KR20240026309A - Pyrimidine and triazine derivatives, the preparation method thereof, and the pharmaceutical compositions for the prevention or treatment of cancer containing the same - Google Patents

Abstract

The present invention relates to pyrimidine and triazine derivatives, methods for producing the same, and pharmaceutical compositions containing the same for preventing or treating cancer. The derivatives are capable of inhibiting Fer kinase activity, thereby preventing various cancers in which Fer kinase is involved. Alternatively, it can be effective in treatment, and in particular, it can be usefully used as an anticancer agent because it has an excellent effect in terms of anticancer activity by overcoming resistance.

Description

Pyrimidine and triazine derivatives, methods for producing the same, and pharmaceutical compositions containing the same for preventing or treating cancer

The present invention relates to pyrimidine and triazine derivatives, and more specifically, to pyrimidine and triazine derivatives that inhibit Fer kinase activity, a method for producing the same, and a pharmaceutical composition containing the same for preventing or treating cancer.

The occurrence of cancer is related to various environmental factors, including chemicals, radiation, and viruses, as well as changes in oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair. Recently, molecular studies of these cancers have been reported. As the mechanism is understood, a new treatment method, targeted anti-cancer treatment, becomes possible.

In general, targeted treatments are made to exert their effects by targeting molecules that cancer cells have characteristically, and the molecular targets include the signal transduction pathway, angiogenesis, and interstitial function of cancer cells. These are genes related to matrix, cell cycle regulator, and apoptosis. Currently, important target treatments used in treatment include signal transduction pathway inhibitors, including tyrosine kinase inhibitors, and angiogenesis inhibitors.

Protein tyrosine kinase has been found to play an important role in many malignant tumors, and the new target Fer (Feline Sarcoma-related Protein) kinase is a non-receptor tyrosine kinase (RTK) that plays a role in resistance to chemotherapy and other cancer treatments. known to be involved. It is known that activation of the Fer-kinase causes continuous cell proliferation, invasion into surrounding tissues, distant metastasis, blood vessel formation, and increases cell survival.

Meanwhile, new drugs to treat non-small cell lung cancer continue to be developed, and their treatment drugs, such as Iressa, have been developed and are currently being used clinically. However, acquired resistance that occurs when these drugs are used in patients has been observed, and the cure rate is low, so there is a high need for the development of new inhibitors. In particular, non-small cell lung cancer has the highest mortality rate and most cases are treated with chemotherapy and targeted therapy simultaneously, but the treatment efficiency is only about 20-30%. Accordingly, the need to develop new structural drugs with new targets that overcome drug resistance and have excellent drug efficacy has emerged.

EGFR mutations were found in approximately 30% of advanced/metastatic patients, and MET amplification was reported to occur in 4% of resistant patients and 7-15% of patients resistant to third-generation EGFR-inhibitors. Therefore, there is a need to develop a treatment that shows high inhibition in patients with drug resistance to EGFR inhibitors (1st, 2nd, and 3rd generation) in which EGFR mutation and MET amplification are simultaneously expressed. There are reports that MET expression and Fer are highly correlated. , Fer-kinase-related substances are expected to be effective in EGFR-TKI drug-resistant patients who simultaneously express EGFR mutation and MET amplification.

Accordingly, the problem to be solved by the present invention is to provide pyrimidine and triazine derivatives that inhibit Fer kinase (kinase) activity.

Another problem to be solved by the present invention is to provide a method for producing or synthesizing the pyrimidine and triazine derivatives.

Another problem to be solved by the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the pyrimidine and triazine derivatives.

Another problem to be solved by the present invention is to provide a health functional food composition for preventing or improving cancer containing the pyrimidine and triazine derivatives.

The problems of the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the description below.

Pyrimidine and triazine derivatives according to an embodiment of the present invention for solving the above problems are compounds represented by the following formula I-1 or I-2, isomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable compounds thereof. Contains possible salts.

[Formula I-1]

[Formula I-2]

In the above formulas I-1 and I-2,

X is C or N,

Y and Z are each independently C, S or O,

Ra and Rb are each independently hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _1-6 alkoxy, hydroxy, carbonyl, carboxyl or amide, or Ra and Rb are directly or indirectly connected to each other to form C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _{2- 8} Form a heteroaryl ring compound,

(The Ra and Rb or the ring compound may each independently be unsubstituted or substituted, and when substituted, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _{6- 10} It may be substituted with one or more selected from the group consisting of aryl, C _2-8 heteroaryl, amino, nitro, cyano, C _1-6 alkoxy, hydroxy, carbonyl, carboxyl and amide, but is limited thereto. No. At this time, the above substituents may also be substituted with one or more selected from the above group.)

A is C _6-10 aryl or C _2-8 heteroaryl,

R ₁ and R ₂ are each independently hydrogen, halogen, amide, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl, R ₁ and R ₂ are directly or indirectly connected to each other to form a ring compound of C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl,

(The R ₁ and R ₂ or the ring compound may each independently be unsubstituted or substituted, and when substituted, halogen, amide, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl , C _6-10 aryl and C _2-8 heteroaryl, but is not limited thereto. In this case, the substituents may also be substituted with one or more selected from the group. there is.)

L ₁ is S or S(O) ₂ ,

R ₈ is C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _2-8 heteroaryl,

(The R ₈ may be unsubstituted or substituted, and when substituted, halogen, amino, amide, alkoxy, hydroxy, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C ₆ It may be substituted with one or more selected from the group consisting of _-10 aryl and C _2-8 heteroaryl, but is not limited thereto. In this case, the substituents may also be substituted with one or more selected from the group.)

L ₂ is N or C,

L ₂ , R ₉ and R ₁₀ together form a C _4-8 ring compound containing one or more heteroatoms among N and O.

(The ring compound may be unsubstituted or substituted, and when substituted, C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 It may be substituted with one or more selected from the group consisting of heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl and carbonyl, but is not limited thereto. In this case, the substituents are also one selected from the group. It can be replaced with the above.)

In a specific embodiment,

When X is C, Y is S or O, and when X is N, Y is C,

Z is C,

Ra and Rb are each independently hydrogen, bromo, methyl, ethyl, propyl, piperidinyl, piperidinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, pyrazolyl, tetrahydropyridinyl, phenyl, C _1-3 alkylene oxide, amide, nitro, hydroxy or carbonyl, or Ra and Rb are linked together to form hexane,

(The Ra and Rb or the hexane are each independently unsubstituted or methyl, hydroxy, methoxy, ethoxy, fluoro, chloro, cyano, amino, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, p It may be substituted with one or more selected from the group consisting of perazinyl, cyclopropyl, and phenyl.)

A is azolyl, phenyl, or pyridinyl,

R ₁ and R ₂ are each independently cyclopropyl, methyl, ethyl, cyclopentyl, butyl, phenyl, furanyl, or amide, or R ₁ and R ₂ are directly or indirectly linked to each other to form tetrahydrothiophene, pyridine, or cyclohexane. or forms benzene,

(The R ₁ and R ₂ or the ring compound may each independently be unsubstituted or substituted with one or more selected from the group consisting of methyl, cyclopropyl, and fluoro.)

R ₈ is C _3-8 cycloalkyl or C _6-10 aryl,

(The R ₈ is unsubstituted or selected from the group consisting of halogen, amino, amide, hydroxy, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, and C _2-8 heterocycloalkyl. It can be replaced with the above.)

L ₂ , R ₉ and R ₁₀ are one of the following formulas,

B is C, N or O,

D and D' are each independently absent or C _1-3 alkylene,

n is an integer from 0 to 4,

R ₁₁ is hydrogen, C _1-6 alkyl, hydroxy, C _3-8 cycloalkyl or C _2-8 heterocycloalkyl,

R ₁₂ is hydrogen, C _1-6 alkyl, hydroxy, cyano, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 heteroaryl, C _1-6 Can be alkoxy, sulfonyl, amide, carboxyl or carbonyl.

R ₁₃ may be hydrogen, halogen, C _1-6 alkyl, amino, nitro, cyano, C _1-6 alkoxy, hydroxy, carboxyl or amide.

Wherein R ₁₁ to R ₁₃ are each independently unsubstituted or C _1-6 alkyl, hydroxy, cyano, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, nitro, It may be substituted with one or more selected from the group consisting of halogen, C _2-8 heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl, and carbonyl.

In addition, B and R ₁₂ may be directly or indirectly connected to each other to form C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl.

In a more specific embodiment, Ra and Rb are expressed as in one of the following formulas, (expressed together with the parent to which Ra and Rb are linked):

A is pyrazolyl, thiazolyl, phenyl, or pyridinyl,

A, R ₁ and R ₂ are one of the following formulas,

R ₈ is cyclopentyl, cyclohexyl, cycloheptyl or benzyl,

(The R ₈ may be unsubstituted or substituted with one or more selected from the group consisting of chloro, fluoro, methyl, cyclohexyl, phenyl, amino, pyrrolidinyl, amide, and hydroxy.)

B is C or N,

n is an integer from 0 to 3,

R ₁₁ is hydrogen, methyl, hydroxy or pyrrolidinyl,

R ₁₂ is hydrogen, methyl, butyl, hydroxy, cyano, morpholinyl, pyrrolidinyl, phenyl, amino, fluoro, Boc (t-butyloxycarbonyl, tert-Butyloxycarbonyl), diazaspirodecane ), triazolyl, thiophenyl, thiazolyl, tetrahydrothiopyranyl, methoxy, sulfonyl, amide, carboxyl or carbonyl.

R ₁₁ and R ₁₂ are each independently unsubstituted or methyl, butyl, hydroxy, cyano, morpholinyl, pyrrolidinyl, phenyl, amino, fluoro, Boc, triazolyl, thiophenyl, thiazolyl, tetra. It may be substituted with one or more selected from the group consisting of hydrothiopyranyl, methoxy, sulfonyl, amide, carboxyl, and carbonyl.

In another embodiment, Ra and Rb are each independently hydrogen, halogen, C _1-5 arylalkyl, aryl, substituted aryl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, substituted heteroaryl, C _{4- 8} heterocyclyl, nitro, -C(OH)R ₆ R ₇ , -COR ₆ , -CONHR ₆ or CONHR ₆ R ₇ ,

R ₆ and R ₇ are each independently hydrogen, hydroxy, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-5 arylalkyl, aryl, substituted aryl, heteroaryl alkyl, substituted heteroarylalkyl, heteroaryl, substituted heteroaryl or C _4-8 heterocyclyl,

R ₁ and R ₂ are each independently hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-5 arylalkyl, aryl, substituted aryl, heteroarylalkyl , substituted heteroarylalkyl, heteroaryl, substituted heteroaryl, C _4-8 heterocyclyl or -CH ₂ -cycloalkyl,

R ₈ is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-5 arylalkyl, aryl, substituted aryl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, substituted heteroaryl, C _4-8 heterocyclyl or -CH ₂ -cycloalkyl,

R ₁₁ is hydrogen, hydroxy, amino, halogen, nitrile, morpholinyl, -CONH-alkyl, -CONH ₂ , -COOH, C _1-6 alkyl, substituted alkyl, alkoxy or sulfonyl,

R ₁₂ is -C(OH)-alkyl, -C(OH)-aryl, -C(OH)-heteroaryl, -C(CN)-alkyl, -C(CN)-aryl, -C(CN)- It may be heteroaryl or -(C _3-8 heterocycloalkyl).

In another specific example, the pyrimidine and triazine derivatives of the present invention may be one of the following formulas II-1 to II-4.

[Formula II-1]

[Formula II-2]

[Formula II-3]

[Formula II-4]

In Formulas II-1 to II-4, A, Ra, Rb, R ₁ , R ₂ , R ₈ , R ₉ , R ₁₀ and L ₁ are as described above.

More specifically, the pyrimidine and triazine derivatives according to an embodiment of the present invention may be one of the following compounds 1 to 212.

(One) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(2) (1-(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(3) (1-(4-((5-ethyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(4) 1-(4-((4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl) Piperidine-4-yl)methanol

(5) (1-(4-((1H-pyrazolo[3,4-b]pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol

(6) (1-(4-((4,5,6,7-tetrahydro-1H-indazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol

(7) (1-(4-((5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)p Peridin-4-yl)methanol

(8) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

(9) 1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

(10) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Acetonitrile

(11) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl)methanol

(12) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl) Ethan-1-ol

(13) (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3- 1) Methanol

(14) (R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3- 1) Methanol

(15) (S)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-yl) ethane-1-ol

(16) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propan-1-ol

(17) (R)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-yl) ethane-1-ol

(18) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propanenitrile

(19) 1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Propane-2-ol

(20) 1-(1-(4-((5-cyclopropylthiazol-2-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propane-2 -all

(21) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) -2-methylpropan-1-ol

(22) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3-yl) Ethan-1-ol

(23) (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3- 1) Methanol

(24) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Propane-1-ol

(25) 3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propane -1-all

(26) 4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Butanenitrile

(27) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) butan-1-ol

(28) (R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3- 1) Methanol

(29) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,8-diazaspiro[4.5]decan-8-yl)thieno[3,2-d]pyrimidine-4 -Amine

(30) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-morpholinopiperidin-1-yl)thieno [3,2-d]pyrimidin-4-amine

(31) 1-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propane -2-all

(32) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)-3-methylpiperidine- 4-yl) ethane-1-ol

(33) 4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Butan-2-ol

(34) 2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl) thieno[3,2-d]pyrimidin-4-amine

(35) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) -2-methylpropan-1-ol

(36) 2-(4-(2-aminoethyl)piperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidine-4 -Amine

(37) 3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propane nitrile

(38) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3,2-d]pyrimidine-4 -Amine

(39) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl) thieno [3,2-d]pyrimidine-4 -Amine

(40) 2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(41) 2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl) thieno[3,2-d]pyrimidin-4-amine

(42) 2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine

(43) 2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(44) 2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(45) 2-(cyclohexylthio)-N-(5-cyclopentyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(46) 2-(cyclohexylthio)-N-(1,5-dimethyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(47) N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine

(48) 2-(cyclohexylthio)-N-(4-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

(49) 2-(cyclohexylthio)-N-(5-(cyclopropylmethyl)-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine

(50) N-(5-cyclohexyl-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine

(51) 2-(cyclohexylthio)-N-(5-isopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(52) 2-(cyclohexylthio)-N-(5-phenyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(53) 2-(cyclohexylthio)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(54) 2-(cyclohexylthio)-N-(5-(1-methylcyclopropyl)-1H-pyrazol-3-yl) thieno[3,2-d]pyrimidin-4-amine

(55) 2-(Cyclohexylsulfonyl)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

(56) 2-(cyclohexylthio)-N-(1H-indazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

(57) 2-((cyclohexylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno [3,2-d] pyrimidin-4-amine

(58) 2-(cycloheptylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(59) 2-(benzylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

(60) 2-((1-cyclohexylethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine

(61) 2-((cyclopentylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine

(62) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d ]pyrimidin-2-yl)piperidin-4-yl)methanol

(63) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4,4-difluoropiperidin-1-yl)methyl)thieno[3 ,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(64) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidine-2 -1)piperidine-4-1)methanol

(65) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((3,3-difluoropyrrolidin-1-yl)methyl)thieno[3 ,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(66) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)piperidine-4- 1) Methanol

(67) (1-(6-bromo-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Methanol

(68) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno [3,2-d] pyrimidin-2-yl)piperidine- 4-yl) ethane-1-ol

(69) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Pyrimidin-2-yl)piperidin-4-yl)methanol

(70) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-phenylthieno[3,2-d]pyrimidin-2-yl)piperidine-4- 1) Methanol

(71) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(4-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidine- 2-yl) piperidin-4-yl) methanol

(72) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)thieno[3 ,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(73) (1-(6-(4-aminophenyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)p Peridin-4-yl) methanol

(74) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)thi no[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

(75) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thi no[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

(76) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thi no[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(77) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thieno[ 3,2-d] pyrimidin-2-yl) piperidin-4-yl) methanol

(78) 2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl)-1H-pyrazole -1-yl)acetonitrile

(79) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2 -d]pyrimidin-2-yl)piperidin-4-yl)methanol

(80) 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) benzonitrile

(81) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)propan-2-ol

(82) tert-Butyl 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyri midin-2-yl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

(83) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d] Pyrimidin-2-yl)pyrrolidin-3-ol

(84) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidine -6-day) Propane-2-ol

(85) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3,2- d]pyrimidin-6-yl)propan-2-ol

(86) 2-(2-(4-((1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazole- 3-yl) amino) thieno [3,2-d] pyrimidin-6-yl) propan-2-ol

(87) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiophen-2-ylmethyl)piperidin-1-yl)thieno[3 ,2-d]pyrimidin-6-yl)propan-2-ol

(88) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiazol-2-ylmethyl)piperidin-1-yl)thieno[3 ,2-d]pyrimidin-6-yl)propan-2-ol

