (0.20 ml, 1.90 mmol) was used instead of morpholine in step 1 of Example 22. The target compound (0.40 g, 96.2%) was obtained using .

Step 2) Synthesis of (1 R ,4 R )-4-((4-chloro-6-(4-methoxypiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,4-Dichloro-6-(4-methoxypiperidin-1-yl)pyrimidine (0.36 g, 1.40 mmol) obtained in Step 1 above was added to the target compound (0.30 g) in the same manner as Step 2 of Example 14. , 63.5%) was obtained.

Step 3) (1 R ,4 R )-4-((4-(4-methoxypiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole Synthesis of -2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1 R ,4 R )-4-((4-chloro-6-(4-methoxypiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol obtained in step 2 above (0.30 g, 0.80 mmol) was reacted in the same manner as step 3 of Example 12 to obtain the target compound (6.1 mg, 1.4%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.46 (s, 1H), 8.22 (s, 1H), 8.10-8.08 (m, 2H), 7.63-7.62 (m, 3H), 6.56-6.54 (d, 1H, J = 2.0 Hz), 5.60 (s, 1H), 4.68 (s, 1H), 3.85-3.82 (m, 3H), 3.46-3.41 (m, 2H), 3.27 (s, 3H), 3.19-3.14 (m, 2H), 2.00 (d, 2H, J =2.0 Hz), 1.91-1.89 (d, 4H, J =2.0 Hz), 1.48-1.46 (m, 2H), 1.36-1.32 (m, 2H).

Example 36. (One R ,4 R )-4-((4-(4-(dimethylamino)piperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of sol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

Step 1) Synthesis of 1-(2,6-dichloropyrimidin-4-yl)- N , N -dimethylpiperidin-4-amine

2,4,6-trichloropyrimidine (0.10 g, 0.50 mmol), except that N , N -dimethyl piperidin-4-amine (0.10 ml, 0.60 mmol) was used in Step 1 of Example 22 instead of morpholine. The target compound (0.11 g, 80.0%) was obtained using the same method as mmol).

Step 2) (1 R ,4 R )-4-((4-chloro-6-(4-(dimethylamino)piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexane-1- synthesis of all

1-(2,6-dichloropyrimidin-4-yl)- N , N -dimethylpiperidin-4-amine (0.40 g, 1.50 mmol) obtained in Step 1 was subjected to the same method as Step 2 of Example 14. The target compound (0.31 g, 59.2%) was obtained.

Step 3) (1 R ,4 R )-4-((4-(4-(dimethylamino)piperidin-1-yl)-6-((5-(5-phenyl-1,3,4- Synthesis of oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1 R ,4 R )-4-((4-chloro-6-(4-(dimethylamino)piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexane- obtained in step 2 above 1-ol (0.30 g, 0.80 mmol) was reacted in the same manner as step 3 of Example 12 to obtain the target compound (12.8 mg, 2.8%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 11.47 (s, 1H), 8.22 (s, 1H), 8.10 (m, 2H), 7.63 (s, 3H), 6.55 (d, 1H, J = 2.0 Hz), 5.60 (s, 1H), 4.69 (s, 1H), 4.23-4.21 (d, 2H, J = 2.0 Hz), 3.89 (s, 1H), 3.47 (s, 1H), 2.83-2.78 (t, 2H, J = 2.0 Hz), 2.25 (s, 6H), 2.01 (s, 2H), 1.91-1.89 (d, 2H, J = 2.0 Hz), 1.83-1.81 (d, 2H, J = 2.0 Hz), 1.48-1.46 (d, 2H, J = 2.0 Hz), 1.34-1.32 (m, 4H).

Example 37. (One R ,4 R )-4-((4-(1H-imidazol-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl) amino) cyclohexan-1-ol synthesis

Step 1) Synthesis of 2,4-dichloro-6-(1 H -imidazol-1-yl)pyrimidine

2,4,6-trichloropyrimidine (0.10 g, 0.50 mmol), except that N , N -dimethyl piperidin-4-amine (0.10 ml, 0.60 mmol) was used in Step 1 of Example 22 instead of morpholine. The target compound (0.11 g, 80.0%) was obtained using the same method as mmol).

Step 2) Synthesis of (1 R ,4 R )-4-((4-chloro-6-(1 H -imidazol-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol

2,4-dichloro-6-(1 H -imidazol-1-yl)pyrimidine (0.40 g, 1.50 mmol) obtained in step 1 above was mixed with the target compound (0.31 g, 59.2%) was obtained.

Step 3) (1 R ,4 R )-4-((4-(1H-imidazol-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1 R ,4 R )-4-((4-chloro-6-(1 H -imidazol-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol ( 0.60 g, 2.00 mmol) was reacted in the same manner as step 3 of Example 12 to obtain the target compound (67.0 mg, 6.7%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 12.00 (s, 1H), 8.59 (s, 1H), 8.28 (s, 1H), 8.10-8.09 (m, 2H), 7.94 (s, 1H) ), 7.70 (s, 1H), 7.67-7.62 (m, 3H), 7.20 (s, 1H), 6.01 (s, 1H), 4.59 (s, 1H), 3.88 (s, 1H), 3.45-3.41 ( m, 1H), 1.94-1.87 (m, 4H), 1.32-1.27 (m, 4H).

Example 38. 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)methyl)-3,4-dihydropyridin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

Step 1) (2,6-dibromopyridin-4-yl)((2S,6R)-2,6-dimethylmorpholino)methanone

2,6-Dibromonicotinic acid (1 g, 3.55 mmol) and 1,1'-carbonyldiimidazole (0.69 g, 4.27 mmol) were dissolved in N,N'-dimethylformamide (3.5 mL). Then stir at room temperature for 5 minutes. Cis-2,6-dimethylmorpholine (0.36 mL, 4.27 mmol) was added dropwise to this solution and stirred at room temperature for 2 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.12 g, 90%).

Step 2) (2S,6R)-4-((2,6-dibromopyridin-4-yl)methyl)-2,6-dimethylmorpholine

(2,6-dibromopyridin-4-yl)((2S,6R)-2,6-dimethylmorpholino)methanone (1.12 g, 3.22 mmol) synthesized in step 1 was dissolved in tetrahydrofuran 3.2. After dissolving in ml, cool to 0°C. 1M borane-tetrahydro solution (3.0 eq) was added dropwise to the cooled reaction solution and stirred at 0°C for 1 hour. Afterwards, borane-tetrahydro solution (3.0 eq) was added dropwise and stirred at 0°C for 3 hours until the starting material disappeared. The reaction solution was adjusted to pH 1 with 1M aqueous hydrochloric acid solution and stirred at 80°C for 1 hour. After cooling the reaction solution to 0°C, adjust the pH to about 8 using saturated aqueous sodium bicarbonate solution, extract using ethyl acetate, and wash with water. The obtained organic layer is dried with magnesium sulfate and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).

Step 3) 4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.2]octane- 1-all

(2S,6R)-4-((2,6-dibromopyridin-4-yl)methyl)-2,6-dimethylmorpholine (200 mg. 0.59 mmol), 4-amino synthesized in step 2 above Bicyclo[2.2.2]octan-1-ol hydrochloride (126 mg, 0.71 mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 10 mol%), xanthos (17 mg, 10 mol%), Sodium-tert-butoxide (170 mg, 1.78 mmol) was dissolved in 1.5 ml of anhydrous 1,4-dioxane and stirred at room temperature for 4 hours. When the reaction was completed, it was extracted with ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (99 mg, 49%).

Step 4) 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)methyl)bicyclo[2.2.2]octane-1 -all

4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.2 synthesized in step 3 above ] Octan-1-ol (287 mg, 0.84 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (551 mg, 1.69 mmol) were placed in a shrink tube, and a nitrogen environment was created. Afterwards, acetylacetone (40 mol%), aqueous ammonia solution (0.65 ml, 16.91 mmol), and anhydrous dimethylformamide (4 ml) were sequentially added, and the mixture was stirred at 90°C overnight. When the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate, washed with water, and the resulting organic layer was dried over magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (53 mg, 23%).