(89) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyri midin-6-yl)methanol

(90) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) ethane-1-ol

(91) 3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) oxetan-3-ol

(92) Cyclopropyl(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)methanol

(93) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) propan-1-ol

(94) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)-2-phenylethan-1-ol

(95) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-methoxypropan-2-yl)thieno[3,2-d]pyrimidine- 2-day)piperidine- 4-day)methanol

(96) 2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyri midin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

(97) 4-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyri midin-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide

(98) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N-methylthieno[3,2- d]pyrimidine-6-carboxamide

(99) Methyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyri Mydine-6-carboxylate

(100) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)ethane-1-one

(101) (S)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2 -d]pyrimidin-6-yl)(3-fluoropyrrolidin-1-yl)methanone

(102) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyri midin-6-yl)(pyrrolidin-1-yl)methanone

(103) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N,N-dimethylthieno[3, 2-d]pyrimidine-6-carboxamide

(104) 2-((2-chloro-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-N-methylbenzamide

(105) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol

(106) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)piperi din-4-yl) propan-1-ol

(107) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)piperi din-4-yl)acetonitrile

(108) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)piperi din-4-yl)ethan-1-ol

(109) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)piperi din-4-yl) -2-methylpropan-1-ol

(110) 2-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno [3,2 -d]pyrimidin-4-amine

(111) 2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5] thieno[3,2-d]pyrimidin-4-amine

(112) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

(113) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(114) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Acetonitrile

(115) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propan-1-ol

(116) 2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl) benzofuro[3,2-d]pyrimidin-4-amine

(117) 3-Cyclopentyl-3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl) amino)benzo[4,5]thieno[3,2-d]pyrimidine-2 -yl)-1H-pyrazole-1-yl)propanenitrile

(118) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl)benzo [4,5]thieno[3,2- d]pyrimidin-4-amine

(119) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)p Rolidin-3-ol

(120) (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl) Pyrrolidin-3-yl)methanol

(121) (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)p Rolidin-3-ol

(122) (R)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d ]Pyrimidin-4-amine

(123) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d ]Pyrimidin-4-amine

(124) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thieno[3 ,2-d]pyrimidin-4-amine

(125) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)p Rolidine-3-carbonitrile

(126) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)benzo[4,5]thieno [3,2-d]pyrimidin-4-amine

(127) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)p Rollidine-3-carboxamide

(128) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)- N,N-methylpyrrolidine-3-carboxamide

(129) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)benzo[4,5] thieno[3,2-d]pyrimidin-4-amine

(130) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-phenylpyrrolidin-1-yl)benzo [4,5]thieno[3,2-d]pyrimidine- 4-amine

(131) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3 -carboxylic acid

(132) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methylpyrrolidin-1-yl)benzo [4,5] thieno [3,2-d ]Pyrimidin-4-amine

(133) (1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol

(134) N-(5-cyclopropylthiazol-2-yl)-2-(pyrrolidin-1-yl)benzo[4,5]thieno [3,2-d]pyrimidin-4-amine

(135) (S)-1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)pyrrolidine- 3-all

(136) (S)-N-(5-cyclopropylthiazol-2-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl) benzo[4,5]thieno[3,2- d]pyrimidin-4-amine

(137) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-fluorobenzo [4,5]thieno[3,2-d]pyrimidine- 2-yl) pyrrolidin-3-ol

(138) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[ 3,2-d]pyrimidine -4-amine

(139) N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(pyrrolidin-1-yl) benzo[4,5]thieno[3,2-d]pyri Mydin-4-amine

(140) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-8-fluorobenzo [4,5]thieno[3,2-d]pyrimidine- 2-yl) pyrrolidin-3-ol

(141) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[ 3,2-d]pyrimidine -4-amine

(142) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5 ]thieno[3,2- d]pyrimidin-4-amine

(143) (S)-1-(7-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5] thieno[3,2-d]pyrimidine-2 -1) Pyrrolidin-3-ol

(144) (S)-7-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3 ,2-d]pyrimidine -4-amine

(145) (S)-7-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5] Thieno[3,2- d]pyrimidin-4-amine

(146) Tert-Butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)-3 ,6-dihydropyridine-1(2H)-carboxylate

(147) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[4,5]thieno[3,2- d]pyrimidine-4 -amine

(148) 2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

(149) 2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazin-4-amine

(150) 2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4]triazine- 4-amine

(151) 2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4]tri Azine-4-amine

(152) 2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazin-4-amine

(153) N-(5-methyl-1H-pyrazol-3-yl)-2-((4-phenylcyclohexyl)thio)pyrrolo[2,1-f] [1,2,4]triazine-4- amine

(154) 2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo[2,1-f][1,2,4]triazin-4-amine

(155) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((4,4-dimethylcyclohexyl)thio)pyrrolo[2,1-f][1,2,4]triazine -4-amine

(156) 2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-amine

(157) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenyl)-4-(4-methylpiperazin-1-yl)benzamide

(158) 2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo [2,1-f][1,2,4]triazine -4-amine

(159) 2-((4-aminophenyl)thio)-N-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-amine

(160) 2-((4-aminophenyl)thio)-N-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

(161) 2-((3-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-amine

(162) 2-((2-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-amine

(163) 2-chloro-N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f] [1,2,4]triazine-2 -yl)thio)phenyl)acetamide

(164) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenyl)cyclohexanecarboxamide

(165) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenyl)benzamide

(166) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio ) phenyl) -2-phenylacetamide

(167) N-(3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio ) phenyl) -2-phenylacetamide

(168) 2-((3-methoxyphenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine-4- amine

(169) 2-((3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine-4- amine

(170) 3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenol

(171) 2-((4-amino-3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4]tri Azine-4-amine

(172) (R)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-(2-fluoro-4-((4-( (5-methyl-1H-pyrazol-3)-yl)amino)pyrrolo[2,1-f][1,2,4] riazin-2-yl)thio)phenyl)acetamide

(173) 4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenol

(174) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl) Pyrrolidin-3-ol

(175) 1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-3 -all

(176) (R)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4 ]Triazine-4-amine

(177) (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4 ]Triazine-4-amine

(178) (S)-N-(5-methyl-1H-pyrazol-3-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1, 2,4]triazine- 4-amine

(179) (S)-2-(3-fluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine

(180) 2-(3,3-difluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl) pyrrolo[2,1-f][1,2,4 ]Triazine-4-amine

(181) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine

(182) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrrolo[2,1-f][ 1,2,4]triazine- 4-amine

(183) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4]triazine-4- amine

(184) 2-(4-aminopiperidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine- 4-amine

(185) N-(5-methyl-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)pyrrolo[2,1-f] [1,2,4]triazine-4 -Amine

(186) 1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperidine-4 -all

(187) 1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperidine-4 -1) Methanol

(188) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4 -Amine

(189) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2, 4]Triazine-7-carboxamide

(190) Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)( Pyrrolidin-1-yl)methanone

(191) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]tri azine-7-yl)(piperazine-1-yl)methanone

(192) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)-N-methylpyrrolo[2,1 -f][1,2,4]triazine-7-carboxamide

(193) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-N-methylpyrrolo[2,1 -f][1,2,4]triazine-7-carboxamide

(194) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-7-carboxamide

(195) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1, 2,4]triazine-7-carboxamide

(196) (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)(pyrrolidin-1-yl)methanone

(197) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N,N-dimethylpy Rolo[2,1-f][1,2,4]triazine-7-carboxamide

(198) (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone

(199) (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)(piperazin-1-yl)methanone

(200) 2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo[2, 1-f][1,2,4]triazine-7-carboxamide

(201) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1- 1) Pyrrolo[2,1- f][1,2,4]triazine-7-carboxamide

(202) Ethyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]tri Azine-6-carboxylate

(203) Ethyl (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4] Triazine-6-carboxylate

(204) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]triazine -6-carboxylic acid

(205) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic acid

(206) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]tri azine-6-yl)(piperazine-1-yl)methanone

(207) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2, 4]Triazine-6-carboxamide

(208) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine -1-yl)-N-methylpyrrolo[2,1-f][1,2,4] triazine-7-carboxamide

(209) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-6-carboxamide

(210) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-6-carboxamide

(211) 2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo[2, 1-f][1,2,4]triazine-6-carboxamide

(212) 6-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4] Triazine-4-amine

The chemical formulas of compounds 1 to 212 are as shown in Table 1 below.

No. chemical formula No. chemical formula One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212

The hydrate or solvate of the pyrimidine and triazine derivatives of the present invention may contain 1 equivalent or more, specifically, 1-5 equivalents of water or solvent.

Isomers of the pyrimidine and triazine derivatives of the present invention may be specifically stereoisomers, and more specifically, may be enantiomers.

Pharmaceutically acceptable salts of the pyrimidine and triazine derivatives of the present invention include, for example, hydrochloride salts, and acid addition salts formed from pharmaceutically acceptable free acids may be used. Acid addition salts can be obtained from hydrochloric acid, inorganic acids, organic acids, aromatic acids, aliphatic acids, etc. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne 1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methylbenzoate Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol Includes nitrate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

These acid addition salts can be prepared by conventional methods. Additionally, a pharmaceutically acceptable metal salt can be prepared using a base.

The pyrimidine and triazine derivatives of the present invention can be prepared and administered in various oral and parenteral dosage forms. When formulated, it can be prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations are prepared by mixing one or more compounds with at least one excipient. Additionally, lubricants other than simple excipients may also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups, and may include commonly used diluents and excipients.

The pyrimidine and triazine derivatives of the present invention can be administered parenterally, and parenteral administration may include subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions.

A pharmaceutical composition for preventing or treating cancer according to an embodiment of the present invention to solve the above other problems includes the pyrimidine and triazine derivatives of the present invention. The derivative may include a compound represented by Formula I-1 or I-2, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. The derivative may be included as an active ingredient in the composition.

The derivative may be an inhibitor of the activity of Fer kinase and may exhibit preventive or therapeutic efficacy against various cancer diseases in which Fer kinase is involved.

Additionally, the composition may be a combination preparation containing at least one additional agent in addition to the derivative of the present invention. The additional agent(s) may be in the form of a single composition or multiple compositions, and the treatment modalities may be administered simultaneously, sequentially, or via some other manner. Combination therapy may have additive or synergistic effects. The additional agent(s) may have inhibitory activity of Fer kinase or may have a distinct mechanism of action other than Fer kinase inhibitory activity.

In one embodiment of the present invention, a method for preventing or treating a cancer disease can be provided, including the step of administering the composition containing the derivative of the present invention to a patient in need of prevention or treatment of a cancer disease.

A health functional food composition for preventing or improving cancer according to an embodiment of the present invention to solve the above other problems includes the pyrimidine and triazine derivatives of the present invention. The derivative may include a compound represented by Formula I-1 or I-2, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. The derivative may be included as an active ingredient in the composition.

The pyrimidine and triazine derivatives of the present invention can be added directly to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention or improvement). For example, the derivative of the present invention may be included in health foods in an amount of 0.1 to 90 parts by weight.

In addition, when the composition is a health functional beverage composition, it may contain various flavoring agents or natural carbohydrates as additional ingredients like ordinary beverages. Furthermore, it may further contain various nutrients, vitamins, flavors, colorants, thickeners, thickeners, pH adjusters, stabilizers, preservatives, carbonating agents, etc. In exemplary embodiments, it may further contain pulp for the production of fruit or vegetable beverages.

A method for producing pyrimidine and triazine derivatives according to an embodiment of the present invention to solve the above other problems includes the following steps, as shown in one of Schemes 1 to 4 below.

[Scheme 1]

(a) reacting the compound 1-1 with the compound a) to obtain the compound 1-2; and

(b) reacting the compound 1-2 with the compound b) to obtain the compound 1-3

Specifically, step (a) is a step of reacting in the presence of one or more of diisopropylethylamine and isopropyl alcohol, and step (b) may be a step of reacting in the presence of one or more of amine and tetrahydrofuran. .

[Scheme 2]

(a) reacting the compound 2-1 with the compound a) to obtain the compound 2-2; and

(b) reacting the compound 2-2 with the compound b) to obtain the compound 2-3

Specifically, step (a) is a step of reacting in the presence of one or more of diisopropylethylamine and isopropyl alcohol, and step (b) may be a step of reacting in the presence of one or more of amine and tetrahydrofuran. .

[Scheme 3]

(a) reacting the compound 3-1 with the compound a) to obtain the compound 3-2; and

(b) reacting the compound 3-2 with the compound b) to obtain the compound 3-3

Specifically, step (a) is a step of reacting in the presence of one or more of diisopropylethylamine and isopropyl alcohol, and step (b) may be a step of reacting in the presence of one or more of amine and tetrahydrofuran. .

[Scheme 4]

(a) reacting the compound 4-1 with the compound a) to obtain the compound 3-2; and

(b) reacting the compound 4-2 with the compound b1) or b2) to obtain the compound 4-3 or 4-4

Specifically, step (a) is a step of reacting in the presence of one or more of diisopropylethylamine and isopropyl alcohol, and step (b) may be a step of reacting in the presence of one or more of amine and tetrahydrofuran. .

In Schemes 1 to 4 above,

Ra, Rb and L ₁ are as described above in Formula I-1 or I-2,

Z is as described above for B in Formula I-1 or I-2,

R ₁ , R ₂ and R ₃ are as described above for R ₁ and R ₂ in Formula I-1 or I-2,

R ₄ is as described above for R ₁₁ in Formula I-1 or I-2,

R ₈ is as described above for Ra or Rb in Formula I-1 or I-2,

R ₉ is as described above for R ₈ in Formula I-1 or I-2.

n is an integer from 0 to 4, and m is an integer from 0 to 3.

Specifically, n may be an integer from 0 to 3, and m may be an integer from 1 to 3.

Q is S, N or O.

Specifically, Q may be S.

R ₅ , R ₆ and R ₇ are each independently hydrogen, C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 heteroaryl , C _1-6 alkoxy, sulfonyl, amide, carboxyl or carbonyl.

Wherein R ₅ , R ₆ and R ₇ are each independently unsubstituted or C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 It may be substituted with one or more selected from the group consisting of heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl, and carbonyl.

Specifically, R ₅ , R ₆ and R ₇ are each independently hydrogen, methyl, butyl, hydroxy, cyano, morpholinyl, pyrrolidinyl, phenyl, amino, fluoro, Boc (t-butyloxycarbonyl , tert-Butyloxycarbonyl), diazaspirodecane, triazolyl, thiophenyl, thiazolyl, tetrahydrothiopyranyl, methoxy, sulfonyl, amide, carboxyl or carbonyl.

Wherein R ₅ , R ₆ and R ₇ are each independently unsubstituted or methyl, butyl, hydroxy, cyano, morpholinyl, pyrrolidinyl, phenyl, amino, fluoro, Boc, triazolyl, thiophenyl, thia It may be substituted with one or more selected from the group consisting of zolyl, tetrahydrothiopyranyl, methoxy, sulfonyl, amide, carboxyl, and carbonyl.

In other embodiments, R ₅ , R ₆ and R ₇ are each independently -C(OH)-alkyl, -C(OH)-aryl, -C(OH)-heteroaryl, -C(CN)-alkyl, -C(CN)-aryl, -C(CN)-heteroaryl, or -(C _3-8 heterocycloalkyl).

R ₈ is specifically hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _{1- 6} Can be alkoxy, hydroxy, carbonyl, carboxyl or amide. R ₈ may be unsubstituted or substituted, and when substituted, it may be halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl. , amino, nitro, cyano, C _1-6 alkoxy, hydroxy, carbonyl, carboxyl, and amide.

In one embodiment, Schemes 1 to 5 are:

Ra and Rb are each independently hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _1-6 alkoxy, hydroxy, carbonyl, carboxyl or amide, or Ra and Rb are directly or indirectly connected to each other to form C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _{2- 8} Form a heteroaryl ring compound,

The Ra and Rb or the ring compound may each independently be unsubstituted or substituted,

R ₁ , R ₂ and R ₃ are each independently hydrogen, halogen, amide, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _2-8 hetero It is aryl, or two or more of R ₁ to R ₃ are directly or indirectly connected to each other to form a ring compound of C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl. do,

The R ₁ , R ₂ and R ₃ or the ring compound may each independently be unsubstituted or substituted,

R ₄ is hydrogen, C _1-6 alkyl, hydroxy or C _2-8 heterocycloalkyl,

R ₅ , R ₆ and R ₇ are each independently hydrogen, C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 heteroaryl , C _1-6 alkoxy, sulfonyl, amide, carboxyl or carbonyl,

Wherein R ₅ , R ₆ and R ₇ are each independently unsubstituted or C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 may be substituted with one or more selected from the group consisting of heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl and carbonyl,

R ₈ is hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _1-6 alkoxy , hydroxy, carbonyl, carboxyl or amide,

R ₈ may be unsubstituted or substituted,

L ₁ is S or S(O) ₂ ,

R ₉ is C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _2-8 heteroaryl,

R ₉ may be unsubstituted or substituted,

Z is C, N or O,

n is an integer from 0 to 4,

m is an integer from 0 to 3,

Q may be S, N or O.

Specific details of other embodiments are included in the detailed description.

Pyrimidine and triazine derivatives according to embodiments of the present invention can inhibit Fer kinase activity and thus can be effective in preventing or treating various cancers involving Fer kinase, especially in terms of anticancer activity by overcoming resistance. Because it shows excellent effects, it can be usefully used as an anticancer agent.

Effects according to embodiments of the present invention are not limited to the contents exemplified above, and further various effects are included in the present specification.

The advantages and features of the present invention and methods for achieving them will become clear with reference to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below and will be implemented in various different forms, and only the embodiments serve to ensure that the disclosure of the present invention is complete, and those skilled in the art It is provided to fully inform the person of the scope of the invention, and the present invention is only defined by the scope of the claims.

The terminology used herein is for describing embodiments and is not intended to limit the invention. As used herein, 'and/or' includes each and every combination of one or more of the mentioned items. Additionally, the singular form also includes the plural form unless specifically stated in the phrase. As used in the specification, 'comprises' and/or 'comprising' do not exclude the presence or addition of one or more other components in addition to the mentioned components. The numerical range indicated using '-' or 'to' indicates a numerical range that includes the values written before and after it as the lower and upper limits, respectively, unless otherwise specified. ‘About’ or ‘approximately’ means a value or numerical range within 20% of the value or numerical range stated thereafter.

Additionally, when describing the components of an embodiment of the present invention, terms such as first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, sequence, or order of the component is not limited by the term.

Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used with meanings that can be commonly understood by those skilled in the art to which the present invention pertains. Additionally, terms defined in commonly used dictionaries are not interpreted ideally or excessively unless clearly specifically defined.

Also, in describing embodiments of the present invention, if detailed descriptions of related known configurations or functions are judged to impede understanding of the embodiments of the present invention, the detailed descriptions will be omitted.

In this specification, 'prevention' means suppressing the occurrence of symptoms or diseases in an individual who does not yet have symptoms or diseases but is susceptible to such symptoms or diseases.

As used herein, 'treatment' or 'improvement' means (a) inhibiting the development (worsening) of a symptom or disease, (b) alleviating a symptom or disease, or (c) eliminating a symptom or disease in an individual.

In this specification, 'individual' refers to animals, especially mammals, including humans, who have symptoms or diseases that can be 'prevented' or 'treated' by administering the composition of the present invention.

In this specification, a compound of 'substituted C _n to C _n+m ' refers to a case where the number of all carbons in the compound including the substituted portion is n to n+m, as well as the number of carbons in the compound excluding the substituted portion. The number includes n to n+m.

As used herein, 'alkyl' refers to a straight-chain, branched-chain or cyclic hydrocarbon radical, and each carbon atom may be optionally substituted with one or more substituents.

As used herein, 'alkoxy' means -O-alkyl, where alkyl is as defined above.

In this specification, 'aryl' refers to an aromatic group including phenyl, naphthyl, etc., and each carbon atom may be optionally substituted with one or more substituents.

As used herein, 'heteroaryl' is an aryl containing 1 to 4 heteroatoms selected from N, O and S, optionally fused with benzo or cycloalkyl, in saturated, partially saturated, or aromatic forms. refers to

As used herein, 'halo(gen)' refers to a substituent of fluoro, chloro, bromo or iodo.

As used herein, 'hydrate' refers to a compound containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.

In this specification, 'solvate' refers to a compound or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents may be volatile, non-toxic, and/or suitable for administration to humans.

In this specification, 'isomer' refers to a compound or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers with asymmetric carbon centers, geometric isomers (trans, cis), and optical isomers (enantiomers).

In this specification, 'Azole' is a five-ring compound containing N and one or more hetero elements, for example, imidazole, pyrazole, triazole, tetrazole ( Tetrazole, Pentazole, Oxazole, Isoxazole, Oxadiazole, Thiazole, Isothiazole, or Thiadiazole. It is not limited to this.

Hereinafter, examples and production examples of the present invention will be described in detail. However, the examples and production examples described below only illustrate a part of the present invention, and the present invention is not limited thereto.

Preparation Example: Preparation of pyrimidine and triazine derivatives of the present invention

[Reaction Scheme 1-1]

Reagents and conditions: (a) diisopropylethylamine, isopropyl alcohol, 80 °C, 24 h; (b) Amine, 165 °C, 2.5 h, tetrahydrofuran, microwave reactor

Example 1

[Reaction Scheme 2-1]

Reagents and conditions: (a) diisopropylethylamine, isopropyl alcohol, 80 °C, 24 h; (b) Amine, 165 °C, 2.5 h, tetrahydrofuran, microwave reactor

Manufacturing Example 1

2-chloro-N- (3-cyclopropyl-1H-pyrazol-5-yl)thieno[3, 2-d]pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2,4-dichlorothieno[3,2-d]pyrimidine (100 mg, 0.49 mmol), diisopropylethylamine (0.40 mL, 2.44 mmol), 3-cyclopropyl-1H-pyrazol-5-amine (72 mg, 0.59 mmol) was dissolved in 2 mL of isopropyl alcohol and reacted at 80°C overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Purified through medium pressure liquid chromatography, 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine 120 mg (0.41 mmol) was prepared (yield 84.3%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (br s, 1H), 10.46 (s, 1H), 8.19 (br s, 1H), 7.34 (br s, 1H), 6.23 (br s, 1H) ), 1.98 (m, 1H), 0.95 (d, J = 1.0 Hz, 2H), 0.71 (br d, J = 3.5 Hz, 2H)

MS(ES): m/z 292.16 [M+H]+.

Production example 2

[1- [4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] thieno [3, 2-d] pyrimidin-2-yl] -4-piperidyl] methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine (500 mg, 1.71 mmol), piperidine-4- Ilmethanol (237 mg, 2.06 mmol) was dissolved in 5 mL of tetrahydrofuran. The reaction was performed in a microwave reactor at 165°C for 2.5 hours. After confirming that the reaction was complete, the solvent was removed under reduced pressure. 200 mg (0.54 mmol) of the target compound was prepared by purification through preparative thin layer chromatography (yield 31.5%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), 9.66 (br s, 1H), 7.91 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.22 (br s, 1H), 4.67 (br d, J = 12.6 Hz, 2H), 4.46 (br t, J = 5.3 Hz, 1H), 3.29-3.25 (m, 2H), 2.90-2.77 ( m, 2H), 1.96 (m, 1H), 1.78-1.55 (m, 3H), 1.18-1.02 (m, 2H), 0.95 (br d, J = 6.9 Hz, 2H), 0.71-0.62 (m, 2H) )

MS(ES): m/z 371.20 [M+H]+.

In Examples 2 to 39 below, the compounds were synthesized in the same manner as in Example 1, or were prepared using appropriate reactants in consideration of Scheme 1 and the structure of the compound to be prepared.

Example 2

(1-(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.65 (br s, 1H), 7.91 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.32 (br s, 1H), 4.68 (br d, J = 12.6 Hz, 2H), 4.47 (t, J = 5.3 Hz, 1H), 3.30-3.23 (m, 2H), 2.82 (bt, J = 11.7 Hz, 2H), 1.76-1.58 (m, 3H), 2.28-2.21 (m, 3H), 1.76-1.58 (m, 3H), 1.18-0.99 (m, 2H)

MS(ES): m/z 344.92 [M+H]+

Example 3

(1-(4-((5-ethyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-ethyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.10 (br s, 1H), 9.67 (br s, 1H), 7.91 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.37 (br s, 1H), 4.69 (br d, J = 12.9 Hz, 2H), 4.45 (br t, J = 5.1 Hz, 1H), 3.24-3.29 (m, 2H), 2.89-2.77 ( m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.74-1.59 (m, 3H), 1.21 (t, J = 7.6 Hz, 3H), 1.17-1.05 (m, 2H)

MS(ES): m/z 359.10 [M+H]+.

Example 4

(1-(4-((4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)amino)thieno[3,2-d] pyrimidin-2-yl)piperidin-4- yl)methanol

1-(4-((4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl) piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.56 (m, 1H), 9.67 (m, 1H), 7.93 (br s, 1H), 7.08 (br s, 1H), 4.62 (br d, J = 12.6 Hz, 2H), 4.46 (br t, J = 5.0 Hz, 1H), 4.05- 3.84 (m, 2H), 3.72 (br s, 2H), 3.29-3.21 (m, 2H), 2.87-2.68 (m , 2H), 1.75-1.53 (m, 3H), 1.13-0.96 (m, 2H)

MS(ES): m/z 386.66 [M+H]+.

Example 5

(1-(4-((1H-pyrazolo[3,4-b]pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((1H-pyrazolo[3,4-b]pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.30 (br s, 1H), 10.04 (br s, 1H), 8.52 (br s, 1H), 8.08 (br d, J = 7.8 Hz, 1H), 7.96 (br d, J = 5.1 Hz, 1H), 7.11 (br d, J = 5.5 Hz, 2H), 4.52-4.38 (m, 3H), 3.25-3.23 (m, 2H), 2.67 (br s, 3H) ), 1.57 (br d, J = 11.3 Hz, 3H), 1.11-0.95 (m, 2H)

MS(ES): m/z 381.77 [M+H]+.

Example 6

(1-(4-((4,5,6,7-tetrahydro-1H-indazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((4,5,6,7-tetrahydro-1H-indazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (s, 1H), 9.05 (br s, 1H), 7.84 (br d, J = 5.0 Hz, 1H), 7.02 (br d, J = 5.3 Hz) , 1H), 5.76 (d, J = 1.1 Hz, 1H), 4.64 (br d, J = 12.3 Hz, 2H), 4.46 (t, J = 1.0 Hz, 1H), 3.27-3.24 (m, 2H), 2.74 (br t, J = 12.4 Hz, 2H), 2.62-2.57 (m, 2H), 2.28-2.20 (m, 2H), 1.78-1.54 (m, 8H), 1.11-0.97 (m, 2H)

MS(ES): m/z 384.81 [M+H]+.

Example 7

(1-(4-((5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)amino)thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)p Peridin-4-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.47 (br s, 1H), 9.79 (br s, 1H), 7.93 (br s, 1H), 7.08 (br s, 1H), 6.49 (br s, 1H), 4.66 (br d, J = 13.4 Hz, 2H), 4.45 (t, J = 1.0 Hz, 1H), 3.30-3.24 (m, 2H), 3.05 (m, 1H), 2.82 (br t, J = 12.4 Hz, 2H), 2.18 (m, 1H), 1.85 (m, 1H), 1.75-1.59 (m, 3H), 1.17-1.02 (m, 2H)

MS(ES): m/z 406.81 [M+H]+.

Example 8

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)ethan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.64 (br s, 1H), 7.90 (br d, J = 4.5 Hz, 1H), 7.05 (br d, J = 4.8 Hz, 1H), 6.23 (br s, 1H), 4.64 (br d, J = 12.5 Hz, 2H), 4.39 (m, 1H), 3.51-3.44 (m, 2H), 2.82 (br t, J = 12.4 Hz, 2H), 1.95 (m, 1H), 1.74-1.60 (m, 3H), 1.42-1.34 (m, 2H), 1.16-1.01 (m, 2H),

0.90-1.00 (m, 2H), 0.66 (br d, J = 3.8 Hz, 2H)

MS(ES): m/z 384.63 [M+H]+.

Example 9

1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)ethan-1-ol

1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.65 (br s, 1H), 7.90 (br d, J = 4.6 Hz, 1H), 7.06 (br d, J = 5.0 Hz, 1H), 6.24 (br s, 1H), 4.71 (br d, J = 12.0

Hz, 2H), 4.37 (br d, J = 4.6 Hz, 1H), 2.84-2.68 (m, 2H), 1.96 (m, 1H), 1.81 (br d, J = 12.6 Hz, 1H), 1.59 (br d, J = 11.6 Hz, 1H), 1.48 (m, 1H), 1.22-1.08 (m, 2H), 1.05 (br d, J = 5.9 Hz, 2H), 0.95 (br d, J = 6.4 Hz, 2H) ), 0.67 (br d, J = 4.0 Hz, 2H)

MS(ES): m/z 384.75 [M+H]+.

Example 10

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)acetonitrile

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Acetonitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (br s, 1H), 9.69 (br s, 1H), 7.92 (br d, J = 4.6 Hz, 1H), 7.07 (br d, J = 5.0 Hz, 1H), 6.22 (br s, 1H), 4.68 (br d, J = 13.1 Hz, 2H), 2.87 (t, J = 1.0 Hz, 2H), 1.97-1.86 (m, 2H), 1.76 (br d, J = 11.9 Hz, 2H), 1.29-1.14 (m, 3H), 0.95 (br d, J = 6.8 Hz, 2H), 0.67 (br d, J = 4.0 Hz, 2H)

MS(ES): m/z 379.77 [M+H]+.

Example 11

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (br s, 1H), 9.68 (br s, 1H), 7.89 (br s, 1H), 7.07 (br d, J = 4.5 Hz, 1H), 6.47 (br s, 1H), 4.69 (br s, 1H), 3.69-3.55 (m, 2H), 3.53-3.37 (m, 4H), 2.43 (m, 1H), 2.05 (m, 1H), 1.89 ( br s, 1H), 1.83 (m, 1H), 0.99-0.88 (m, 2H), 0.71-0.65 (m, 2H)

MS(ES): m/z 356.70 [M+H]+.

Example 12

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl)ethan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl) Ethan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (br s, 1H), 9.68 (br s, 1H), 7.89 (br s, 1H), 7.07 (br d, J = 4.5 Hz, 1H), 6.47 (br s, 1H), 4.69 (br s, 1H), 3.69-3.55 (m, 2H), 3.53-3.37 (m, 4H), 2.43 (m, 1H), 2.05 (m, 1H), 1.89 ( br s, 1H), 1.83 (m, 1H), 0.99-0.88 (m, 2H), 0.71-0.65 (m, 2H)

MS(ES): m/z 370.69 [M+H]+.

Example 13

(S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3-yl)methanol

(S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3- 1) Methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.66 (br s, 1H), 7.90 (br d, J = 4.6 Hz, 1H), 7.06 (br d, J = 4.9 Hz, 1H), 6.29 (br s, 1H), 4.66 (br d, J = 12.0 Hz, 1H), 4.54 (br s, 2H), 2.86 (br t, J = 11.3 Hz, 1H), 1.95 (m , 1H), 1.77 (br d, J = 11.9 Hz, 1H), 1.68 (br d, J = 12.4 Hz, 1H), 1.62 (m, 1H), 1.48 (m, 1H), 1.23 (m, 1H) , 0.93 (br d, J = 7.3 Hz, 2H), 0.74-0.66 (m, 2H)

MS(ES): m/z 370.76 [M+H]+.

Example 14

(R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3-yl)methanol

(R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3- 1) Methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.66 (br s, 1H), 7.91 (br d, J = 5.0 Hz, 1H), 7.06 (br d, J = 4.9 Hz, 1H), 6.29 (br s, 1H), 4.66 (br d, J = 11.4 Hz, 1H), 4.54 (br s, 2H), 2.91 (m, 1H), 1.94 (m, 1H), 1.78 ( br d, J = 12.1 Hz, 1H), 1.68 (br d, J = 11.8 Hz, 1H), 1.62 (m, 1H), 1.49 (m,1H), 1.22 (m, 1H), 0.93 (br d, J = 6.6 Hz, 2H), 0.70 (br d, J = 3.5 Hz, 2H)

MS(ES): m/z 370.88 [M+H]+.

Example 15

(S)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin -2-yl)piperidin-4-yl)ethan- 1-ol

(S)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-yl) ethane-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.64 (br s, 1H), 7.90 (br d, J = 4.6 Hz, 1H), 7.06 (br d, J = 4.6) Hz, 1H), 6.24 (br s, 1H), 4.71 (br d, J = 12.3 Hz, 2H), 4.36 (br d, J = 4.8 Hz, 1H), 2.81-2.69 (m, 2H), 1.94 ( m, 1H), 1.81 (br d, J = 11.9 Hz, 1H), 1.62 (m, 1H), 1.50 (m, 1H), 1.22-1.09 (m, 2H), 1.05 (br d, J = 6.3 Hz) , 3H), 0.95 (br d, J = 6.3 Hz, 2H), 0.71-0.63 (m, 2H)

MS(ES): m/z 384.75 [M+H]+.

Example 16

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.63 (br s, 1H), 7.90 (br d, J = 4.5 Hz, 1H), 7.06 (br d, J = 4.9 Hz, 1H), 6.23 (br s, 1H), 4.72 (br d, J = 12.6 Hz, 2H), 4.40 (m, 1H), 2.81-2.68 (m, 2H), 1.96 (m, 1H), 1.68 -1.54 (m, 3H), 1.44 (m, 1H), 1.22-1.05 (m, 2H), 0.95 (br d, J = 5.9 Hz, 2H), 0.81 (br d, J = 6.6 Hz, 3H), 0.71-0.63 (m, 2H)

MS(ES): m/z 398.80 [M+H]+.