Step 5) 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole

2-Bromo-5-formylthiazole (0.50 g, 2.60 mmol) and benzhydrazide (0.35 g, 2.60 mmol) were dissolved in 26 ml of ethanol and heated to reflux for 1 hour. When the reaction was completed, the solvent was distilled under reduced pressure. The obtained residue was dissolved in 13 ml of dimethyl sulfoxide, and then potassium carbonate (1.08 g, 7.80 mmol) and iodine (0.79 g, 3.12 mmol) were added. This solution was stirred at 100°C for 1 hour. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.72 g, 90%).

Step 6) 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)methyl)-3,4-dihydropyridin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)methyl)bicyclo[2.2.2]octane obtained in step 4 above -1-ol (0.10 g, 0.25 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.06 g) obtained in step 1 of Example 21 , 0.20 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.02 mmol), xantphos (0.01 g, 0.02 mmol), and sodium-tert-butoxide (0.03 g, 0.31 mmol) in 1.0 ml 1, After dissolving in 4-dioxane, stir at 10°C for 5 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (10 mg, 8%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.39 (s, 1H), 8.22 (s, 1H), 8.12-8.11 (m, 2H), 7.63-7.62 (m, 3H), 6.32 (s) , 1H), 6.20 (s, 1H), 6.15 (s, 1H), 4.33 (s, 1H), 3.58-3.56 (m, 1H), 3.21 (s, 2H), 2.69-2.66 (m, 2H), 2.18-2.16 (m, 6H), 2.79-2.76 (m, 6H), 1.62 (t, 2H, J= 10.48 Hz), 1.03 (d, 6H, J= 5.8 Hz)

Example 39. 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)adamantane-1-ol

Step 1) 4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantan-1-ol

The reaction was repeated in the same manner except that trans-4-amino-1-adamantanol hydrochloride was used instead of 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride in step 3 of Example 38 to obtain the target compound ( 99 mg, 49%) was obtained.

Step 2) 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantan-1-ol

4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantane-1- synthesized in step 1 above All (0.49 g, 1.41 mmol) was reacted in the same manner as step 4 of Example 38 to obtain the target compound (53 mg, 23%).

Step 3) 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)adamantane-1-ol

4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantan-1-ol synthesized in step 2 (0.10 g, 0.25 mmol) was reacted in the same manner as step 6 of Example 38 to obtain the target compound (158 mg, 64%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.46 (s, 1H), 8.21 (s, 1H), 8.12-8.11 (m, 2H), 7.63-7.62 (m, 3H), 6.57 (d) , 6H, J= 6.7 Hz), 6.34 (s, 1H), 6.19 (s, 1H), 4.39 (s, 1H), 4.27-4.26 (m, 1H), 3.59-3.57 (3, 2H), 3.25 ( s, 2H), 3.16 (s, 1H) 2.71-2.69 (m, 2H), 2.18 (s, 2H), 2.03-2.00 (m, 5H), 1.72-1.61 (m, 6H), 1.36-1.64 (m , 2H), 1.04 (d, 6H, J= 5.8 Hz)

Example 40. 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol

Step 1) 4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.1]heptane- 1-all

React in the same manner except that 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride was used instead of 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride in step 3 of Example 38. The target compound (99 mg, 49%) was obtained.

Step 2) 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.1]heptane-1 -all

4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.1 synthesized in step 1 above ]Heptan-1-ol (0.49 g, 1.41 mmol) was reacted in the same manner as step 4 of Example 38 to obtain the target compound (53 mg, 23%).

Step 3) 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol

4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.1] synthesized in step 2 above Heptan-1-ol (0.10 g, 0.25 mmol) was reacted in the same manner as step 6 of Example 38 to obtain the target compound (158 mg, 64%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ11.41 (s, 1H), 8.21 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.68 (s) , 1H), 6.27 (s, 1H), 6.19 (s, 1H), 4.89 (s, 1H), 3.59-3.58 (m, 2H), 3.27 (s, 2H), 3.71-3.68 (m, 2H), 2.33-2.23 (m, 2H), 1.94-1.84 (m, 7H), 1.64 (t, 4H, J= 9.0 Hz), 1.09 (d, 6H, J= 5.8 Hz)

Example 41. (S)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)propan-1-ol

Step 1) 2-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)ethane-1-ol

2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, and then 1-piperazineethanol (4.96 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) were slowly added thereto. Add. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7.40 g, 70%).

Step 2) (S)-2-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)propan-1-ol

2-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)ethan-1-ol (0.5 g, 1.80 mmol) obtained in step 1 was added to 2 ml of 1-propanol. Dissolve. Then, (S)-(+)-2-amino-1-propanol (0.17 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 77%).

Step 3) 5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-amine

Example 38 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.50 g, 1.62 mmol) obtained in step 5 of synthesis was dissolved in 3.2 ml of ethanol. After this, aqueous ammonia (1.85 ml, 16.20 mmol) is added at room temperature and the tube is sealed. Afterwards, heat it at 15℃ for 16 hours. After the reaction was completed, the obtained residue was adsorbed on silica and purified using column chromatography to obtain the target compound (225 mg, 57%).

Step 4) (S)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadia Zol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)propan-1-ol

(S)-2-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)propane-1-synthesized in step 2 above. All (0.1 g, 0.31 mmol), 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.08 g, 0.37 mmol), palladium acetate (0.01 g, 0.03 mmol), xanthos (0.04 g, 0.06 mmol), and cesium carbonate (0.30 g, 0.92 mmol) were dissolved in 3.0 ml of 1,4-dioxane and then heated at 16°C in the microwave for 1 hour. Reaction takes place. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the obtained organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue is purified using column chromatography to obtain the target compound (113 mg, 70%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.38 (s, 1H), 8.20 (s, 1H), 8.11-8.06 (m, 2H), 7.63-7.62 (m, 3H), 5.97 (s) , 1H), 5.60 (s, 1H), 4.42 (s, 1H), 4.29 (s, 1H), 3.54-3.53 (m, 2H), 3.45-3.44 (m, 2H), 3.25-3.20 (m, 1H) ), 3.09-3.05 (m, 1H), 2.75-2.70 (m, 1H), 2.46-2.43 (m, 2H), 2.42-2.40 (m, 2H), 1.19-0.85 (m, 7H).

Example 42. 4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia sol-2-yl) amino) pyrimidin-2-yl) amino) bicyclo [2.2.2] octan-1-ol

Step 1) 4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)bicyclo[2.2.2]octane-1- all

Example 41 2-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)ethan-1-ol (0.5 g, 1.80 mmol) obtained in synthesis step 1 was added to 2 ml of 1. -Dissolves in propanol. Then, 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (0.33 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.53 mg, 77%).

Step 2) 4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- I) thiazol-2-yl) amino) pyrimidin-2-yl) amino) bicyclo [2.2.2] octan-1-ol

4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)bicyclo[2.2.2]octane synthesized in step 1 above -1-ol (0.09 g, 0.25 mmol) was reacted in the same manner as step 4 of Example 41 to obtain the target compound (74 mg, 50%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.38 (s, 1H), 8.20 (s, 1H), 8.11-8.06 (m, 2H), 7.63-7.62 (m, 3H), 5.97 (s) , 1H), 5.60 (s, 1H), 4.42 (s, 1H), 4.29 (s, 1H), 3.54-3.539 (m, 2H), 3.45-3.44 (m, 2H), 2.46-2.43 (m, 2H) ), 2.42-2.40 (m, 2H), 2.14-2.12 (m, 6H), 2.71-2.70 (m, 6H), 1.00-0.98 (m, 4H)

Example 43. (S)-3-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)piperidine-1-carbonitrile

Step 1) tert-Butyl (S)-3-((4,6-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate

2,4,6-Trichloropyrimidine (0.7 g, 3.87 mmol) was dissolved in 76 ml of dichloromethane and then (S)-tert-butyl-3-aminopiperidine-1-carboxylate (802 mg) , 4.00 mmol) and DIPEA (0.67 ml, 4.00 mmol) were slowly added. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (434 mg, 32%).