Example 17

(R)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin -2-yl)piperidin-4-yl)ethan- 1-ol

(R)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-yl) ethane-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.65 (br s, 1H), 7.90 (br d, J = 5.0 Hz, 1H), 7.06 (br d, J = 5.1 Hz, 1H), 6.23 (br s, 1H), 4.71 (br d, J = 12.8 Hz, 2H), 4.37 (bd, J = 4.5 Hz, 1H), 2.82-2.68 (m, 2H), 1.95 (m , 1H), 1.81 (br d, J = 13.0 Hz, 1H), 1.59 (br d, J = 13.1 Hz, 1H), 1.49 (m, 1H), 1.21-1.08 (m, 2H), 1.04 (br d , J = 6.1 Hz, 3H), 0.95 (br d, J = 6.4 Hz, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z 384.75 [M+H]+.

Example 18

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propanenitrile

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propanenitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.66 (br s, 1H), 7.91 (br d, J = 4.4 Hz, 1H), 7.06 (br d, J = 4.9 Hz, 1H), 6.23 (br s, 1H), 4.66 (br d, J = 12.5 Hz, 2H), 2.84 (br t, J = 12.3 Hz, 2H), 1.94 (m, 1H), 1.72 (br d , J = 12.8 Hz, 2H), 1.65 (m, 1H), 1.57-1.47 (m, 2H), 1.17-1.02 (m, 2H), 0.95 (br d, J = 6.1 Hz, 2H), 0.70-0.64 (m, 2H)

MS(ES): m/z 393.82 [M+H]+

Example 19

1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propan-2-ol

1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Propane-2-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.64 (br s, 1H), 7.90 (br d, J = 4.5 Hz, 1H), 7.05 (br d, J = 5.1 Hz, 1H), 6.22 (br s, 1H), 4.63 (br d, J = 12.5 Hz, 2H), 4.33 (br d, J = 3.5 Hz, 1H), 3.78 (m, 1H), 2.82 (br t , J = 10.8 Hz, 2H), 1.94 (m, 1H), 1.77-1.74 (m, J = 12.9 Hz, 2H), 1.65 (m, J = 13.5 Hz, 2H), 1.37 (m, 1H), 1.21 -1.09 (m, 2H), 1.06 (br d, J = 6.0 Hz, 3H), 1.03 (m, 1H), 0.95 (br d, J = 6.4 Hz, 2H), 0.66 (br d, J = 4.3 Hz) , 2H)

MS(ES): m/z 398.74 [M+H]+

Example 20

1-(1-(4-((5-cyclopropylthiazol-2-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propan-2-ol

1-(1-(4-((5-cyclopropylthiazol-2-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propane-2 -all

^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (s, 1H), 7.99 (br s, 1H), 7.12 (m, J = 5.6 Hz, 2H), 4.79 (br d, J = 11.0 Hz, 2H), 4.36 (br d, J = 4.9 Hz, 1H), 3.79 (m, 1H), 2.99-2.88 (m, 2H), 2.05 (m, 1H), 1.85-1.66 (m, 3H), 1.33 ( m, 1H), 1.22-1.09 (m, 3H), 1.06 (br d, J = 6.0 Hz, 3H), 0.95 (br d, J = 7.8 Hz, 2H), 0.67 (br d, J = 4.5 Hz, 2H)

MS(ES): m/z 415.95 [M+H]+.

Example 21

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-2-methylpropan-1 -ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) -2-methylpropan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.63 (br s, 1H), 7.90 (br d, J = 4.8 Hz, 1H), 7.06 (br d, J = 4.6) Hz, 1H), 6.25 (br s, 1H), 4.75 (br d, J = 12.4 Hz, 2H), 4.47 (m, 1H), 3.21-3.15 (m, 2H), 2.76-2.65 (m, 2H) , 1.97 (m, 1H), 1.65 (br d, J = 12.0 Hz, 2H), 1.60 (m, 1H), 1.22-1.09 (m, 2H), 0.95 (br d, J = 6.3 Hz, 2H), 0.75 (s, 6H), 0.69-0.64 (m, 2H)

MS(ES): m/z 412.73 [M+H]+.

Example 22

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3-yl)ethan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3-yl) Ethan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.65 (br s, 1H), 7.90 (br d, J = 4.0 Hz, 1H), 7.06 (br d, J = 4.5 Hz, 1H), 6.27 (br s, 1H), 4.54 (br d, J = 12.6 Hz, 2H), 4.42 (m, 1H), 3.54-3.47 (m, 2H), 2.87 (br t, J = 12.0 Hz, 1H), 2.61 (br t, J = 11.3 Hz, 1H), 1.94-1.81 (m, 2H), 1.67 (br d, J = 12.8 Hz, 1H), 1.61 (m, 1H), 1.50-1.29 (m, 4H), 1.22 (m, 1H), 0.94 (br d, J = 7.0 Hz, 2H), 0.73-0.66 (m, 2H)

MS(ES): m/z 384.69 [M+H]+.

Example 23

(S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl)methanol

(S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3- 1) Methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (br s, 1H), 9.68 (br s, 1H), 7.89 (br s, 1H), 7.07 (br s, 1H), 6.47 (br s, 1H), 4.73 (m, 1H), 3.68-3.55 (m, 2H), 3.52-3.36 (m, 3H), 2.44 (m, 1H), 2.06 (m, 1H), 1.93 (m, 1H), 1.79 (m, 1H), 0.99-0.90 (m, 2H), 0.73-0.64 (m, 2H)

MS(ES): m/z 356.70 [M+H]+.

Example 24

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)propan-1-ol

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.64 (br s, 1H), 7.90 (br d, J = 4.8 Hz, 1H), 7.05 (br d, J = 5.3 Hz, 1H), 6.23 (br s, 1H), 4.65 (br d, J = 12.5 Hz, 2H), 4.39 (m, 1H), 3.43-3.37 (m, 2H), 2.87-2.76 (m, 2H) , 1.95 (m, 1H), 1.70 (br d, J = 12.5 Hz, 2H), 1.55-1.40 (m, 3H), 1.29-1.19 (m, 2H), 1.06(q, J = 10.8 Hz, 2H) , 0.95 (br d, J = 6.3 Hz, 2H), 0.66 (br d, J = 4.3 Hz, 2H)

MS(ES): m/z 398.87 [M+H]+.

Example 25

3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propan-1-ol

3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propane -1-all

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), 9.67 (br s, 1H), 7.92 (br d, J = 4.8 Hz, 1H), 7.07 (br d, J = 5.0 Hz, 1H), 6.21 (br s, 1H), 4.46 (br s, 1H), 3.74-3.65 (m, 4H), 3.46 (br t, J = 5.9 Hz, 2H), 2.45-2.31 (m, 7H) ), 1.95 (m, 1H), 1.68-1.57 (m, 2H), 0.95 (br d, J = 7.1 Hz, 2H), 0.71-0.65 (m, 2H)

MS(ES): m/z 399.88 [M+H]+.

Example 26

4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)butanenitrile

4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Butanenitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.65 (br s, 1H), 7.90 (br d, J = 4.8 Hz, 1H), 7.06 (br d, J = 5.3 Hz, 1H), 6.22 (br s, 1H), 4.65 (br d, J = 12.6 Hz, 2H), 2.83 (br t, J = 12.4 Hz, 2H), 1.94 (m, 1H), 1.70 (br d , J = 11.8 Hz, 2H), 1.66-1.49 (m, 3H), 1.37-1.26 (m, 2H), 1.14-1.01 (m, 2H), 0.95 (br d, J = 7.0 Hz, 2H), 0.67 (br d, J = 4.50 Hz, 2H)

MS(ES): m/z 408.00 [M+H]+.

Example 27

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)butan-1-ol

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) butan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.64 (br s, 1H), 7.90 (br d, J = 5.4 Hz, 1H), 7.06 (d, J = 5.4 Hz) , 1H), 6.23 (br s, 1H), 4.73 (br d, J = 12.5 Hz, 2H), 4.32 (t, J = 5.0 Hz, 1H), 3.52-3.43 (m, 2H), 2.83-2.68 ( m, 2H), 1.94 (m, 1H), 1.66-1.50 (m, 3H), 1.49-1.39 (m, 2H), 1.29-1.11 (m, 3H), 0.95 (br d, J = 6.6 Hz, 2H ), 0.81 (d, J = 6.3 Hz, 3H), 0.70-0.64 (m, 2H)

MS(ES): m/z 412.96 [M+H]+.

Example 28

(R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl)methanol

(R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3- 1) Methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.72 (br s, 1H), 7.91 (br s, 1H), 7.08 (br d, J = 4.9 Hz, 1H), 6.46 (br s, 1H), 4.71 (t, J = 4.9 Hz, 1H),

3.68-3.58 (m, 2H), 2.43 (m, 1H), 2.06 (m, 1H), 1.94 (m, 1H), 1.79 (m, 1H), 1.30-1.20 (m, 2H), 0.94 (br d , J = 6.3 Hz, 2H), 0.68 (br d, J = 4.6 Hz, 2H)

MS(ES): m/z 356.95 [M+H]+.

Example 29

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,8-diazaspiro[4.5]decan-8-yl)thieno[3,2-d]pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,8-diazaspiro[4.5]decan-8-yl)thieno[3,2-d]pyrimidine-4 -Amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.46 (br s, 1H), 9.24 (br s, 2H), 8.28 (br s, 1H), 7.48 (br s, 1H), 6.24 (br s, 1H), 3.96-3.80 (m, 5H), 3.30-3.25 (m, 2H), 3.08 (br t, J = 5.6 Hz, 2H), 2.08 (s, 2H), 1.99 (m, 1H), 1.92- 1.85 (m, 2H), 1.79-1.64 (m, 4H), 1.03-0.95 (m, 2H), 0.74-0.66 (m, 2H)

MS(ES): m/z 395.90 [M+H]+

Example 30

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-morpholinopiperidin-1-yl)thieno [3,2-d]pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-morpholinopiperidin-1-yl)thieno [3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), 9.66 (br s, 1H), 7.91 (br d, J = 5.3 Hz, 1H), 7.06 (d, J = 5.3 Hz) , 1H), 6.22 (br s, 1H), 4.67 (br d, J = 12.5 Hz, 2H), 3.59-3.52 (m, 4H), 2.91-2.80 (m, 2H), 1.95 (m, 1H), 1.82 (br d, J = 10.6 Hz, 2H), 1.39-1.27 (m, 2H), 0.95 (br d, J = 6.3 Hz, 2H), 0.71-0.64 (m, 2H)

MS(ES): m/z 425.97 [M+H]+.

Example 31

1-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propan-2-ol

1-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propane -2-all

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.67 (br s, 1H), 7.92 (br d, J = 5.4 Hz, 1H), 7.07 (d, J = 5.4 Hz) , 1H), 6.21 (br s, 1H), 4.32 (d, J = 4.0 Hz,1H), 3.86 (m, 1H), 3.73-3.67 (m, 4H), 2.48-2.45 (m, 4H), 2.32 -2.18 (m, 2H), 1.96 (m, 1H), 1.07 (d, J = 6.1 Hz, 3H), 0.95 (br d, J = 6.8 Hz, 2H), 0.70-0.64 (m, 2H)

MS(ES): m/z 400.00 [M+H]+.

Example 32

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)-3-methylpiperidin-4-yl)ethan-1 -ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)-3-methylpiperidine- 4-yl) ethane-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.69 (s, 1H), 9.73 (m, 1H), 7.90 (t, J = 5.3 Hz, 1H), 7.05 (dd , J = 5.3, 8.3 Hz, 1H), 6.24 (br s, 1H), 4.66 (br d, J = 12.8 Hz, 1H), 4.57 (br d, J = 12.0 Hz, 1H), 4.46-4.26 (m , 2H), 3.53-3.40 (m, 2H), 3.23 (m, 1H), 3.08 (m, 1H), 2.83 (m, 1H), 1.94-1.72 (m, 3H), 1.51-1.35 (m, 2H) ), 1.21 (m, 1H), 0.99-0.91 (m, 3H), 0.81 (d, J = 6.8 Hz, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z

MS(ES): m/z 399.06 [M+H]+

Example 33

4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)butan-2-ol

4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) butan-2-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.64 (br s, 1H), 7.90 (br d, J = 5.1 Hz, 1H), 7.06 (d, J = 5.3 Hz) , 1H), 6.23 (br s, 1H), 4.65 (br d, J = 12.5 Hz, 2H), 4.32 (dd, J = 1.4, 4.6 Hz, 1H), 3.60 (m, 1H), 3.33-3.32 ( m, 2H), 2.81 (br t, J = 12.1 Hz, 2H), 1.95 (m, 1H), 1.70 (br d, J = 11.9 Hz, 2H), 1.47 (br s, 1H), 1.40-1.14 ( m, 7H), 1.11-1.02 (m, 5H), 0.95 (br d, J = 6.88 Hz, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z 413.05 [M+H]+

Example 34

2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (br s, 1H), 9.65 (s, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.35-7.24 (m, 2H), 7.24 -7.15 (m, 3H), 7.06 (d, J = 5.4 Hz, 1H), 6.20 (s, 1H), 4.64 (br d, J = 12.9 Hz, 2H), 2.79 (br t, J = 11.7 Hz, 2H), 2.63-2.52 (m, 2H), 1.93 (m, 1H), 1.80 (ddd, J = 3.8, 7.3, 10.9 Hz, 1H), 1.61 (br d, J = 11.0 Hz, 2H), 1.19- 1.08 (m, 2H), 0.97-0.89 (m, 2H), 0.69-0.59 (m, 2H)

MS(ES): m/z 431.95 [M+H]+

Example 35

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-2-methylpropan-1 -ol

3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) -2-methylpropan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.64 (br s, 1H), 7.90 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.22 (br s, 1H), 4.65 (br d, J = 12.9 Hz, 2H), 4.38 (t, J = 5.3 Hz, 1H), 3.30 (m, 1H), 3.22 (m, 1H), 2.89-2.77 (m, 2H), 1.94 (m, 1H), 1.77-1.56 (m, 4H), 1.31 (m, 1H), 1.14-0.91 (m, 5H), 0.86 (d, J = 6.6 Hz, 3H), 0.70-0.62 (m, 2H)

MS(ES): m/z 413.98 [M+H]+

Example 36

2-(4-(2-aminoethyl)piperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(4-(2-aminoethyl)piperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidine-4 -Amine

^1H NMR (400 MHz, DMSO- d6 ) δ 13.79 (m, 1H), 11.61 (m, 1H), _10.62 (br dd, J = 4.8, 11.6 Hz, 1H), 8.32 (m, 1H), 8.03 (br s, 2H), 7.67 (m, 1H), 6.35 (m, 1H), 4.71-4.54 (m, 2H), 3.20-3.08 (m, 2H), 2.89-2.80 (m, 2H), 1.96 ( ddd, J = 4.9, 8.3, 13.3 Hz, 1H), 1.86-1.69 (m, 3H), 1.60-1.49 (m, 2H), 1.29-1.17 (m, 2H), 1.02-0.95 (m, 2H), 0.70 (br s, 2H)

MS(ES): m/z 384.18 [M+H]+

Example 37

3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propanenitrile

3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)propane nitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), 9.69 (br s, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.08 (d, J = 5.4 Hz, 1H), 6.21 (br s, 1H), 3.76-3.69 (m, 4H), 2.75-2.70 (m, 2H), 2.64-2.59 (m, 2H), 2.56 (m, 1H), 2.49 (m, 1H) ), 1.95 (m, 1H), 0.95 (br d, J = 6.9 Hz, 2H), 0.72-0.64 (m, 2H)

MS(ES): m/z 395.21 [M+H]+

Example 38

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3,2-d]pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3,2-d]pyrimidine-4 -Amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.65 (br s, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.23 (br s, 1H), 4.64 (br d, J = 12.4 Hz, 2H), 3.58 (br t, J = 4.1 Hz, 4H), 2.84 (br t, J = 11.9 Hz, 2H), 2.37-2.31 (m, 4H), 2.13 (br d, J = 6.9 Hz, 2H), 1.95 (m, 1H), 1.84-1.70 (m, 3H), 1.06 (q, J = 10.4 Hz, 2H), 0.95 (br d, J = 7.5 Hz, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z 440.02 [M+H]+.

Example 39

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl)thieno [3,2-d]pyrimidin-4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl)thieno [3,2-d]pyrimidine-4 -Amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (br s, 1H), 9.77 (br s, 1H), 7.92 (br d, J = 5.1 Hz, 1H), 7.11 (d, J = 5.4 Hz) , 1H), 6.43 (br s, 1H), 5.53 (m, 1H), 3.89-3.69 (m, 3H), 3.65 (br d, J = 12.3 Hz, 1H), 3.59 (m, 1H), 2.32- 2.08 (m, 2H), 1.98 (m, 1H), 0.94 (br d, J = 7.4 Hz, 2H), 0.73-0.66 (m, 2H)

MS(ES): m/z 344.92 [M+H]+.

[Reaction Scheme 1-2]

Reagents and conditions: (a) diisopropylethylamine, isopropyl alcohol, 80 °C, 24 h; (b) Amine, 165 °C, 2.5 h, tetrahydrofuran, microwave reactor

Example 40

2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.23 (br s, 1H), 10.15 (br s, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 6.38 (br s, 1H), 3.83 (m, 1H), 2.30-2.23 (m, 3H), 2.13-2.04 (m, 2H), 1.79-1.68 (m, 2H), 1.67 (m, 1H) ), 1.49-1.34 (m, 4H), 1.32 (m, 1H)

MS(ES): m/z 346.18 [M+H]+.

In Examples 41 to 61 below, the compounds were synthesized in the same manner as in Example 40, or were prepared using appropriate reactants in consideration of Scheme 1-2 and the structure of the compound to be prepared.

Example 41

2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.25 (br s, 1H), 10.14 (br s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.27 (d, J = 5.4 Hz, 1H), 6.34 (br s, 1H), 3.87 (br t, J = 10.2 Hz, 1H), 2.26 (s, 3H), 2.19 (br d, J = 13.0 Hz, 2H), 1.86-2.13 (m, 4H), 1.75-1.62 (m, 2H)

MS(ES): m/z 383.11 [M+H]+.

Example 42

2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.22 (br s, 1H), 10.13 (br s, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.25 (d, J = 5.4 Hz, 1H), 6.37 (br s, 1H), 3.69 (br t, J = 10.9 Hz, 1H), 2.27 (s, 3H), 2.00-1.91 (m, 2H), 1.64-1.52 (m, 2H), 1.48 -1.38 (m, 2H), 1.38-1.26 (m, 2H), 0.93 (d, J = 3.00 Hz, 6H)

MS(ES): m/z 373.91 [M+H]+.

Example 43

2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (br s, 1H), 10.08 (br s, 1H), 8.08 (br d, J = 4.4 Hz, 1H), 7.24 (br d, J = 5.3) Hz, 1H), 6.27 (br s, 1H), 3.82 (m, 1H), 2.08-2.02 (m, 2H), 1.99 (m, 1H), 1.79-1.68 (m, 2H), 1.65 (m, 1H) ), 1.50-1.36 (m, 4H), 1.34 (m, 1H), 0.95 (br d, J = 6.9 Hz, 2H), 0.72 (br d, J = 4.3 Hz, 2H)

MS(ES): m/z 371.89 [M+H]+.

Example 44

2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.24 (s, 1H), 10.08 (s, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.25 (br d, J = 5.1 Hz, 1H ), 6.37 (s, 1H), 3.84 (m, 1H), 2.66-2.60 (m, 2H), 2.06 (br s, 1H), 1.78-1.69 (m, 2H), 1.60 (br d, J = 12.5 Hz, 1H), 1.49-1.34 (m, 4H), 1.34 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H)

MS(ES): m/z 356.89 [M+H]+.

Example 45

2-(cyclohexylthio)-N-(5-cyclopentyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-cyclopentyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (br s, 1H), 10.09 (br s, 1H), 8.09 (br d, J = 5.3 Hz, 1H), 7.25 (d, J = 5.4 Hz) , 1H), 6.37 (br s, 1H), 3.85 (m, 1H), 3.13 (m, 1H), 2.13-1.99 (m, 4H), 1.79-1.55 (m, 8H), 1.51-1.33 (m, 4H), 1.29 (br d, J = 11.1 Hz, 1H)

MS(ES): m/z 399.81 [M+H]+.

Example 46

2-(cyclohexylthio)-N-(1,5-dimethyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

2-(cyclohexylthio)-N-(1,5-dimethyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (br s, 1H), 10.48 (br s, 1H), 8.19 (br s, 1H), 7.34 (br s, 1H), 6.23 (br s, 1H), 1.97 (m, 1H), 0.95 (br d, J = 8.0 Hz, 2H), 0.71 (br d, J = 4.4 Hz, 2H)

MS(ES): m/z 359.79 [M+H]+.

Example 47

N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine

N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (s, 1H), 10.06 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 7.25 (d, J = 1.0 Hz, 1H) , 6.34 (s, 1H), 3.81 (t, J = 1.0 Hz, 1H), 2.04 (br d, J = 9.9 Hz, 2H), 1.71 (br d, J = 8.6 Hz, 2H), 1.62 (m, 1H), 1.49-1.38 (m, 4H), 1.31 (s, 9H)

MS(ES): m/z 387.39 [M+H]+

Example 48

2-(cyclohexylthio)-N-(4-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(4-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 8.35 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), _7.36 (d, J = 5.5 Hz, 1H), 5.68 (s, 2H) , 3.90 (m, 1H), 2.15-2.05 (m, 2H), 1.99 (s, 3H), 1.80-1.70 (m, 2H), 1.66 (m, 1H), 1.54-1.46 (m, 4H), 1.38 (m, 1H)

MS(ES): m/z 345.61 [M+H]+.

Example 49

2-(cyclohexylthio)-N-(5-(cyclopropylmethyl)-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-(cyclopropylmethyl)-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.26 (br s, 1H), 10.12 (br s, 1H), 8.09 (br d, J = 4.8 Hz, 1H), 7.25 (br d, J = 5.1 Hz, 1H), 6.42 (br s, 1H), 3.83 (m, 1H), 2.55 (br s, 2H), 2.09-2.05 (m, 2H), 1.74-1.71 (m, 2H), 1.62 (m, 1H), 1.50-1.37 (m, 4H), 1.02 (br d, J = 6.4 Hz, 1H), 0.50 (br d, J = 7.5 Hz, 2H), 0.22 (br d, J = 4.6 Hz, 2H)

MS(ES): m/z 385.63 [M+H]+.

Example 50

N-(5-cyclohexyl-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine

N-(5-cyclohexyl-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.25 (br s, 1H), 10.10 (br s, 1H), 8.08 (br d, J = 4.6 Hz, 1H), 7.24 (br d, J = 4.0) Hz, 1H), 6.36 (br s, 1H), 3.85 (m, 1H), 2.10-2.03 (m, 2H), 2.00-1.93 (m, 2H), 1.82-1.65 (m, 6 H), 1.64 ( m, 1H), 1.49-1.27 (m, 11H)

MS(ES): m/z 413.74 [M+H]+.

Example 51

2-(cyclohexylthio)-N-(5-isopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-isopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (br s, 1H), 10.09 (br s, 1H), 8.09 (br d, J = 4.3 Hz, 1H), 7.25 (br d, J = 5.1 Hz, 1H), 6.36 (br s, 1H), 3.86 (m, 1H), 2.98 (m, 1H), 2.10-2.02 (m, 2H), 1.76-1.68 (m, 2H), 1.63 (m, 1H) ), 1.50-1.35 (m, 4H), 1.27 (br d, J = 6.9 Hz, 6H)

MS(ES): m/z 373.78 [M+H]+.

Example 52

2-(cyclohexylthio)-N-(5-phenyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-phenyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.07 (br s, 1H), 10.29 (br s, 1H), 8.12 (br d, J = 5.0 Hz, 1H), 7.78 (br d, J = 7.3 Hz, 2H), 7.53-7.42 (m, 2H), 7.39 (m, 1H), 7.28 (br d, J = 4.9 Hz, 1H), 7.03 (br s, 1H), 3.86 (m, 1H), 2.12 -2.02 (m, 2H), 1.72-1.61 (m, 2H), 1.52-1.27 (m, 6 H)

MS(ES): m/z 407.75 [M+H]+.

Example 53

2-(cyclohexylthio)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.07 (br s, 1H), 10.29 (br s, 1H), 8.12 (br d, J = 5.0 Hz, 1H), 7.78 (br d, J = 7.3 Hz, 2H), 7.53-7.42 (m, 2H), 7.39 (m, 1H), 7.28 (br d, J = 4.9 Hz, 1H), 7.03 (br s, 1H), 3.86 (m, 1H), 2.12 -2.02 (m, 2H), 1.72-1.61 (m, 2H),1.52-1.27 (m, 6H)

MS(ES): m/z 397.73 [M+H]+.

Example 54

2-(cyclohexylthio)-N-(5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.20 (br s, 1H), 10.08 (br s, 1H), 8.09 (br d, J = 4.5 Hz, 1H), 7.25 (br d, J = 5.3) Hz, 1H), 6.33 (br s, 1H), 3.84 (m, 1H), 2.11-1.99 (m, 2H), 1.78-1.67 (m, 2H), 1.60 (br d, J = 11.4 Hz, 1H) , 1.42 (s, 8 H), 1.30 (br s, 1H), 0.93 (br s, 2H), 0.78 (br s, 2H)

MS(ES): m/z 385.82 [M+H]+.

Example 55

2-(cyclohexylsulfonyl)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

2-(cyclohexylsulfonyl)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.38 (br s, 1H), 10.85 (br s, 1H), 8.35 (br d, J = 3.8 Hz, 1H), 7.58 (br d, J = 4.9) Hz, 1H), 6.48 (br s, 1H), 3.68 (br t, J = 11.2 Hz, 1H), 2.32-2.25 (m, 3H), 1.99 (br d, J = 12.1 Hz, 2H), 1.82 ( br d, J = 12.0 Hz, 2H), 1.66 (br d, J = 12.1 Hz, 1H), 1.45 (q, J = 12.3 Hz, 2H), 1.37-1.13 (m, 4H)

MS(ES): m/z 377.82 [M+H]+.

Example 56

2-(cyclohexylthio)-N-(1H-indazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(1H-indazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.91 (br s, 1H), 10.19 (br s, 1H), 8.09 (br d, J = 5.0 Hz, 1H), 7.55 (br d, J = 8.4) Hz, 2H), 7.38 (br t, J = 7.7 Hz, 1H), 7.27 (br d, J = 5.4 Hz, 1H), 7.10 (br t, J = 7.6 Hz, 1H), 3.46 (m, 1H) , 1.85 (br d, J = 10.6 Hz, 2H), 1.52 (br d, J = 11.5 Hz, 2H) 1.43 (br d, J = 11.5 Hz, 1H), 1.43 (br d, J = 11.5 Hz, 1H ), 1.31-1.19 (m, 4H), 1.19 (m, 1H), 1.01-0.89 (m, 2H)

MS(ES): m/z 381.72 [M+H]+.

Example 57

2-((cyclohexylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

2-((cyclohexylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.28 (br s, 1H), 10.06 (br s, 1H), 8.09 (br d, J = 5.3 Hz, 1H), 7.25 (br d, J = 5.1 Hz, 1H), 6.26 (br s, 1H), 3.06 (br d, J = 6.6 Hz, 2H), 1.97 (m, 1H), 1.85 (br d, J = 13.0 Hz, 2H), 1.68 (br d , J = 11.1 Hz, 2H), 1.65-1.47 (m, 2H), 1.23-1.10 (m, 3H), 1.07-0.98 (m, 2H), 0.95 (br d, J = 7.8 Hz, 2H), 0.71 (br d, J = 4.1 Hz, 2H)

MS(ES): m/z 385.69 [M+H]+.

Example 58

2-(cycloheptylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

2-(cycloheptylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (br s, 1H), 10.05 (br s, 1H), 8.09 (br s, 1H), 7.24 (br d, J = 5.0 Hz, 1H), 6.26 (br s, 1H), 4.01 (m, 1H), 2.13-2.03 (m, 2H), 1.96 (m, 1H), 1.73-1.62 (m, 4H), 1.61-1.48 (m, 6H), 0.96 (br d, J = 6.9 Hz, 2H), 0.76-0.66 (m, 2H)

MS(ES): m/z 385.76 [M+H]+.

Example 59

2-(benzylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-(benzylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.32 (br s, 1H), 10.12 (br s, 1H), 8.11 (br d, J = 4.6 Hz, 1H), 7.42 (br d, J = 7.4 Hz, 2H), 7.32-7.27 (m, 3H), 7.27 (m,1H), 6.22 (br s, 1H), 4.43 (s, 2H), 1.93 (m, 1H), 0.90 (br d, J = 6.8 Hz, 2H), 0.66-0.60 (m, 2H)

MS(ES): m/z 379.71 [M+H]+.

Example 60

2-((1-Cyclohexylethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-((1-cyclohexylethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.29 (br s, 1H), 10.07 (br s, 1H), 8.09 (br s, 1H), 7.25 (br d, J = 4.9 Hz, 1H), 6.24 (br s, 1H), 3.94 (m, 1H), 1.96 (m, 1H), 1.83 (br d, J = 11.5 Hz, 1H), 1.77-1.69 (m, 3H), 1.67-1.53 (m, 2H), 1.34 (br d, J = 6.9 Hz, 3H), 1.28-1.05 (m, 6H), 0.96 (br d, J = 6.6 Hz, 2H), 0.72-0.65 (m, 2H)

MS(ES): m/z 399.69 [M+H]+.

Example 61

2-((cyclopentylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

2-((cyclopentylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.28 (br s, 1H), 10.09 (br s, 1H), 8.09 (br d, J = 4.9 Hz, 1H), 7.25 (br d, J = 4.9) Hz, 1H), 6.28 (br s, 1H), 3.16 (d, J = 1.0 Hz, 2H), 2.23 (m, 1H), 1.98 (m, 1H), 1.86-1.74 (m, 2H), 1.67- 1.58 (m, 2H), 1.56-1.46 (m, 2H), 1.39-1.20 (m, 2H), 0.95 (br d, J = 6.4 Hz, 2H), 0.76-0.66 (m, 2H)

MS(ES): m/z 371.64 [M+H]+

[Scheme 1-3]

Reagents and conditions: (a) diisopropylethylamine, isopropyl alcohol, 80 °C, 24 h; (b) Amine, 165 °C, 2.5 h, tetrahydrofuran, microwave reactor

Example 62

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperidin-1-yl) methyl)thieno[3,2-d]pyrimidin-2-yl )piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d ]pyrimidin-2-yl)piperidin-4-yl)methanol

[Reaction Scheme 2-2]

Reagents and conditions: (a) 4-methylpiperidine, diisopropylethylamine, 1,2-dichloroethane, sodium triacetoxyborohydride, 40° C. to room temperature, 24 h; (b) sulfuryl chloride, acetonitrile, dichloromethane, 0°C; (c) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, 80°C, 24 h; (d) piperidine methanol, tetrahydrofuran, 170 °C, 2 h, microwave reactor

Production example 3

2-chloro-6- [(4-methyl-1-piperidyl) methyl] -4-methylsulfanyl-thieno[3, 2-d]pyrimidine

2-Chloro-6-((4-methylpiperidin-1-yl)methyl)-4-(methylthio)thieno[3,2-d]pyrimidine

2-Chloro-4-methylsulfanyl-thieno[3,2-d]pyrimidine-6-carbaldehyde (400 mg, 1.64 mmol), 4-methylpiperidine (243 mg, 2.45 mmol), diiso Propylethylamine (0.57 mL, 3.27 mmol) was dissolved in 5 mL of 1,2-dichloroethane and reacted at 40°C for 2 hours. The temperature was lowered to room temperature, sodium triacetoxyborohydride (693 mg, 3.27 mmol) was added, and reaction was performed at room temperature overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 280 mg (0.85 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 52.2%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 7.45 (s, 1H), 3.86 (s, 2H), 2.86 (br d, J = 10.5 Hz, 2H), 2.76-2.68 (m, 3H), 2.08 (br t, J = 11.4 Hz, 2H), 1.60 (br d, J = 12.8 Hz, 2H), 1.42 (m, 1H), 1.23-1.11 (m, 2H), 0.91 (br d, J = 6.4 Hz , 3H)

MS(ES): m/z 327.83 [M+H]+

Production example 4

2,4-dichloro-6- [(4-methyl-1-piperidyl) methyl] thieno [3, 2-d] pyrimidine

2,4-dichloro-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d]pyrimidine

2-Chloro-6-((4-methylpiperidin-1-yl)methyl)-4-(methylthio)thieno[3,2-d]pyrimidine (280 mg, 0.85 mmol) was dissolved in acetonitrile: It was dissolved in dichloromethane (5 mL: 2 mL) and stirred at 0°C for 10 minutes. Dissolve in 2 mL of dichloromethane at 0°C and add sulfuryl chloride. (0.35 mL, 4.27 mmol) was slowly added and reacted for 30 minutes. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 130 mg (0.41 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 48.1%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 7.60 (s, 1H), 3.91 (s, 2H), 2.88 (br d, J = 10.4 Hz, 2H), 2.12 (br t, J = 11.3 Hz, 2H), 1.61 (br d, J = 12.5 Hz, 2H), 1.38 (m, J = 3.7, 6.9 Hz, 1H), 1.27-1.13 (m, 3H), 0.92 (br d, J = 6.5 Hz, 3H) )

MS(ES): m/z 315.80 [M+H]+.