Step 2) (S)-4,6-dichloro-N-(piperidin-3-yl)pyrimidin-2-amine

2 mL of tert-butyl (S)-3-((4,6-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate (434 mg, 1.25 mmol) synthesized in step 1 above. After dissolving in anhydrous dichloromethane, 4.0M hydrochloric acid (3.12 mL, 12.5 mmol) dissolved in dioxane is slowly added. This solution is stirred at room temperature for 18 hours. When the reaction was completed, it was neutralized with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (293 mg, 94%).

Step 3) (S)-3-((4,6-dichloropyrimidin-2-yl)amino)piperidine-1-carbonitrile

(S)-4,6-dichloro-N-(piperidin-3-yl)pyrimidin-2-amine (224 mg, 0.90 mmol) synthesized in step 2 above was mixed with sodium bicarbonate (305 mg, 3.63 mmol). Dissolve in 2 ml of dichloromethane and 2 ml of methanol. After the solution is sufficiently cooled, cyanogen bromide (385 mg, 3.66 mmol) is added. Afterwards, the temperature is slowly raised to room temperature and stirred overnight. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (122 mg, 50%).

Step 4) (S)-3-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)piperidine-1-carbon trill

(S)-3-((4,6-dichloropyrimidin-2-yl)amino)piperidine-1-carbonitrile (122 mg, 0.45 mmol) obtained in step 3 above was added to 2 ml of 1-propanol. Dissolve. Then, 1-piperazineethanol (0.06 mL, 0.90 mmol) and DIPEA (0.15 ml, 0.90 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (120 mg, 80%).

Step 5) (S)-3-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadia Zol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)piperidine-1-carbonitrile

(S)-3-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)piperidine-synthesized in step 4 above. 1-Carbonitrile (0.12 g, 0.32 mmol) was reacted in the same manner as step 4 of Example 41 to obtain the target compound (110 mg, 60%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.38 (s, 1H), 8.20 (s, 1H), 8.11-8.06 (m, 2H), 7.63-7.62 (m, 3H), 5.97 (s) , 1H), 5.60 (s, 1H), 4.42 (s, 1H), 3.80-3.77 (m,1H), 3.54-3.44 (m, 3H), 3.45-3.44 (m, 2H), 3.04-2.28 (m) , 4H), 2.42-2.09 (m, 3H), 1.97-1.79 (m, 2H), 1.55-1.47 (m, 1H), 1.24-1.23 (m, 1H), 1.00-0.98 (m, 4H).

Example 44. 3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2 -yl)amino)piperidine -1-carbonitrile/

Step 1) Synthesis of (2,6-dibromopyridin-4-yl)(morpholino)methanone

2,6-Dibromonicotinic acid (1 g, 3.55 mmol) and 1,1'-carbonyldiimidazole (0.69 g, 4.27 mmol) were dissolved in N,N'-dimethylformamide (3.5 mL). Then stir at room temperature for 5 minutes. Morpholine (0.36 mL, 4.27 mmol) was added dropwise to this solution and stirred at room temperature for 2 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.12 g, 90%).

Step 2) Synthesis of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine

(2,6-dibromopyridin-4-yl)(morpholino)methanone (1.12 g, 3.22 mmol) obtained in Step 1 above was dissolved in 3.2 ml of tetrahydrofuran and cooled to 0°C. 1M borane-tetrahydro solution (3.0 eq) was added dropwise to the cooled reaction solution and stirred at 0°C for 1 hour. Afterwards, borane-tetrahydro solution (3.0 eq) was added dropwise and stirred at 0°C for 3 hours until the starting material disappeared. The reaction solution was adjusted to pH 1 with 1M hydrochloric acid aqueous solution and stirred at 80°C for 1 hour. After cooling the reaction solution to 0°C, adjust the pH to about 8 using saturated aqueous sodium bicarbonate solution, extract using ethyl acetate, and wash with water. The obtained organic layer is dried with magnesium sulfate and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).

Step 3) Synthesis of tert-butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclonucleic acid-1-carboxylate

4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), (S)-3-amino-1-tert-butoxycarbo obtained in step 2 above Nilpiperidine (0.13 mL, 0.71 mmol), tris(dibenzylindeneacetone)dipalladium (27 mg, 10 mol%), xantphos (17 mg, 10 mol%), sodium-tert-butoxyte (85 mg, 0.89 mmol) was dissolved in 1.5 ml of anhydrous 1,4-dioxane and stirred at room temperature for 4 hours. When the reaction is completed, it is extracted with ethyl acetate, washed with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (155 mg, 58%).

Step 4) Synthesis of tert-butyl (3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclonucleic acid-1-carboxylate

tert-Butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate obtained in step 3 (380 mg, 0.84 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (551 mg, 1.69 mmol) were placed in a shrink tube, and a nitrogen environment was created. Then, acetylacetone (40 mol%), aqueous ammonia solution (0.65 mL, 16.91 mmol) and anhydrous dimethylformamide (4 mL) were sequentially added, and stirred at 90°C overnight. When the reaction is complete, the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the resulting organic layer is dried over magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (88 mg, 27%).

Step 5) tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyridine- 2-yl)amino)piperidine-1-carboxylate

Example 38 Compound synthesized in step 5 of the synthesis (285 mg, 0.92 mmol) and tert-butyl (3S)-3-((6-amino-4-(morpholinomethyl)pyridine-2 synthesized in step 4 above -yl)amino)cyclonucleic acid-1-carboxylate (300 mg, 0.77 mmol) is dissolved in 2 ml of dioxane. To this solution, tris(dibenzylindenacetone)dipalladium (70 mg, 10 mol%), xantphos (44 mg, 10 mol%), and sodium-tert-butoxyte (111 mg, 0.89 mmol) were added, and then 80 Stir at ℃ for 2 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (360 mg, 76%).

Step 6) (S)-4-(morpholinomethyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6- (piperidin-3-yl)pyridine-2,6-diamine

tert-butyl (S)-3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) synthesized in step 5 above ) Thiazol-2-yl) amino) pyridin- 2-yl) amino) piperidine-1-carboxylate (360 mg, 0.58 mmol) was dissolved in 2.5 ml of dichloromethane and 2.5 ml of methanol. Then, 4.0M hydrochloric acid (1.45 ml, 5.82 mmol) dissolved in dioxane is slowly added. This solution is stirred at room temperature for 12 hours. When the reaction is completed, the extract is extracted using dichloromethane and methanol, washed with water, the resulting organic layer is dried over sodium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (296 mg, 98%).

Step 7) (S)-3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- Synthesis of 1) amino) pyridin-2-yl) amino) piperidine-1-carbonitrile

(30.0 mg, 0.10 mmol) synthesized in step 6 above was dissolved in dichloromethane and methanol, and then sodium bicarbonate (34.0 mg, 0.4 mmol) and cyanogen bromide (34.0 mg, 0.32 mmol) were added. This solution is stirred at room temperature for 2 hours. When the reaction was completed, the extract was extracted using dichloromethane and distilled water, washed with aqueous sodium chloride solution, and the resulting organic layer was dried over sodium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (9.90 mg, 18.2%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.71 (s, 1H), 8.23 (s, 1H), 8.07-8.06 (m, 2H), 7.65-7.64 (m, 4H), 7.05 (d) , 1H, J = 4.0 Hz), 6.30 (s, 1H), 6.21 (s, 1H), 4.50 (s, 2H), 4.27-4.25 (m, 1H), 3.63-3.61 (m, 3H), 3.17- 3.13 (m, 2H), 3.11-3.08 (m, 2H), 2.99-2.95 (m, 2H), 2.36 (s, 2H), 2.13-2.12 (m, 2H), 1.90-1.84 (m, 4H).

Example 45. 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.2]octan-1-ol

Step 1) 4-(2,6-dichloropyrimidin-4-yl)morpholine

2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, and then morpholine (3.49 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) were slowly dissolved at 0°C. Add. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7.14 g, 80%).

Step 2) 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

Dissolve 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in Step 1 in 2 ml of 1-propanol. Then, 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (0.33 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.48 g, 80%).

Step 3) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)bicyclo[2.2.2]octan-1-ol

4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol (0.10 g, 0.25 mmol) synthesized in step 2 was used as an example. By reacting in the same manner as step 4 in 41, the target compound (82 mg, 60%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.45 (s, 1H), 8.22 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.61 (m, 3H), 6.05 (s) , 1H), 5.60 (s, 1H), 4.31 (s, 1H), 3.67-3.66 (m, 4H), 3.43-3.42 (m, 4H), 2.14-2.12 (m, 6H), 1.71-1.69 (m , 6H).

Example 46. 1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2- 1) Pyrrolidin-3-ol

Step 1) (2,6-dibromopyridin-4-yl)(morpholino)methanone

2,6-Dibromonicotinic acid (1 g, 3.55 mmol) and 1,1'-carbonyldiimidazole (0.69 g, 4.27 mmol) were dissolved in N,N'-dimethylformamide (3.5 mL). Then stir at room temperature for 5 minutes. Morpholine (0.36 mL, 4.27 mmol) was added dropwise to this solution and stirred at room temperature for 2 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.12 g, 90%).

Step 2) 4-((2,6-dibromopyridin-4-yl)methyl)morpholine

(2,6-dibromopyridin-4-yl)(morpholino)methanone (1.12 g, 3.22 mmol) was dissolved in 3.2 ml of tetrahydrofuran and cooled to 0°C. 1M borane-tetrahydro solution (3.0 eq) was added dropwise to the cooled reaction solution and stirred at 0°C for 1 hour. Afterwards, borane-tetrahydro solution (3.0 eq) was added dropwise and stirred at 0°C for 3 hours until the starting material disappeared. The reaction solution was adjusted to pH 1 with 1M aqueous hydrochloric acid solution and stirred at 80°C for 1 hour. After cooling the reaction solution to 0°C, adjust the pH to about 8 using saturated aqueous sodium bicarbonate solution, extract using ethyl acetate, and wash with water. The obtained organic layer is dried with magnesium sulfate and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).

Step 3) 1-(6-bromo-4-(morpholinomethyl)pyridin-2-yl)pyrrolidin-3-ol

4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), 3-pyrrolidinol (0.06 mL0.71 mmol), tris(dibenzylideneacetone)di Palladium (27 mg, 10 mol%), Xantphos (17 mg, 10 mol%), and sodium-tert-butoxide (85 mg, 0.89 mmol) were dissolved in 1.5 ml of anhydrous 1,4-dioxane and then dissolved at room temperature. It was stirred for 4 hours. When the reaction was completed, it was extracted with ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (98 mg, 49%).

Step 4) 1-(6-amino-4-(morpholinomethyl)pyridin-2-yl)pyrrolidin-3-ol

1-(6-bromo-4-(morpholinomethyl)pyridin-2-yl)pyrrolidin-3-ol (287 mg, 0.84 mmol), cupric acetylacetone (10) synthesized in step 3 above. mol%), cesium carbonate (551 mg, 1.69 mmol) was placed in a shrink tube, and a nitrogen environment was created. Afterwards, acetylacetone (40 mol%), aqueous ammonia solution (0.65 ml, 16.91 mmol), and anhydrous dimethylformamide (4 ml) were sequentially added, and the mixture was stirred at 90°C overnight. When the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate, washed with water, and the resulting organic layer was dried over magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (93 mg, 40%).

Step 5) 1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine -2-yl)pyrrolidin-3-ol

1-(6-amino-4-(morpholinomethyl)pyridin-2-yl)pyrrolidin-3-ol (0.07 g, 0.25 mmol) obtained in step 4 and 2 obtained in step 5 of Example 38 -(2bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.06 g, 0.20 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.02 mmol), Xantphos (0.01 g, 0.02 mmol) and sodium-tert-butoxide (0.03 g, 0.31 mmol) were dissolved in 1.0 ml 1,4-dioxane and stirred at 10°C for 5 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (101 mg, 80%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.56 (s, 1H), 8.20 (s, 1H), 8.08-8.06 (m, 2H), 7.64-7.62 (m, 3H), 6.30 (s) , 1H), 5.97 (s, 1H), 5.06 (d, 1H, J =2.8 Hz), 4.46 (s, 1H), 3.66-3.50 (m, 8H), 3.36 (s, 2H), 2.38-2.67 ( m, 4H), 2.12-2.06 (m, 1H), 1.98-1.96 (m, 1H).

Example 47. 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Synthesis of amino)phenol

Step 1) Synthesis of 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)phenol

Example 45 Instead of 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.25 g, 1.10 mmol) obtained in step 1 of synthesis and aminobicyclocyclo[2.2.2]octan-1-ol hydrochloride. The target compound (0.12 g, 36.3%) was obtained by reacting in the same manner as step 2 of synthesis in Example 45, except that 4-aminophenol (0.14 g, 1.30 mmol) was used.

Step 2) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- Synthesis of 2-yl)amino)phenol

4-((4-Chloro-6-morpholinopyrimidin-2-yl)amino)phenol (44.0 mg, 0.18 mmol) obtained in step 2 was reacted in the same manner as step 4 of Example 41 to obtain the target compound. (0.50 mg, 3.2%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.62 (s, 1H), 9.23 (s, 1H), 8.99 (s, 1H), 8.23 (s, 1H), 8.10-8.09 (m, 2H) ), 7.66-7.65 (m, 3H), 7.19 (s, 1H), 7.16-7.14 (m, 2H), 7.09-7.06 (m, 2H), 3.70 (s, 4H), 3.47 (s, 4H).

Example 48. (1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2 -yl)piperidine-4 -yl)methanol

Step 1) (1-(6-bromo-4-(morpholinomethyl)pyridin-2-yl)piperidin-4-yl)methanol

Example 46 4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), 4-piperidinemethanol (0.08 mL, 0.71%) synthesized in step 2 of synthesis mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 10 mol%), xantphos (17 mg, 10 mol%), and sodium-tert-butoxide (85 mg, 0.89 mmol) in anhydrous 1,4 -Dissolved in 1.5 ml of dioxane and stirred at room temperature for 4 hours. When the reaction was completed, it was extracted with ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (103 mg, 50%).

Step 2) (1-(6-amino-4-(morpholinomethyl)pyridin-2-yl)piperidin-4-yl)methanol

(1-(6-bromo-4-(morpholinomethyl)pyridin-2-yl)piperidin-4-yl)methanol (0.92 g, 0.25 mmol) synthesized in step 1 was prepared in Example 46. By reacting in the same manner as step 4, the target compound (57 mg, 75%) was obtained.