Production example 5

2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) -6- [(4-methyl-1-piperidyl) methyl] thieno [3, 2-d] pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d]pyrimidine -4-amine

2,4-dichloro-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d]pyrimidine (130 mg, 0.41 mmol), 5-cyclopropyl-1H-pyramidine Zol-3-amine (66 mg, 0.53 mmol) and diisopropylethylamine (0.36 mL, 2.06 mmol) were dissolved in 2 mL of isopropyl alcohol and reacted at 80°C overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 105 mg (0.26 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 63.4%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.39 (br s, 1H), 10.28 (br s, 1H), 7.18 (br s, 1H), 6.21 (br s, 1H), 3.75 (br s, 2H), 2.83 (br d, J = 10.0 Hz, 2H), 2.08 (s, 1H), 2.02 (br t, J = 11.3 Hz, 2H), 1.96 (m, 1H), 1.59 (br d, J = 12.8 Hz, 2H), 1.41 (m, 1H), 1.20-1.08 (m, 2H), 0.96 (br d, J = 7.0 Hz, 2H), 0.90 (br d, J = 6.3 Hz, 3H), 0.72 ( br d, J = 3.8 Hz, 2H)

MS(ES): m/z 403.22 [M+H]+.

Production example 6

[1- [4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] -6- [(4-methyl-1-piperidyl) methyl] thieno [3, 2-d] pyrimidin-2-yl ] -4-piperidyl] methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d ]pyrimidin-2-yl)piperidin-4-yl)methanol

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((4-methylpiperidin-1-yl)methyl)thieno[3,2-d]pyrimidine -4-amine (105 mg, 0.26 mmol) and piperidine methanol (45 mg, 0.39 mmol) were dissolved in 2 mL of tetrahydrofuran. Reaction was performed in a microwave reactor at 170 ^o C for 2 hours. After confirming that the reaction was complete, the solvent was removed under reduced pressure. 60 mg (0.12 mmol) of the target compound was prepared by purification through preparative thin layer chromatography (yield 47.8%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.46 (br s, 1H), 6.91 (s, 1H), 6.20 (br s, 1H), 4.64 (br d, J = 12.5 Hz, 2H), 4.49 (m, 1H), 3.67 (s, 2H), 3.29-3.22 (m, 4H), 2.82 (br d, J = 6.0 Hz, 3H), 1.98 (br t, J = 11.6 Hz, 2H), 1.93 (m, 1H), 1.68 (br d, J = 12.5 Hz, 2H), 1.58 (br d, J = 13.4 Hz, 2H), 1.41-1.29 (m, 2H), 1.21- 1.04 (m, 5H), 0.94 (br d, J = 7.0 Hz, 2H), 0.90 (br d, J = 6.3 Hz, 3H), 0.87-0.77 (m, 2H), 0.66 (br d, J = 3.8 Hz, 2H)

MS(ES): m/z 482.00 [M+H]+.

In Examples 63 to 68 below, the compounds were synthesized in the same manner as in Example 62, or were prepared using appropriate reactants in consideration of Scheme 2-2 and the structure of the compound to be prepared.

Example 63

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4,4-difluoropiperidin-1-yl)methyl)thieno[3,2-d]pyrimidin-2 -yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4,4-difluoropiperidin-1-yl)methyl)thieno[3 ,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.49 (br s, 1H), 6.95 (s, 1H), 6.20 (br s, 1H), 4.64 (br d, J = 13.1 Hz, 2H), 4.45 (br t, J = 5.3 Hz, 1H), 3.81(s, 2H), 3.28-3.23 (m, 4H), 2.81 (br t, J = 12.4 Hz, 2H), 2.03 -1.83 (m, 6H), 1.73-1.61 (m, 3H), 1.21-1.03 (m, 2H), 0.99-0.91 (m, 2H), 0.88-0.77 (m, 2H), 0.69-0.62 (m, 2H)

MS(ES): m/z 504.24 [M+H]+.

Example 64

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)piperidin-4- yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidine-2 -1)piperidine-4-1)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (br s, 1H), 9.45 (br s, 1H), 6.91 (s, 1H), 6.19 (br s, 1H), 4.64 (br d, J = 12.3 Hz, 2H), 4.48 (m, 1H), 3.81 (s, 2H), 2.81 (br t, J = 12.6 Hz, 2H), 1.79-1.61 (m, 8H), 1.12-1.05 (m, 2H) ), 0.99-0.92 (m, 2H), 0.88-0.82 (m, 2H), 0.68-0.62 (m, 2H)

MS(ES): m/z 454.33 [M+H]+

Example 65

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((3,3-difluoropyrrolidin-1-yl)methyl)thieno[3,2-d]pyrimidin-2 -yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((3,3-difluoropyrrolidin-1-yl)methyl)thieno[3 ,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.53 (br s, 1H), 6.95 (s, 1H), 6.19 (br s, 1H), 4.64 (br d, J = 12.6 Hz, 2H), 4.46 (t, J = 5.3 Hz, 1H), 3.88 (s, 2H), 3.29-3.25 (m, 4H), 2.95 (br t, J = 13.3 Hz, 2H), 2.86- 2.73 (m, 4H), 2.31-2.21 (m, 2H), 1.93 (m, 1H), 1.73-1.61 (m, 3H), 1.13-1.04 (m, 2H), 0.95 (br d, J = 7.9 Hz , 2H), 0.69-0.63 (m, 2H)

MS(ES): m/z 490.38 [M+H]+.

Example 66

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)piperidine-4- 1) Methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.46 (br s, 1H), 6.79 (s, 1H), 6.20 (br s, 1H), 4.64 (br d, J = 12.6 Hz, 2H), 4.48 (m, 1H), 3.29-3.24 (m, 2H), 2.80 (br t, J = 12.5 Hz, 2H), 1.94 (m, 1H), 1,73-1.58 (m , 3H), 1.16-1.01 (m, 2H), 1.00-0.91 (m, 2H), 0.70-0.62 (m, 2H)

MS(ES): m/z 384.69 [M+H]+.

Example 67

(1-(6-bromo-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(6-bromo-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.24 (br s, 1H), 9.70 (br s, 1H), 7.23 (s, 1H), 6.17 (br s, 1H), 4.64 (br d, J = 12.5 Hz, 2H), 4.51 (m, 1H), 3.30-3.24 (m, 2H), 2.83 (br t, J = 12.4 Hz, 2H), 1.95 (m, 1H), 1.75-1.57 (m, 3H) ), 1.17-1.01 (m, 2H), 0.96 (br d, J = 6.9 Hz, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z 448.70 [M+H]+.

Example 68

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl)ethan-1 -ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d] pyrimidin-2-yl)piperidine- 4-yl) ethane-1-ol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.45 (br s, 1H), 9.45 (br s, 1H), 6.78 (s, 1H), 6.19 (br s, 1H) ), 4.61 (br d, J = 12.5 Hz, 2H), 4.36 (br t, J = 4.6 Hz, 1H), 3.50-3.44 (m, 2H), 2.80 (br t, J = 12.3 Hz, 2H), 1.94 (m, 1H), 1.73-1.60 (m, 3H), 1.38 (q, J = 5.5 Hz, 2H), 1.14-1.01 (m, 2H), 0.95 (br d, J = 6.4 Hz, 2H), 0.66 (br d, J = 4.4 Hz, 2H)

MS(ES): m/z 398.68 [M+H]+.

Example 69

[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-6-(1-methylpyrazol-4-yl)thieno[3,2-d]pyrimidin-2-yl]-4 -piperidyl]methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Pyrimidin-2-yl)piperidin-4-yl)methanol

[Scheme 2-3]

Reagents and conditions: (a) 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, 6-bromo-2, 4-dichloro-thieno[3,2-d]pyrimidine, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), potassium carbonate, 1,4-dioxane: distilled water (10 :1), 65℃, 24h; (b) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, 80°C, 24 h; (c) Piperidinemethanol, tetrahydrofuran, 110°C, microwave reactor, 3h

Production example 7

2,4-Dichloro-6-(1-methylpyrazol-4-yl)thieno[3,2-d]pyrimidine

2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine

6-Bromo-2,4-dichloro-thieno[3,2-d]pyrimidine (2000 mg, 7.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (515 mg, 0.70 mmol), potassium carbonate (1425 mg, 14.09 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1759 mg, 8.45 mmol) 1,4-dioxane: was dissolved in distilled water (20 mL: 2 mL) and reacted at 65°C overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 1500 mg (5.26 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 74.7%).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.54 (s, 1H), _8.16 (s, 1H), 7.82 (s, 1H), 3.92 (s, 3H)

MS(ES): m/z 285.04 [M+H]+.

Production example 8

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(1-methylpyrazol-4-yl)thieno[3,2-d]pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- 4-amine

2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine (1500 mg, 5.26 mmol), 5-cyclopropyl-1H-pyrazole -3-amine (972 mg, 7.89 mmol) and diisopropylethylamine (9.16 mL, 52.6 mmol) were dissolved in 20 mL of isopropyl alcohol and reacted at 80°C overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 1000 mg (2.69 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 51.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.39 (br s, 1H), 10.38 (br s, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 6.22 (br s, 1H), 3.90 (s, 3H), 2.00 (m, 1H), 0.96 (br d, J = 7.0 Hz, 2H), 0.73 (d, J = 1.0 Hz, 2H)

MS(ES): m/z 372.02 [M+H]+.

Production example 9

[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-6-(1-methylpyrazol-4-yl)thieno[3,2-d]pyrimidin-2-yl]-4 -piperidyl]methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Pyrimidin-2-yl)piperidin-4-yl)methanol

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- 4-amine (600 mg, 1.61 mmol) and piperidine methanol (372 mg, 3.23 mmol) were dissolved in 4 mL of tetrahydrofuran. Reaction was performed at 110°C for 3 hours in a microwave reactor. After confirming that the reaction was complete, the solvent was removed under reduced pressure. 300 mg (0.67 mmol) of the target compound was prepared by recrystallization using methanol (yield 41.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (s, 1H), 9.58 (br s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.83 (s, 1H), 7.19 (s, 1H), 6.20 (s, 1H), 4.64 (d, J = 1.0 Hz, 2H), 4.46 (t, J = 1.0 Hz, 1H), 3.89 (s, 3H), 2.90-2.77 (m, 2H), 1.73-1.62 (m, 3H), 1.13-1.05 (m, 2H), 0.95 (br d, J = 7.3 Hz, 2H), 0.66 (br d, J = 4.5 Hz, 2H)

MS(ES): m/z 451.24 [M+H]+.

In Examples 70 to 80 below, the compounds were synthesized in the same manner as in Example 69, or were prepared using appropriate reactants in consideration of Scheme 2-3 and the structure of the compound to be prepared.

Example 70

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-phenylthieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-phenylthieno[3,2-d]pyrimidin-2-yl)piperidine-4- 1) Methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), 9.72 (br s, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.55-7.40 (m, 4H), 6.23 (br s, 1H), 4.68 (br d, J = 13.0 Hz, 2H), 4.47 (t, J = 5.2 Hz, 1H), 3.29-3.23 (m, 4H), 2.85 (br t, J = 12.3 Hz, 2H), 1.95 (m, 1H), 1.75-1.62 (m, 3H), 1.17-1.06 (m, 2H), 0.96 (br d, J = 7.1Hz, 2H), 0.70-0.64 (m, 2H) )

MS(ES): m/z 448.22 [M+H]+.

Example 71

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(4-(trifluoromethyl) phenyl)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(4-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidine- 2-yl)piperidine-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.21 (br s, 1H), 9.82 (br s, 1H), 7.97 (br d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.3 Hz) , 2H), 7.70 (s, 1H), 6.24 (br s, 1H), 4.68 (br d, J = 13.0 Hz, 2H), 4.47 (br t, J = 5.1 Hz, 1H), 3.30-3.26 (m , 2H), 2.86 (br t, J = 12.3 Hz, 2H), 1.96 (m, 1H), 1.76-1.64 (m, 3H), 1.17-1.06 (m, 2H), 0.96(br d, J = 7.0 Hz, 2H), 0.70-0.64 (m, 2H)

MS(ES): m/z 516.16 [M+H]+.

Example 72

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin- 2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)thieno[3 ,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), δ 9.70 (br s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.03 (m, 1H) , 7.39 (s, 1H), 6.22 (br s, 1H), 4.66 (br d, J = 12.5 Hz, 2H), 4.46 (t, J = 5.3 Hz, 1H), 3.30-3.24 (m, 2H), 2.84 (br t, J = 12.2 Hz, 2H), 1.95 (m, 1H), 1.77-1.60 (m, 3H), 1.19-1.04 (m, 2H), 0.96 (br d, J = 7.0 Hz, 2H) , 0.67 (br d, J = 4.6 Hz, 2H)

MS(ES): m/z 488.11 [M+H]+.

Example 73

(1-(6-(4-aminophenyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno [3,2-d]pyrimidin-2-yl)piperidin-4-yl) methanol

(1-(6-(4-aminophenyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno [3,2-d]pyrimidin-2-yl)p Peridin-4-yl) methanol

^1H NMR (400 MHz, DMSO- d6 ) δ 12.60 (s, 1H), _11.19 (s, 1H), 7.47 (br s, 1H), 7.30 (br s, 1H), 6.69 (br d, J = 7.0 Hz, 2H), 6.19 (s, 1H), 4.47-4.42 (m, 2H), 3.73-3.61 (m, 4H), 2.00 (m, 1H), 1.83-1.78 (m, 3H), 1.00 (br) d, J = 8.5 Hz, 2H), 0.69 (br d, J = 6.8 Hz, 2H)

MS(ES): m/z 462.59 [M+H]+.

Example 74

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)thieno[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)thi no[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d6 ) δ 12.87 (s, 1H), 12.52 (s, 1H), 8.93 ( _m , 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.05 ( br s, 1H), 7.36 (br s, 1H), 6.30 (m, 1H), 4.58 (br s, 1H), 4.50 (br s, 2H), 3.69 (br dd, J = 13.7, 4.8 Hz, 3H ), 3.11-3.06 (m, 5H), 2.28-2.13 (m, 5H), 1.98 (m, 1H), 1.84-1.78 (m, 3H), 0.99 (br d, J = 6.9 Hz, 2H), 0.69 (br d, J = 6.3 Hz, 2H)

MS(ES): m/z 520.44 [M+H]+.

Example 75

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thieno[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thi no[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.14 (s, 1H), 11.40 (s, 1H), 9.45 (br s, 1H), 9.39 (br s, 1H), 8.60 (br s, 1H) , 8.09 (br s, 1H), 7.45 (br s, 1H), 6.36 (s, 1H), 6.24 (br s, 1H), 5.27 (br s, 1H), 4.52 (br d, J = 11.6 Hz, 2H), 3.23-3.12 (m, 4H), 2.00 (m, 1H), 1.86-1.70 (m, 3H), 1.03-0.96 (m, 2H), 0.75-0.63 (m, 2H)

MS(ES): m/z 506.26 [M+H]+

Example 76

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thieno[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thi no[3,2- d]pyrimidin-2-yl)piperidin-4-yl)methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.58 (br s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.22 (s, 1H), 6.20 (br s, 1H), 5.14 (m, 1H), 4.65 (br d, J = 12.8 Hz, 2H), 4.45 (br t, J = 5.1 Hz, 1H),4.06-3.81 (m, 4H), 3.30-3.21 (m, 2H), 2.83 (br t, J = 12.3 Hz, 2H), 2.48-2.24 (m, 4H), 1.95 (m, 1H), 1.75-1.60 (m, 3H), 1.10 (q) , J = 10.6 Hz, 2H), 0.95 (br d, J = 7.5 Hz, 2H), 0.66 (br d, J = 5.0 Hz, 2H)

MS(ES): m/z 408.40 [M+H]+.

Example 77

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thieno[ 3,2-d] pyrimidin-2-yl) piperidin-4-yl) methanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.58 (br s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.22 (s, 1H), 6.20 (br s, 1H), 5.14 (m, 1H), 4.65 (br d, J = 12.8 Hz, 2H), 4.45 (br t, J = 5.1 Hz, 1H), 4.06-3.81 (m, 4H), 3.30-3.21 (m, 2H), 2.83 (br t, J = 12.3 Hz, 2H), 2.48-2.24 (m, 4H), 1.95 (m, 1H), 1.75-1.60 (m, 3H), 1.10 (q) , J = 10.6 Hz, 2H), 0.95 (br d, J = 7.5 Hz, 2H), 0.66 (br d, J = 5.0 Hz, 2H)

MS(ES): m/z 496.49 [M+H]+.

Example 78

2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6 -yl)-1H-pyrazol-1-yl)acetonitrile

2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6 -yl)-1H-pyrazol-1-yl)acetonitrile

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (br s, 1H), 9.63 (br s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.28 (s, 1H), 6.20 (br s, 1H), 5.76 (s, 1H), 5.54 (s, 2H), 4.66 (br d, J = 12.0 Hz, 2H), 4.46 (t, J = 5.3 Hz, 1H), 3.30-3.25 (m, 2H), 2.84 (br t, J = 12.3 Hz, 2H), 1.95 (m, 1H), 1.77-1.60 (m, 3H), 1.18-1.03 (m, 2H), 0.95 (br d, J = 7.1 Hz, 2H), 0.67 (d, J = 4.8 Hz, 2H)

MS(ES): m/z 476.07 [M+H]+.