Step 3) (1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Pyridin-2-yl)piperidin-4-yl)methanol

(1-(6-amino-4-(morpholinomethyl)pyridin-2-yl)piperidin-4-yl)methanol (0.1 g, 0.35 mmol) synthesized in step 2 above was added to the step of Example 38. By reacting in the same manner as in 6, the target compound (136 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.60 (s, 1H), 8.21 (s, 1H), 8.07-8.05 (m, 2H), 7.64-7.62 (m, 3H), 6.39 (s) , 1H), 6.36 (s, 1H), 4.50 (t, 1H, J=4.2Hz), 4.42 (d, 2H, J=10.32 Hz), 3.60-3.58 (m, 4H), 3.37 (s, 2H) , 3.32-3.29 (m, 2H), 2.97 (t, 2H, J=9.4Hz), 2.35-3.37 (m, 4H), 1.78 (d, 2H, J=9.52Hz), 1.73-1.69 (m, 1H) ), 1.26-1.21 (m, 1H).

Example 49. (S)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)propan-1-ol

Step 1) (S)-2-((4-chloro-6-morpholinopyrimidin-2-yl)amino)propan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (S)-(+)-2-amino-1-propanol (0.17 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.37 mg, 77%).

Step 2) (S)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)amino)propan-1-ol

(S)-2-((4-chloro-6-morpholinopyrimidin-2-yl)amino)propan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 above was added to the step of Example 41. By reacting in the same manner as in 4, the target compound (90 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.53 (s, 1H), 8.21 (s, 1H), 8.09-8.07 (m, 2H), 7.66-7.62 (m, 3H), 6.43 (s) , 1H), 5.57 (s, 1H), 4.72-4.72 (s, 1H), 4.21-4.01 (m, 1H), 3.54-3.53 (m, 4H), 3.43-3.33 (m, 6H), 1.19 (s) , 3H).

Example 50. (R)-N-(2-chloro-6-methylphenyl)-2-((2-(3-hydroxypyrrolidin-1-yl)-6-morpholinopyrimidin-4-yl)amino) Thiazole-5-carboxamide

Step 1) (R)-1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (-)-3-pyrrolidinol (0.15 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.39 mg, 77%).

Step 2) (R)-N-(2-chloro-6-methylphenyl)-2-((2-(3-hydroxypyrrolidin-1-yl)-6-morpholinopyrimidin-4-yl )Amino)thiazole-5-carboxamide

(R)-1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-ol (0.7 g, 0.25 mmol) synthesized in step 1 was mixed with 2-(2-amino Example using 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide instead of thiazol-5-yl)-5-phenyl-1,3,4-oxadiazole By reacting in the same manner as step 4 in 41, the target compound (96 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.30 (s, 1H), 9.85 (s, 1H), 8.21 (m, 1H), 7.39-7.37 (m, 1H), 7.29-7.23 (m , 2H), 5.66 (s, 1H), 5.54 (s, 1H), 4.97-4.90 (m, 1H), 4.35-4.34 (m, 1H), 3.67-3.56 (m, 6H), 3.49-3.43 (m , 6H), 2.23 (s, 3H), 1.99-1.98 (m, 1H), 1.85-1.84 (m, 1H).

Example 51. (1R,4R)-4-(methyl(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-)amino) Pyrimidin-2-yl)amino)cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)(methyl)amino)cyclohexan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, trans-4-methylamino-cyclohexanol (0.44 g, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.45 mg, 77%).

Step 2) (1R,4R)-4-(methyl(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- ) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)(methyl)amino)cyclohexan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 above. Reacted in the same manner as step 4 of Example 41 to obtain the target compound (100 mg, 75%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.57 (s, 1H), 8.23 (s, 1H), 8.10-8.09 (m, 2H), 7.63-7.61 (m, 3H), 5.58 (s) , 1H), 4.75 (s, 1H), 4.62 (s, 1H), 3.67-3.66 (m, 4H), 3.44-3.40 (m, 4H), 2.98 (s, 3H), 1.94-1.90 (m, 2H) ), 1.66-1.22 (m, 7H).

Example 52. (R)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)pyrrolidin-3-yl)methanol

Step 1) (R)-(1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-yl)methanol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (3R)-3-pyrrolidinemethanol (0.19 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 80%).

Step 2) (R)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)pyrrolidin-3-yl)methanol

(R)-(1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-yl)methanol (0.07 g, 0.25 mmol) synthesized in step 1 was prepared in Example 41. By reacting in the same manner as step 4, the target compound (94 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.57 (s, 1H), 8.21 (s, 1H), 8.08-8.06 (m, 2H), 7.64-7.62 (m, 4H), 5.56 (s) , 1H), 4.77-4.73 (m, 1H), 3.82-3.81 (m, 1H), 3.67-3.61 (m, 6H), 3.46-3.44 (m, 7H), 1.70-1.64 (m, 1H), 1.44 -1.40 (m, 1H), 1.29-1.20 (m, 1H).

Example 53. (S)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)pyrrolidin-3-yl)methanol

Step 1) (S)-(1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-yl)methanol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (3S)-3-pyrrolidinemethanol (0.19 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 80%).

Step 2) (S)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)pyrrolidin-3-yl)methanol

(S)-(1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-yl)methanol (0.07 g, 0.25 mmol) synthesized in step 1 was prepared in Example 41. By reacting in the same manner as step 4, the target compound (94 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.56 (s, 1H), 8.21 (s, 1H), 8.08-8.06 (m, 2H), 7.66-7.61 (m, 4H), 5.56 (s) , 1H), 4.74-4.72 (m, 1H), 3.81-3.79 (m, 1H), 3.75-3.65 (m, 6H), 3.50-3.45 (m, 7H), 2.40-2.36 (m, 1H), 2.06 -2.00 (m, 1H), 1.86-1.72 (m, 1H).

Example 54. (S)-1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)pyrrolidine- 2-carboxamide

Step 1) (S)-1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidine-2-carboxamide

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (S)-3-pyrrolidine-2-carboxamide hydrochloride (0.28 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.28 mg, 5%).

Step 2) (S)-1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Pyrimidine-2-yl)pyrrolidine-2-carboxamide

(S)-1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidine-2-carboxamide (0.10 g, 0.25 mmol) synthesized in Step 1 was prepared in Example 41. By reacting in the same manner as step 4, the target compound (6.5 mg, 5%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.45 (s, 1H), 8.22 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.61 (m, 3H), 7.38 (s) , 1H), 6.98 (s, 1H), 5.60 (s, 1H), 3.67-3.66 (m, 4H), 3.51-3.45 (m, 1H), 3.43-3.42 (m, 4H), 2.78-2.70 (m) , 2H), 1.98-1.89 (m, 1H), 1.78-1.53 (m, 3H.)

Example 55. (R)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)propan-1-ol

Step 1) (R)-2-((4-chloro-6-morpholinopyrimidin-2-yl)amino)propan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (R)-(+)-2-amino-1-propanol (0.17 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.37 mg, 77%).

Step 2) (R)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)amino)propan-1-ol

(R)-2-((4-chloro-6-morpholinopyrimidin-2-yl)amino)propan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 above was added to the step of Example 41. By reacting in the same manner as in 4, the target compound (90 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.53 (s, 1H), 8.21 (s, 1H), 8.09-8.07 (m, 2H), 7.66-7.62 (m, 3H), 6.43 (s) , 1H), 5.57 (s, 1H), 4.72-4.72 (s, 1H), 4.21-4.01 (m, 1H), 3.54-3.53 (m, 4H), 3.43-3.33 (m, 6H), 1.19 (s) , 3H).

Example 56. 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.1]heptan-1-ol

Step 1) 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride (0.39 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 75%).

Step 2) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)bicyclo[2.2.1]heptan-1-ol

4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 was used as an example. By reacting in the same manner as step 4 in 41, the target compound (93 mg, 70%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.45 (s, 1H), 8.20 (s, 1H), 8.10-8.09 (m, 2H), 7.64-7.63 (m, 3H), 6.80 (s) , 1H), 5.59 (s, 1H), 4.87 (s, 1H), 3.69-3.67 (m, 4H), 3.44-3.43 (m, 4H), 2.08-2.07 (s, 2H), 1.90-1.87 (m , 4H), 1.73-1.72 (m, 2H), 1.58-1.57 (m, 2H).

Example 57. 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)adamantane-1-ol

Step 1) 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)adamantan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Trans-4-amino-1-adamantanol hydrochloride (0.38 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.50 mg, 77%).

Step 2) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)adamantane-1-ol

4-((4-Chloro-6-morpholinopyrimidin-2-yl)amino)adamantan-1-ol (0.09 g, 0.25 mmol) synthesized in step 1 was mixed with step 4 of Example 41. By reacting in the same way, the target compound (102 mg, 72%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.53 (s, 1H), 8.22 (s, 1H), 8.12-8.11 (m, 2H), 7.65-7.61 (m, 3H), 6.35 (d) , 1H, J=5.76 Hz), 5.60 (s, 1H), 4.41 (s, 1H), 3.66-3.64 (m, 4H), 3.45-3.43 (m, 4H), 2.19-2.18 (s, 2H), 2.00-1.98 (m, 5H), 1.71-1.66 (m, 5H), 1.36-1.33 (m, 2H).

Example 58. 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

Step 1) 4-(2,6-dichloropyrimidin-4-yl)-2,6-dimethylmorpholine

2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, then cis-2,6-dimethylmorpholine (4.96 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) is added slowly. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7.14 g, 80%).

Step 2) 4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

4-(2,6-dichloropyrimidin-4-yl)-2,6-dimethylmorpholine (0.42 g, 1.80 mmol) obtained in Step 1 is dissolved in 2 ml of 1-propanol. Then, 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (0.33 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.52 mg, 80%).

Step 3) 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol

4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octane-synthesized in step 2 above 1-ol (0.91 g, 0.25 mmol) was reacted in the same manner as step 4 of Example 41 to obtain the target compound (86 mg, 60%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.39 (s, 1H), 8.21 (s, 1H), 8.11-8.10 (m, 2H), 7.65-7.61 (m, 3H), 6.09 (s) , 1H), 5.60 (s, 1H), 4.32 (s, 1H), 4.01-3.99 (m, 2H), 3.55-3.54 (m, 2H), 2.48-2.47 (m, 2H), 2.15-2.13 (m) , 6H), 1.71-1.69 (m, 6H), 1.13 (d, 6H, J=4.8 Hz).

Example 59. 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)adamantane-1-ol

Step 1) 4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)adamantan-1-ol

Example 58 4-(2,6-dichloropyrimidin-4-yl)-2,6,-dimethylmorpholine (0.42 g, 1.80 mmol) obtained in step 1 of synthesis was dissolved in 2 ml of 1-propanol. do. Then, trans-5-amino-1-adamantanol hydrochloride (0.38 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.56 mg, 80%).

Step 3) 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-2-yl)amino)adamantane-1-ol

4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)adamantan-1-ol (0.97 g, 0.25 mmol) was reacted in the same manner as step 4 of Example 41 to obtain the target compound (89 mg, 60%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.47 (s, 1H), 8.22 (s, 1H), 8.12-8.11 (m, 2H), 7.65-7.61 (m, 3H), 6.39 (d) , 1H, J=5.76 Hz), 5.60 (s, 1H), 4.41 (s, 1H), 4.06-4.00 (m, 2H), 3.57-3.54 (m, 2H), 2.50-2.42 (m, 2H), 2.19 (s, 2H), 2.02-1.99 (m, 5H), 1.72-1.66 (m, 5H), 1.36-1.33 (m, 2H), 1.15 (d, 6H, J=6.24 Hz).

Example 60. (1R,4R)-1-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin -2-yl) amino) cyclohexan-1-ol

Step 1) (1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)-1-methylcyclohexan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, trans-4-amino-1-methylcyclohexanol (0.24 g, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.39 mg, 67%).

Step 2) (1R,4R)-1-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol

(1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)-1-methylcyclohexan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 ) was reacted in the same manner as step 4 of Example 41 to obtain the target compound (93 mg, 70%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.52 (s, 1H), 8.22 (s, 1H), 8.10-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.58 (d) , 1H, J= 6.52 Hz), 5.56 (s, 1H), 4.32 (s, 1H), 4.00 (s, 1H), 3.66-3.65 (m, 4H), 3.44-3.43 (m, 4H), 1.94- 1.93 (m, 2H), 1.62-1.61 (m, 4H), 1.47-1.45 (m, 2H), 1.19 (s, 3H).

Example 61. 3-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl) amino butan-1-ol

Step 1) 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)-3-methylbutan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, 4-amino-3-methyl-1-butanol (0.21 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.37 mg, 70%).

Step 2) 3-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)amino)butan-1-ol

4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)-3-methylbutan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 was added to the step of Example 41. By reacting in the same manner as in 4, the target compound (95 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.53 (s, 1H), 8.21 (s, 1H), 8.07-8.06 (m, 2H), 7.66-7.62 (m, 3H), 6.90 (s) , 1H), 5.56 (s, 1H), 4.32 (s, 1H), 3.65-3.64 (m, 4H), 3.51-3.47 (m, 1H), 3.44-3.43 (m, 6H), 3.25-3.24 (m , 1H), 2.08-2.07 (m, 1H), 1.75-1.74 (m, 1H), 1.25-1.23 (m, 1H), 1.05-0.89 (m, 3H).

Example 62. N-(2-chloro-6-methylphenyl)-2-((2-((5-hydroxyadamantan-2-yl)amino)-6-morpholinopyrimidin-4-yl)amino)thia Sol-5-carboxamide

Step 1) N-(2-chloro-6-methylphenyl)-2-((2-((5-hydroxyadamantan-2-yl)amino)-6-morpholinopyrimidin-4-yl) Amino)thiazole-5-carboxamide

Example 57 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)adamantan-1-ol (0907 g, 0.25 mmol) synthesized in step 1 of synthesis was 2-( Instead of 2-aminothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole, use 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. The reaction was carried out in the same manner as step 4 of Example 41 to obtain the target compound (92 mg, 65%).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.22 (s, 1H), 9.80 (s, 1H), 8.20 (s, 1H), 7.39-7.38 (m, 1H), 7.28-7.23 (m , 2H), 6.18 (s, 1H), 5.56 (s, 1H), 4.25 (s, 1H), 3.64-3.63 (m, 4H), 3.42-3.41 (m, 4H), 2.23 (s, 3H), 2.14 (s, 2H), 1.97-1.85 (m, 5H), 1.58-1.57 (m, 4H), 1.31-1.28 (m, 2H).

Example 63. 3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[1.1.1]pentan-1-ol

Only 1) 3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-ol

Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (0.25 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.46 mg, 88%).

Step 2) 3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)bicyclo[1.1.1]pentan-1-ol

3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 was used as an example. By reacting in the same manner as step 4 in 41, the target compound (94 mg, 75%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.45 (s, 1H), 8.22 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.61 (m, 3H), 6.05 (s) , 1H), 5.60 (s, 1H), 4.31 (s, 1H), 3.67-3.66 (m, 4H), 3.43-3.42 (m, 4H), 2.38-2.36 (m, 6H).

Example 64. 3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Synthesis of amino)phenol

Step 1) Synthesis of 3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)phenol

The target compound (0.41 g, 63.9%) was obtained in the same manner as step 2 of synthesis in Example 14, except that 3-aminophenol (0.30 g, 2.50 mmol) was used instead of trans-4-aminocyclohexanol.

Step 2) 3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- Synthesis of 2-yl)amino)phenol

3-((4-Chloro-6-morpholinopyrimidin-2-yl)amino)phenol (0.37 g, 0.90 mmol) obtained in step 2 was reacted in the same manner as step 4 of Example 12 to obtain the target compound. (48.8 mg, 10.5%) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ11.62 (s, 1H), 9.23 (s, 1H), 8.99 (s, 1H), 8.23 (s, 1H), 8.10-8.09 (m, 2H) ), 7.66-7.65 (m, 3H), 7.19 (s, 1H), 7.16-7.14 (d, 1H, J = 2.0 Hz), 7.09-7.06 (t, 1H, J = 2.0 Hz), 6.40-6.38 ( d, 1H, J = 2.0 Hz), 5.77 (s, 1H), 3.70 (s, 4H), 3.47 (s, 4H).