Example 79

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-d]pyrimidin- 2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2 -d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.09 (br s, 1H), 7.33 (br s, 1H), 6.42 (s, 1H), 6.22 (s, 1H), 4.58-4.43 (m, 2H) ), 3.82 (br s, 2H), 3.76-3.67 (m, 2H), 3.31-3.29 (m, 2H), 3.21-3.06 (m, 2H), 2.72 (br s, 1H), 2.00 (m, 1H) ), 1.83-1.76 (m, 3H), 0.99 (br d, J = 7.8 Hz, 2H), 0.72-0.64 (m, 2H)

MS(ES): m/z 452.25 [M+H]+.

Example 80

4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) benzonitrile

4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) benzonitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.21 (br s, 1H), 9.85 (br s, 1H), 7.98-7.92 (m, 4H), 7.74 (s, 1H), 6.23 (br s, 1H), 4.67 (br d, J = 12.9 Hz, 2H), 4.47 (t, J = 5.1 Hz, 1H), 3.29-3.26 (m, 2H), 2.86 (br t, J = 12.0 Hz, 2H), 1.96 (m, 1H), 1.75-1.62 (m, 3H), 1.18-1.03 (m, 2H), 0.96 (br d, J = 6.9 Hz, 2H), 0.67 (br d, J = 4.6 Hz, 2H)

MS(ES): m/z 471.98 [M+H]+.

[Scheme 1-4]

Reagents and conditions: (a) tetramethylethylenediamine, n-butyllithium, acetone, tetrahydrofuran, -78°C to -40°C (b) sulfuryl chloride, acetonitrile, dichloromethane, 0°C; (c) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, 80°C, 24 h; (d) Piperidinemethanol, tetrahydrofuran, 100 °C, sealed tube, 24 h.

Example 81

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) propan-2-ol

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) propan-2-ol

[Scheme 2-4]

Reagents and conditions: (a) tetramethylethylenediamine, n-butyllithium, acetone, tetrahydrofuran, -78°C to -40°C; (b) sulfuryl chloride, acetonitrile, dichloromethane, 0°C; (c) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, 80°C, 24 h; (d) Piperidinemethanol, tetrahydrofuran, 100 °C, sealed tube, 24 h.

Production example 10

2- (2-Chloro-4-methylsulfanyl-thieno [3, 2-d] pyrimidin-6-yl) propan-2-ol

2-(2-chloro-4-(methylthio)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol

Dissolve 2-chloro-4-methylsulfanyl-thieno[3,2-d]pyrimidine (3000 mg, 13.84 mmol) in anhydrous tetrahydrofuran:tetramethylethylenediamine (30 mL:1.5 mL) - After stirring at 78°C, 2.5 M n-butyllithium hexane solution (11.07 mL, 27.69 mmol) was slowly added dropwise. After stirring at -40°C for 30 minutes, the temperature was lowered back to -78°C. Then acetone (2.14 mL, 27.69 mmol) was added. After reacting for 1 hour and confirming that the reaction was complete, the temperature was raised to 5°C and the reaction was stopped with 0.25 N hydrochloric acid. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 2200 mg (8.00 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 57.8%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.41 (s, 1H), 6.12 (br s, 1H), 2.72 (s, 3H), 1.58 (s, 6H)

Production example 11

2- (2, 4-Dichlorothieno [3, 2-d] pyrimidin-6-yl) propan-2-ol

2-(2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)propan-2-ol

2-(2-chloro-4-(methylthio)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol (2200 mg, 8.00 mmol) was reacted with acetonitrile:dichloromethane (15 mL:7 mL) and stirred at 0°C for 10 minutes. Sulfuryl chloride dissolved in dichloromethane at 0 °C. (5403 mg, 40.0 mmol) was slowly added and reacted for 30 minutes. After confirming that the reaction is complete, saturated sodium bicarbonate The reaction was stopped with an aqueous solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Purification was performed through medium pressure liquid chromatography to prepare 1200 mg (4.56 mmol) of the target compound (yield 57.0%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.59 (s, 1H), 6.27 (br s, 1H), 1.58 (s, 6H)

MS(ES): m/z 262.85 [M+H]+.

Production example 12

2- [2-chloro-4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] thieno [3, 2-d] pyrimidin-6-yl] propan-2-ol

2-(2-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol

2-(2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (970 mg, 3.69 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (545 mg, 4.42 mmol) and diisopropylethylamine (6.42 mL, 36.86 mmol) were dissolved in 10 mL of isopropyl alcohol and reacted at 80°C overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 600 mg (1.72 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 46.5%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 7.45 (s, 1H), 3.86 (s, 2H), 2.86 (br d, J = 10.5 Hz, 2H), 2.76-2.68 (m, 3H), 2.08 (br t, J = 11.4 Hz, 2H), 1.60 (br d, J = 12.8 Hz, 2H), 1.42 (m, 1H), 1.23-1.11 (m, 2H), 0.91 (br d, J = 6.4 Hz , 3H)

MS(ES): m/z 349.89 [M+H]+.

Production Example 13

2- [4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] -2- [4- (hydroxymethyl) -1-piperidyl] thieno [3, 2-d] pyrimidin-6-yl] propan -2-ol

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) propan-2-ol

2-(2-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol (600 mg, 1.72 mmol) and piperidine methanol (296 mg, 2.57 mmol) were dissolved in 6 mL of tetrahydrofuran. Reaction was performed overnight at 100°C in a sealed tube. After confirming that the reaction was complete, the solvent was removed under reduced pressure. It was purified through preparative thin layer chromatography and recrystallized from acetonitrile to prepare 350 mg (0.82 mmol) of the target compound (yield 47.6%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.46 (br s, 1H), 6.87 (s, 1H), 6.20 (br s, 1H), 5.64 (br s, 1H) ), 4.63 (br d, J = 12.6 Hz, 2H), 4.49 (m, 1H), 3.29-3.23 (m, 4H), 2.86-2.76 (m, 2H), 1.94 (m, 1H), 1.72-1.62 (m, 3H), 1.51 (s, 6H), 1.14-1.02 (m, 2H), 0.95 (br d, J = 4.6 Hz, 2H), 0.65 (br d, J = 4.4 Hz, 2H)

MS(ES): m/z 428.99 [M+H]+.

In Examples 82 to 97 below, the compounds were synthesized in the same manner as in Example 81, or were prepared using appropriate reactants in consideration of Scheme 2-4 and the structure of the compound to be prepared.

Example 82

tert-butyl 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyrimidin-2-yl) -2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

tert-Butyl 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyri midin-2-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.61 (br s, 1H), 6.91 (s, 1H), 6.29 (br s, 1H), 5.66 (s, 1H) , 4.77 (br s, 1H), 4.49 (m, 1H), 3.58 (m, 1H), 3.48 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 1.97-1.82 (m, 3H), 1.52 (s, 6H), 1.43-1.31 (m, 9H), 0.94 (br d, J = 6.8 Hz, 2H), 0.70-0.62 (m, 2H)

MS(ES): m/z 512.12 [M+H]+.

Example 83

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thie no[3,2-d]pyrimidin-2- yl)pyrrolidin-3-ol

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d] Pyrimidin-2-yl)pyrrolidin-3-ol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.03 (br s, 1H), 9.52 (br s, 1H), 6.90 (s, 1H), 6.43 (br s, 1H), 5.64 (s, 1H) , 4.90 (d, J = 3.3 Hz, 1H), 4.37 (br s, 1H), 3.64-3.50 (m, 3H), 3.50-3.36 (m, 2H), 2.06 (m, 1H), 1.95-1.83 ( m, 2H), 1.52 (s, 6H), 0.93 (br d, J = 7.0 Hz, 2H), 0.68 (br d, J = 4.6 Hz, 2H)

MS(ES): m/z 401.14 [M+H]+.

Example 84

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl)propan-2 -ol

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidine -6-day) Propane-2-ol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (br s, 1H), 9.48 (br s, 1H), 6.88 (s, 1H), 6.18 (br s, 1H), 5.64 (s, 1H) , 4.64 (br d, J = 12.5 Hz, 2H), 3.58-3.53 (m, 4H), 2.89-2.77 (m, 2H), 1.94 (m, 1H), 1.80 (br d, J = 12.8 Hz, 2H) ), 1.51 (s, 6H), 1.38-1.29 (m, 2H), 0.94 (br d, J = 7.9 Hz, 2H), 0.66 (br d, J = 5.0 Hz, 2H)

MS(ES): m/z 484.45 [M+H]+.

Example 85

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(morpholinomethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) propan-2-ol

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3,2- d]pyrimidin-6-yl) propan-2-ol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.10 (br s, 1H), 9.46 (br s, 1H), 6.87 (s, 1H), 6.19 (br s, 1H), 5.64 (s, 1H) , 4.61 (br d, J = 12.6 Hz, 2H), 4.44 (br t, J = 5.0 Hz, 1H), 3.60-3.55 (m, 4H), 2.82 (br t, J = 12.2 Hz, 2H), 2.35 -2.31 (m, 4H), 2.13 (br d, J = 6.9 Hz, 2H), 1.94 (m, 1H), 1.84-1.69 (m, 3H), 1.51 (s, 6 H), 1.10-1.00 (m , 2H), 0.94 (br d, J = 6.8 Hz, 2H), 0.66 (br d, J = 4.8 Hz, 2H)

MS(ES): m/z 498.32 [M+H]+.

Example 86

2-(2-(4-((1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino )thieno[3,2-d]pyrimidin-6-yl)propan-2-ol

2-(2-(4-((1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazole- 3-yl)amino)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol

^1H NMR (400 MHz, DMSO- d6 ) δ 12.11 (s, 1H), 9.48 (s, 1H), _8.12 (s, 1H), 7.73 (s, 1H), 6.88 (s, 1H), 6.19 ( br s, 1H), 5.64 (br s, 1H), 4.61 (br d, J = 13.1 Hz, 2H), 4.31 (br d, J = 6.9 Hz, 2H), 2.22-2.07 (m, 2H), 1.94 -1.83 (m, 2H), 1.51 (s, 6 H), 0.93 (br d, J = 7.9 Hz, 2H), 0.63 (d, J = 1.0 Hz, 2H)

MS(ES): m/z 480.36 [M+H]+.

Example 87

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiophen-2-ylmethyl)piperidin-1-yl)thieno[3,2-d]pyrimidin- 6-yl)propan-2-ol

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiophen-2-ylmethyl)piperidin-1-yl)thieno[3 ,2-d]pyrimidin-6-yl)propan-2-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.45 (br s, 1H), 7.33 (d, J = 5.0 Hz, 1H), 6.95 (t, J = 4.4 Hz, 1H), 6.83-6.90 (m, 2H), 6.19 (br s, 1H), 5.64 (s, 1H), 4.61 (br d, J = 13.3 Hz, 2H), 2.86-2.73 (m, 5H), 1.95 (m, 1H), 1.80 (m, 1H), 1.83 (m, 1H), 1.68 (br d, J = 11.8 Hz, 2H), 1.51 (s, 6H), 1.21-1.07 (m, 2H), 0.93 (br d, J = 7.1 Hz, 2H), 0.64 (br d, J = 3.8 Hz, 2H)

MS(ES): m/z 495.42 [M+H]+.

Example 88

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiazol-2-ylmethyl)piperidin-1-yl)thieno[3,2-d]pyrimidin- 6-yl)propan-2-ol

2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiazol-2-ylmethyl)piperidin-1-yl)thieno[3 ,2-d]pyrimidin-6-yl)propan-2-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (br s, 1H), 9.47 (br s, 1H), 7.72 (d, J = 3.4 Hz, 1H), 7.58 (d, J = 3.4 Hz, 1H), 6.87 (s, 1H), 6.19 (br s, 1H), 5.64 (s, 1H), 4.61 (br d, J = 13.5 Hz, 2H), 2.95 (br d, J = 6.9 Hz, 2H) , 2.83 (t, J = 1.0 Hz, 2H), 2.07 (m, 1H), 1.94 (m, 1H), 1.68 (br d, J = 11.1 Hz, 2H), 1.51 (s, 6 H), 1.23- 1.13 (m, 2H), 0.93 (br d, J = 6.9 Hz, 2H), 0.64 (br d, J = 4.4 Hz, 2H)

MS(ES): m/z 496.30 [M+H]+.

Example 89

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin -1-yl)thieno[3,2-d]pyrimidin-6-yl)methanol

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyri midin-6-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.51 (br s, 1H), 6.88 (s, 1H), 6.21 (br s, 1H), 5.68 (br s, 1H) ), 4.71-4.59 (m, 3H), 4.49 (m, 1H), 3.30-3.24 (m, 2H), 2.81 (br t, J = 12.2 Hz, 2H), 1.96 (m, 1H), 1.75-1.57 (m, 3H), 1.08 (q, J = 10.8 Hz, 2H), 0.99-0.90 (m, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z 400.76 [M+H]+

Example 90

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) ethan-1-ol

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) ethane-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.49 (br s, 1H), 6.87 (s, 1H), 6.19 (br s, 1H), 5.77 (br s, 1H) ), 4.96 (br s, 1H), 4.63 (br d, J = 13.1 Hz, 2H), 4.48 (t, J = 5.2 Hz, 1H), 2.87-2.74 (m, 2H), 1.93 (m, 1H) , 1.73-1.63 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.13-1.02 (m, 2H), 0.95 (br d, J = 7.5 Hz, 2H), 0.68-0.63 (m, 2H)

MS(ES): m/z 415.38 [M+H]+.

Example 91

3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) oxetan-3-ol

3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) oxetan-3-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (s, 1H), 9.57 (s, 1H), 7.20 (s, 1H), 6.90 (s, 1H), 6.21 (s, 1H), 4.78- 4.71 (m, 4H), 4.66 (br d, J = 12.5 Hz, 2H), 4.46 (t, J = 5.1 Hz, 1H), 2.83 (br t, J = 12.1 Hz, 2H), 1.95 (m, 1H) ), 1.74-1.60 (m, 3H), 1.15-1.03 (m, 2H), 0.96 (br d, J = 8.4 Hz, 2H), 0.66 (br d, J = 4.4 Hz, 2H)

MS(ES): m/z 443.11 [M+H]+.

Example 92

cyclopropyl(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl)methanol

Cyclopropyl(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.49 (br s, 1H), 6.94 (s, 1H), 6.21 (br s, 1H), 5.77 (br s, 1H) ), 4.64 (br d, J = 12.4 Hz, 2H), 4.46 (br t, J = 5.3 Hz, 1H), 4.25 (m, 1H), 2.85-2.77 (m, 2H), 1.89 (br t, J = 4.4 Hz, 1H), 1.72-1.55 (m, 4H), 1.17-1.03 (m, 3H), 0.95 (br d, J = 7.1 Hz, 2H), 0.68-0.61 (m, 2H), 0.54-0.47 (m, 2H), 0.47-0.40 (m, 2H)

MS(ES): m/z 442.42 [M+H]+.

Example 93

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) propan-1-ol

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) propan-1-ol

^1H NMR (400 MHz, DMSO- d6 ) δ 12.13 (br s, 1H), _9.48 (br s, 1H), 6.87 (s, 1H), 6.18 (s, 1H), 5.74 (br d, J = 4.5 Hz, 1H), 4.76 (m, 1H), 4.64 (br d, J = 12.8 Hz, 2H), 4.46 (br t, J = 5.2 Hz, 1H), 3.29-3.25 (m, 4H), 2.81 ( br t, J = 12.2 Hz, 2H), 1.94 (m, 1H), 1.74-1.62 (m, 5H),1.14-1.05 (m, 2H), 0.95 (br d, J = 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H), 0.68-0.63 (m, 2H)

MS(ES): m/z 430.32 [M+H]+.

Example 94

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) -2-phenylethan-1-ol

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)-2-phenylethan-1-ol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.51 (br s, 1H), 7.30-7.16 (m, 5H), 6.80 (s, 1H), 6.19 (br s, 1H), 5.93 (br d, J = 3.9 Hz, 1H), 5.08 (m,1H), 4.63 (br d, J = 12.9 Hz, 2H), 4.46 (br t, J = 5.1 Hz, 1H), 3.29 -3.23 (m, 4H), 3.01 (br d, J = 6.4 Hz, 2H), 2.84-2.74 (m, 2H), 1.95 (m, 1H), 1.75-1.60 (m, 3H), 1.13-1.02 ( m, 2H), 0.95 (br d, J = 7.0 Hz, 2H), 0.69-0.62 (m, 2H)

MS(ES): m/z 491.64 [M+H]+.