Experimental Example 1: Intracellular Compounds p -BTK IC ₅₀ and p-PLCr2 IC ₅₀ evaluation

Western blot analysis was performed to measure the IC ₅₀ of the BTK inhibitor against intracellular BTK. Ramos cells were added to culture medium without the addition of fetal bovine serum, BTK inhibitors were serially diluted, and reacted in an incubator at 37°C for 4 hours. The Ramos cells are a B lymphocyte cell line derived from a 3-year-old, white male patient with Burkitt's Lymphoma. Afterwards, cells were treated with 15 μg/ml of anti-human IgM (SouthernBiotech 2020-01) and stimulated for 10 minutes at a low temperature of 2-8°C. The culture medium remaining in the cells was removed with low-temperature DPBS (Dulbecco's Phosphate-Buffered Saline), and the cell membrane was incubated at low temperature for 30 minutes with RIPA buffer (Radioimmunoprecipitation assay buffer, Thermo 89901) containing protease and phosphatase inhibitors (Thermo 78442). dissolved.

Proteins were extracted using a high-speed centrifuge, quantified using bicinchoninic acid (BCA) solution (Thermo 23225), and samples were prepared by adding 4x sample buffer solution (Invitrogen NP0007). Proteins from each sample were electrophoresed and then transferred to a membrane composed of nitrocellulose (Invitrogen IB23001). To block protein-free areas, a solution containing 5% bovine serum albumin (BSA) (GenDEPOT A0100-010) was prepared in TBS-T (TBS-Tween, Thermo 28360) and treated at room temperature for 30 minutes. The primary antibody was diluted and added to the protein-attached membrane and reacted on a shaker at a low temperature for 16 to 20 hours (or 1 hour at room temperature). TBS-T was added and the primary antibody not attached to the membrane was removed on a shaker at room temperature for 10 minutes, and this process was repeated three times. A secondary antibody tagged with horseradish peroxidase (HRP) was diluted and added to the membrane and reacted for 45 minutes. TBS-T was added and left on a shaker at room temperature for 10 minutes to remove primary antibodies and unattached secondary antibodies. The process was repeated three times. The HRP enzyme was reacted using an enhanced chemiluminescent (ECL) solution (Thermo 34095), and the protein level of the membrane was confirmed. IC ₅₀ was calculated based on the proteins of the negative and positive controls and using the calculated values. The results are shown in Table 1 below.

Experimental Example 2: IC of BTK wild-type (WT) and mutant C481S compounds ₅₀ analyze

To measure the IC ₅₀ of the BTK inhibitor against the BTK enzyme, the BTK WT/C481S kinase enzyme system (Promega V9071, VA7033) was used. BTK inhibitor was serially diluted to prepare 1 μl each and reacted with 2 μl of BTK kinase for 10 minutes at room temperature. Substrate using BTK kinase buffer consisting of 40mM Tris (pH 7.5), 20mM MgCl ₂ , 0.1mg/ml bovine serum albumin (BSA), 2mM MnCl ₂ , and 50 μM dithiothreitol (DTT). /ATP mix (ATP final concentration: 50 μM) was prepared, 2 μl each was added, and incubated at room temperature for 60 minutes. 5 μl of ADP Glo™ reagent was added and reacted at room temperature for 40 minutes, and luminescence (integration time 0.5 second) was measured 30 minutes after addition of the kinase detection reagent. The evaluation was performed on duplicate experiments, negative and positive controls were calculated, and IC ₅₀ was calculated based on those values. The results are shown in Table 1 below.

Example enzyme
BTK IC50, nM enzyme
BTK C481S IC50, nM Ramos Cell,
p-BTK IC50, nM Ramos Cell,
p-PLCr2 IC50, nM One 1.7 0.7 7.6 9.4 2 >100 >100 3 5.9 2.9 28.6 >100 4 12.1 50.3 5 1.1 2.3 6 2 1.4 7 2.6 2.5 8 2 3.7 9 1.3 0.5 0.9 1.1 10 > 100 > 100 11 1.5 3.2 12 3.5 1.1 1.2 2 13 0.2 0.1 One 1.2 14 1.1 0.8 15 2.5 0.9 16 1.1 1.3 17 1.1 1.5 18 1.2 2.8 19 4.5 1.7 20 One 1.6 21 2.6 2.9 22 2.2 1.9 23 6.9 7.9 24 1.1 9.4 25 1.3 1.3 26 1.1 1.7 27 2.8 1.5 28 0.9 1.7 29 0.3 0.3 30 0.9 0.3 31 >100 >100 32 One 1.4 33 3.4 6.4 34 1.1 6.7 35 One One 36 2.4 2.9 37 38 11.7 8.9 >100 >100 39 >100 >100 40 >100 >100 41 3.1 4 42 10.2 5 43 86.3 46.7 44 51.6 93.3 45 1.5 0.7 One 1.2 46 11.4 > 100 47 22.4 19.5 48 >100 96.6 49 One 1.8 50 1.2 1.2 51 4.5 1.8 52 2.5 0.2 53 One 0.003 54 One 1.2 55 One 5.6 56 1.5 2.2 57 0.9 1.7 58 <1.0 48.8 59 0.5 1.5 60 0.4 0.9 61 2.7 2 62 1.1 1.1 63 >100 >100 64 43.6 22.5

As shown in Table 1, the compounds of Examples 1 to 64 had excellent activity in inhibiting BTK activity in in vitro enzyme or cell experiments. Additionally, the example compounds were confirmed to exhibit excellent pharmacodynamic (PK) efficacy. Specifically, the example compounds showed C _max values and AUC _last sufficient to demonstrate efficacy when orally administered to mice at a dose of 25 mg/kg.

Claims (14)

Compounds of Formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof:
[Formula 1]

In Formula 1,
Cy is C _3-12 aryl, C _3-12 cycloalkyl or C _3-10 heteroaryl, and the C _3-12 aryl, C _3-12 cycloalkyl or C _3-10 heteroaryl is C _1-6 alkyl, C _1-6 alkoxy, halo, cyano, -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), C _{1- 6} alkylNR ₃ - (wherein R ₃ is hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), and hydroxy;
A is a 5-membered ring having 2 or more N atoms or -CONH-;
X is CH or S;
Y is NH or O when X is CH, or CH when X is S;
Z ₁ is C;
R ₁ is C _1-6 alkyl (where C _1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC _1-6 alkyl (where C _1-6 alkyl may be substituted with one or more halo or hydroxy), may be substituted with halo or hydroxy), NR ₃ R ₄ C _1-6 alkyl (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl) , -NR ₃ R ₄ (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), NR ₃ R ₄ C _1-6 alkylcarbonyl (here R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, hydroxy, C 1-6 alkoxy, halo, C _3-6 cycloether, and C _3-10 heterocycloalkyl-(CH2)n1 (n1 is an integer of 0 to 6), which may be substituted with one or more substituents selected from the group consisting _of C 1-6 alkylcarbonyl, C _3-10 oxohetero Cycloalkyl, -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl), -OR ₃ (wherein R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl), or -SR ₃ ( where R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl);
Z ₂ is CH or N;
R ₂ is C _3-12 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 heterocycloalkyl, C 3-10 formed by combining N and carbon of L 2 Heterocycloalkyl, C _3-10 heteroaryl, or C _3-12 aryl, and the C _3-12 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 10} heterocycloalkyl, C3-10 heterocycloalkyl formed by bonding N and carbon of L2, C _3-10 heteroaryl, or C _3-12 aryl is hydroxy, C _1-6 alkoxy, -NR ₃ R ₄ ( where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, halo, C _1-6 alkyl (where C _1-6 alkyl is 1 may be substituted with one or more halo or hydroxy), C _1-6 alkylsulfonyl, C _1-6 alkylphosphonyl, aminosulfonyl, -CONH ₂ , or C _3-12 cycloalkyl (where C _{3- 12} Cycloalkyl may be substituted with hydroxy or hydroxyC _1-6 alkyl) and may be substituted with one or more substituents selected from the group consisting of;
L ₁ and L ₂ are independently NH, N, O, or S, or -N together with carbon to form C3-10 heterocycloalkyl -NR ₃ R ₄ (where R ₃ and R ₄ are combined N together with to form C3-10 heterocycloalkyl);
n is an integer of 0 or 1. The compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy is C _5-12 aryl, C _5-12 cycloalkyl, or C _3-6 heteroaryl. The compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 2, wherein Cy is phenyl, cyclohexyl, pyrazolyl, or pyridyl. The compound of formula 1 according to claim 1, wherein A is a 5-membered ring having 2 to 4 N atoms, or 2 or 3 N atoms and 1 O atom, or -CONH-, its Stereoisomer or pharmaceutically acceptable salt thereof. The compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 4, wherein A is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-. The method of claim 1, wherein R ₁ is C _1-6 alkyl (where C _1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC _1-6 alkyl (where C _1-6 Alkyl may be substituted with one or more halo or hydroxy), NR ₃ R ₄ C _1-6 alkyl (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), -NR ₃ R ₄ (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), NR ₃ R ₄ C _1-6 alkylcarbonyl (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, hydroxy, halo, C _3-6 cycloether, and C _3-10 heterocycloalkyl which may be substituted with one or more substituents selected from the group consisting of C _1-6 alkylcarbonyl, -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl), -OR ₃ (where R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl), or -SR ₃ (wherein R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 7, wherein R ₁ is C _1-6 alkyl (where C _1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC _1-6 alkyl (where C _1-6 Alkyl may be substituted with one or more halo or hydroxy), NR ₃ R ₄ C _1-6 alkyl (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), -NR ₃ R ₄ (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), NR ₃ R ₄ C _1-6 alkylcarbonyl (wherein R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, or C _1-6 alkylcarbonyl), cyano, hydroxy, halo, C _3-6 cycloether, and morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl which may be substituted with one or more substituents selected from the group consisting of C _1-6 alkylcarbonyl; -NR ₃ R ₄ (where R ₃ and R ₄ are each independently hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl) ; -OR ₃ where R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl); or -SR ₃ wherein R ₃ is C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-10 heterocycloalkyl or hydroxyC _1-6 alkyl, stereoisomers thereof. or a pharmaceutically acceptable salt thereof. The compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ is C _3-12 cycloalkyl, C _1-6 alkyl, or C _3-12 aryl. The compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 8, wherein R ₂ is C _4-7 cycloalkyl, C _1-6 alkyl, or C _5-12 aryl. The method of claim 9, wherein R ₂ is C _4-7 cycloalkyl, C _1-6 alkyl, or C _5-12 aryl, and the C _4-7 cycloalkyl, C _1-6 alkyl, or C _5-12 aryl is A compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which may be substituted with hydroxy or aminosulfonyl. The compound of formula 1 according to claim 1, wherein L ₁ and L ₂ are independently NH or O, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein the following compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof:
(1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia zol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(piperazine -1-yl)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-(4-isopropylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-(4-ethylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia zol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol;
N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-(4-(2-hydroxyethyl)piperazine -1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide;
(1R,4R)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole -2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia zol-2-yl))amino)pyrimidin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl ) amino) pyridin-2-yl) amino) cyclohexan-1-ol; and
(1R,4R)-4-((4-((4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia sol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol.
(1R,4R)-4-((4-(4-fluoropiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl ) thiazol-2-yl ) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
N-(2-chloro-6-methylphenyl)-2-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-morpholinopyrimidin-4-yl)amino) Thiazole-5-carboxamide
(1R,4R)-4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl) thiazol -2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
(1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-(piperic din-1-yl) pyrimidin-2-yl) amino) cyclohexan-1-ol
(1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyridin-2-yl)amino)cyclohexan-1-ol
N-(2-chloro-6-methylphenyl)-2-((6-(4-fluoropiperidin-1-yl)-2-(((1R,4R)-4-hydroxycyclohexyl)amino ) pyrimidin-4-yl) amino) thiazole-5-carboxamide
(1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -6-morpholinopyrimidin- 2-yl) amino) cyclohexan-1-ol
(1R,4R)-4-((4-(methylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino ) pyrimidin-2 -yl) amino) cyclohexan-1-ol
(1R,4R)-4-((4-(dimethylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino ) pyrimidin-2 -yl) amino) cyclohexan-1-ol
(1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-thiomopoly Nopyrimidin-2-yl) amino) cyclohexan-1-ol
(1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclopentan-1-ol
(1R,3R)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclobutan-1-ol
6-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)spiro[3.3]heptan-2-ol
(1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) pyrimidin-2-yl)amino)cyclopentan-1-ol
(1S,4R)-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((5-(5-phenyl- 1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
(1R,4R)-4-((4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole -2-yl) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
1-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-4-yl)piperidin-4-ol
(1R,4R)-4-((4-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-6-(2, 2,6,6-tetrafluoromorpholino) pyrimidin-2-yl) amino) cyclohexan-1-ol
(1R,4R)-4-((4-((2-methoxyethyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
1-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one
1-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile
(1R,4R)-4-((4-methoxy-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyri midin-2-yl)amino)cyclohexan-1-ol
1-(4-(2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one
(1R,4R)-4-((4-(4-methoxypiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) Thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
(1R,4R)-4-((4-(4-(dimethylamino)piperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol- 2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
(1R,4R)-4-((4-(1H-imidazol-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)methyl)-3,4-dihydropyridin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)adamantane-1-ol
4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol
(S)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)propan-1-ol
4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia sol-2-yl) amino) pyrimidin-2-yl) amino) bicyclo [2.2.2] octan-1-ol
(S)-3-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)piperidine-1-carbonitrile
3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2 -yl)amino)piperidine -1-carbonitrile
4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.2]octan-1-ol
1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2- 1) Pyrrolidin-3-ol
4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Synthesis of amino)phenol
(1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine-2 -yl)piperidin-4-yl)methanol
(S)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)propan-1-ol
(R)-N-(2-chloro-6-methylphenyl)-2-((2-(3-hydroxypyrrolidin-1-yl)-6-morpholinopyrimidin-4-yl)amino) Thiazole-5-carboxamide
(1R,4R)-4-(methyl(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-)amino) Pyrimidin-2-yl)amino)cyclohexan-1-ol
(R)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)pyrrolidin-3-yl)methanol
(S)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)pyrrolidin-3-yl)methanol
(S)-1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)pyrrolidine-2-carboxamide
(R)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)propan-1-ol
4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.1]heptan-1-ol
4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)adamantan-1-ol
4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)adamantane-1-ol
(1R,4R)-1-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin -2-yl) amino) cyclohexan-1-ol
3-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)butan-1-ol
N-(2-chloro-6-methylphenyl)-2-((2-((5-hydroxyadamantan-2-yl)amino)-6-morpholinopyrimidin-4-yl)amino)thia Sol-5-carboxamide
3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[1.1.1]pentan-1-ol
3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)phenol. A pharmaceutical for use in treating diseases mediated by protein kinases, comprising the compound of formula 1 according to any one of claims 1 to 12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Composition. The composition of claim 13, wherein the disease is cancer, inflammatory disease, or autoimmune disease.