Example 95

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-methoxypropan-2-yl)thieno[3,2-d]pyrimidin-2-yl)piperidin- 4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-methoxypropan-2-yl)thieno[3,2-d]pyrimidine- 2-day)piperidine- 4-day)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.54 (br s, 1H), 6.96 (s, 1H), 6.19 (br s, 1H), 4.64 (br d, J = 12.8 Hz, 2H), 4.46 (t, J = 5.3 Hz, 1H), 3.29-3.22 (m, 4H), 3.08 (s, 3H), 2.82 (br t, J = 12.3 Hz, 2H), 1.95 ( m, 1H), 1.73-1.62 (m, 3H), 1.54 (s, 6H), 1.14-1.03 (m, 2H), 0.95 (br d, J = 7.5 Hz, 2H), 0.68-0.63 (m, 2H) )

MS(ES): m/z 399.18 [M+H]+.

Example 96

2-[4-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-6-(1-hydroxy-1-methyl-ethyl)thieno[3,2-d]pyrimidin-2- yl]pyrazol-1-yl]-2-methyl-propanenitrile

2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyri midin-2-yl) -1H-pyrazol-1-yl) -2-methylpropanenitrile

2-[2-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-6-yl]propan-2-ol (15 mg, 0.043 mmol ), 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propanenitrile (16.80 mg, 0.064 mmol), [ 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.14 mg, 0.0043 mmol), potassium carbonate (8.68 mg, 0.086 mmol) was dissolved in 1,4-dioxane:distilled water (5:1 = 2 mL:0.4 mL). Reaction was performed at 170°C for 2 hours in a microwave reactor. After confirming that the reaction was complete, the reaction was stopped with sodium bicarbonate and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and water and extracted. The extracted organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. 5 mg (0.011 mmol) of the target compound was prepared by purification through preparative thin layer chromatography (yield 26%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.23 (br s, 1H), 9.92 (s, 1H), 8.43 (br s, 1H), 8.14 (s, 1H), 7.18 (s, 1H), 6.48 (m, 1H), 5.80 (s, 1H), 4.47 (m, 1H), 2.06 (s, 6H), 1.98 (m, 1H), 1.56 (s, 6H), 0.97 (br d, J = 7.8 Hz, 2H), 0.77 (br d, J = 3.8 Hz, 2H)

MS(ES): m/z 449.35 [M+H]+.

Example 97

4-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyrimidin-2-yl) -1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide

4-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyri midin-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (s, 1H), 9.84 (s, 1H), 8.37 (br s, 1H), 8.01 (s, 1H), 7.16 (s, 1H), 6.41 (s, 1H), 5.78 (s, 1H), 4.79 (t, J = 1.0 Hz, 1H), 3.74 (t, J = 12.8 Hz, 1H), 3.61 (br d, J = 13.1 Hz, 1H), 2.21-2.13 (m, 2H), 2.02- 1.88 (m, 2H), 1.56 (s, 6 H), 0.97 (br d, J = 10.4 Hz, 2H), 0.76 (br d, J = 5.5 Hz, 2H) )

MS(ES): m/z 514.39 [M+H]+.

Example 98

4-[(5-cyclopropyl-1H-pyrazol-3-yl) amino] -2- [4- (hydroxymethyl) -1-piperidyl] -N-methyl-thieno [3, 2-d] pyrimidine-6-carboxamide

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N-methylthieno[3,2- d]pyrimidine-6-carboxamide

[Scheme 2-5]

Scheme: Reagents and conditions: (a) sodium carbonate, methyl iodide, dimethylformamide, rt, 24 h; (b) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, 80°C, 24 h; (c-1) sodium hydroxide, tetrahydrofuran:distilled water:methanol (5:1:0.5), rt, 5h; (c-2) Methylamine hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, diisopropylethylamine, dimethylformamide, rt, 24 h; (d) Piperidinemethanol, tetrahydrofuran, 110°C, microwave reactor, 3h

Production Example 15

Methyl 2, 4-dichlorothieno [3, 2-d] pyrimidine-6-carboxylate

Methyl 2,4-dichlorothieno[3,2-d]pyrimidine-6-carboxylate

2,4-dichlorothieno[3,2-d]pyrimidine-6-carboxylic acid (500 mg, 2.00 mmol), sodium carbonate (319 mg, 3.01 mmol) was dissolved in 2 mL of dimethylformamide, and then methyl iodide (0.19 mL, 3.01 mmol) was added. The reaction was performed overnight at room temperature. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Purification was performed through medium pressure liquid chromatography to prepare 400 mg (1.52 mmol) of the target compound (yield 75.7%).

^1H NMR (400 MHz _, DMSO- d6 ) δ 8.37 (s, 1H), 3.98 (s, 3H)

MS(ES): m/z 262.66 [M+H]+.

Production example 16

Methyl 2-chloro-4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] thieno [3, 2-d] pyrimidine-6-carboxylate

Methyl 2-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxylate

Methyl 2,4-dichlorothieno[3,2-d]pyrimidine-6-carboxylate (307 mg, 1.17 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (216 mg, 1.75 mmol) ), diisopropylethylamine (2.03 mL, 11.67 mmol) was dissolved in 2 mL of isopropyl alcohol and reacted at 80°C overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 250 mg (0.71 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 61.3%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.98 (m, 1H), 11.38 (m, 1H), _8.11 (m, 1H), 6.60 (m, 1H), 3.95-3.84 (m, 3H), 2.03 (m, 1H), 1.04-0.91 (m, 2H), 0.79-0.66 (m, 2H)

MS(ES): m/z 350.02 [M+H]+.

Production Example 17

2-chloro-4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] -N-methyl-thieno [3, 2-d] pyrimidine-6-carboxamide

2-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylthieno[3,2-d] pyrimidine-6-carboxamide

Methyl 2-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidine-6-carboxylate (600 mg, 1.71 mmol), Sodium hydroxide (103 mg, 2.57 mmol) was dissolved in tetrahydrofuran:distilled water:methanol (5 mL:1 mL:0.5 mL) and reacted at room temperature for 5 hours. After confirming that the reaction was complete, some of the solvent was removed under reduced pressure. 37% hydrochloric acid is slowly added to the concentrate and then filtered with water to obtain an intermediate. Intermediate (600 mg, 1.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (514 mg, 2.68 mmol), hydroxybenzotriazole (338 mg, 2.50 mmol), diisopropylethyl Amine (0.62 mL, 3.57 mmol) and methylamine hydrochloride (181 mg, 2.68 mmol) were dissolved in 30 mL of dimethylformamide, and the reaction proceeded at room temperature overnight. After confirming that the reaction was complete, the reaction was stopped with saturated aqueous ammonium chloride solution and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and distilled water and extracted. The extracted organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Purification was performed through medium pressure liquid chromatography to prepare 420 mg (1.20 mmol) of the target compound (yield 67.4%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (br s, 1H), 7.85 (s, 1H), 6.26 (br s, 1H), 2.01 (m, 1H), 1.03-0.91 (m, 2H) ), 0.78-0.70 (m, 2H)

MS(ES): m/z 335.78 [M+H]+.

Production Example 18

4-[(5-cyclopropyl-1H-pyrazol-3-yl) amino] -2- [4- (hydroxymethyl) -1-piperidyl] -N-methyl-thieno [3, 2-d] pyrimidine-6-carboxamide

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N-methylthieno[3,2- d]pyrimidine-6-carboxamide

2-Chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylthieno[3,2-d]pyrimidine-6-carboxamide (500 mg, 1.43 mmol), piperidine methanol (330 mg, 2.87 mmol) was dissolved in 4 mL of tetrahydrofuran. The reaction was performed in a microwave reactor at 110°C for 3 hours. After confirming that the reaction was complete, the solvent was removed under reduced pressure. 350 mg (0.82 mmol) of the target compound was prepared by recrystallization using methanol (yield 57.1%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.23 (br s, 1H), 9.83 (br s, 1H), 8.69 (br d, J = 4.1 Hz, 1H), 7.60 (s, 1H), 6.21 (br s, 1H), 4.64 (br d, J = 12.5 Hz, 2H), 4.49 (br t, J = 4.9 Hz, 1H), 3.30-3.25 (m, 2H), 2.89-2.77 (m, 6H) , 1.96 (m, 1H), 1.70 (m, 3H), 1.16-1.02 (m, 2H), 0.95 (br d, J = 7.3 Hz, 2H), 0.66 (br d, J = 4.9 Hz, 2H)

MS(ES): m/z 427.99 [M+H]+.

In Examples 99 to 103 below, the compounds were synthesized in the same manner as in Example 98, or were prepared using appropriate reactants in consideration of Scheme 2-5 and the structure of the compound to be prepared.

Example 99

methyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxylate

Methyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyri Mydine-6-carboxylate

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (br s, 1H), 9.98 (br s, 1H), 7.64 (s, 1H), 6.22 (br s, 1H), 4.66 (br d, J = 12.8 Hz, 2H), 4.48 (t, J = 5.1 Hz, 1H), 3.87 (s, 3H), 3.30-3.25 (m, 2H), 2.85 (br t, J = 12.3 Hz, 2H), 1.95 ( m, 1H), 1.75-1.60 (m, 3H), 1.17-1.02 (m, 2H), 0.96 (br d, J = 6.8 Hz, 2H), 0.70-0.63 (m, 2H)

MS(ES): m/z 430.32 [M+H]+.

Example 100

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl) ethan-1-one

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl) ethane-1-one

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.26 (br s, 1H), 9.98 (br s, 1H), 7.97 (m, 1H), 6.23 (br s, 1H), 4.66 (br d, J = 12.9 Hz, 2H), 4.51 (m, 1H), 3.27 (br t, J = 4.7 Hz, 2H), 2.86 (br t, J = 12.5 Hz, 2H), 2.64-2.59 (m, 3H), 2.57 (br s, 1H), 1.95 (m, 1H), 1.70 (br d, J = 12.3 Hz, 3H), 1.15-1.04 (m, 2H), 0.96 (br d, J = 7.9 Hz, 2H), 0.71 -0.62 (m, 2H)

MS(ES): m/z 413.30 [M +H]+

Example 101

(S)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6- yl)(3-fluoropyrrolidin-1-yl)methanone

(S)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2 -d]pyrimidin-6- yl)(3-fluoropyrrolidin-1-yl)methanone

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.28 (m, 1H), 9.89 (m, 1H), 7.51 (br d, J = 18.8 Hz, 1H), 6.21 (br s, 1H), 5.50 ( m, 1H), 4.66 (br d, J = 12.8 Hz, 2H), 4.48 (t, J = 5.2 Hz, 1H), 4.16-3.86 (m, 2H), 3.83-3.66 (m, 2H), 2.85 ( br t, J = 12.1 Hz, 2H), 1.95 (m, 1H), 1.75-1.61 (m, 3H), 1.14-1.10 (m, 2H), 0.96 (d, J = 1.0 Hz, 2H), 0.67 ( d, J = 1.0 Hz, 2H)

MS(ES): m/z 486.09 [M+H]+.

Example 102

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl) piperidin-1-yl)thieno[3,2-d]pyrimidin-6-yl)(pyrrolidin -1-yl)methanone

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2-d]pyri midin-6-yl)(pyrrolidin-1-yl)methanone

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.22 (br s, 1H), 9.80 (br s, 1H), 7.45 (s, 1H), 6.21 (br s, 1H), 4.66 (br d, J = 12.8 Hz, 2H), 4.47 (t, J = 5.1 Hz, 1H), 3.76 (br t, J = 6.4 Hz, 2H), 3.50 (br t, J = 6.7 Hz, 3H), 3.30-3.23 (m , 3H), 2.84 (br t, J = 12.3 Hz, 2H), 1.97-1.82 (m, 5H), 1.76-1.60 (m, 3H), 1.18-1.02 (m, 2H), 0.96 (br d, J = 7.0 Hz, 2H), 0.70-0.61 (m, 2H)

MS(ES): m/z 469.33 [M+H]+.

Example 103

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N,N-dimethylthieno[3,2-d]pyrimidine-6- carboxamide

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N,N-dimethylthieno[3, 2-d]pyrimidine-6-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.21 (br s, 1H), 9.79 (br s, 1H), 7.33 (s, 1H), 6.21 (br s, 1H), 5.76 (s, 1H) , 4.66 (br d, J = 12.8 Hz, 2H), 4.46 (t, J = 5.2 Hz, 1H), 3.30-3.26 (m, 2H), 3.17 (br s, 3H), 3.02 (br s, 3H) , 2.85 (br t, J = 12.4 Hz, 2H), 1.94 (m, 1H), 1.75-1.59 (m, 3H), 1.17-1.02 (m, 2H), 0.96 (br d, J = 7.0 Hz, 2H ), 0.70-0.64 (m, 2H)

MS(ES): m/z 443.3 [M+H]+.

Example 104

2-[[2-chloro-6-(1-hydroxy-1-methyl-ethyl)thieno[3,2-d]pyrimidin-4-yl]amino]-N-methyl-benzamide

2-((2-chloro-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-N-methylbenzamide

[Scheme 2-6]

Reagents and conditions: (a) 2-amino-N-methylbenzamide, sodium iodide, tetraethylamine, dimethylformamide, 80 °C, 24 h; (b) piperidin-4-ylmethanol, tetrahydrofuran, microwave reactor, 110°C, 3h

Production Example 19

2-[[2-chloro-6-(1-hydroxy-1-methyl-ethyl)thieno[3,2-d]pyrimidin-4-yl]amino]-N-methyl-benzamide

2-[[2-chloro-6-(1-hydroxy-1-methyl-ethyl)thieno[3,2-d]pyrimidin-4-yl]amino]-N-methyl-benzamide

2-(2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (50 mg, 0.19 mmol), 2-amino-N-methylbenzamide (57.07 mg, 0.38 mmol), sodium iodide (8.54 mg, 0.057 mmol), and tetraethylamine (0.053 mL, 0.38 mmol) were dissolved in dimethylformamide (2 mL) and reacted at 80°C for 12 hours. After confirming that the reaction was complete, the reaction was stopped with distilled water and diluted with ethyl acetate solvent. The organic layer was washed with ethyl acetate and water and extracted. The extracted organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. 30 mg (0.080 mmol) of the target compound was prepared by purification through medium pressure liquid chromatography (yield 42%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (s, 1H), 8.87 (br s, 1H), 8.62 (br d, J = 8.4 Hz, 1H), 7.83 (br d, J = 8.0 Hz) , 1H), 7.62 (br t, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.21 (br t, J = 7.4 Hz, 1H), 6.06 (s, 1H), 2.84 (d, J = 4.4 Hz, 3H), 1.60 (s, 6H)

MS(ES): m/z 377.06 [M+H]+.

Production example 20

2-[[6-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]thieno[3,2-d]pyrimidin-4-yl]amino]-N- methyl-benzamide

2-((2-(4-(hydroxymethyl)piperidin-1-yl)-6-(2-hydroxypropan-2-yl)thieno [3,2-d]pyrimidine-4- I)amino)-N-methylbenzamide

2-[[2-Chloro-6-(1-hydroxy-1-methyl-ethyl)thieno[3,2-d]pyrimidin-4-yl]amino]-N-methyl-benzamide (10 mg , 0.027 mmol) and piperidin-4-ylmethanol (9.17 mg, 0.080 mmol) were dissolved in tetrahydrofuran (2 mL). Reaction was performed at 110°C for 3 hours in a microwave reactor. After confirming that the reaction was complete, the solvent was removed under reduced pressure. 5 mg (0.011 mmol) of the target compound was prepared by purification through preparative thin layer chromatography (yield 41%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.70 (s, 1H), 8.70-8.85 (m, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 5.81 (s, 1H), 4.65 (br d, J = 12.9 Hz, 2H), 4.49 (m, 1H), 3.29 -3.22 (m, 2H), 2.93-2.81 (m, 4H), 1.80-1.61 (m, 3H), 1.56 (s, 3H), 1.19-1.01 (m, 2H), 0.90 (m, 1H)

MS(ES): m/z 456.41 [M+H]+.

[Scheme 1-5]

Reagents and conditions: (a) diisopropylethylamine, isopropyl alcohol, 80 °C, 24 h; (b) Amine, tetrahydrofuran, 165 °C, microwave reactor, 2.5 h

Example 105

(1-(4- ((5-cyclopropyl-1H-pyrazol-3-yl) amino) benzo [4, 5] thieno [3, 2-d] pyrimidin-2-yl) piperidin-4-yl) methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol

[Scheme 2-7]

Reagents and conditions: (a) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60 °C, 15 h; (b) piperidin-4-ylmethanol, methylpyrrolidone, 180 °C, microwave reactor, 2 h

Production example 21

2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) benzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine

2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d] pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine (1 g. 3.92 mmol) After dissolving in 10 mL of dimethylformamide, 5-cyclopropyl-1H-pyrazol-3-amine (483 mg, 3.92 mmol) and diisopropylethylamine (1.2 mL, 7.25 mmol) were added, and the mixture was incubated at 60 °C. Stirred at ℃ for 15 hours. Afterwards, the reactant was cooled to room temperature and an excess amount of water was added to precipitate the solid. After filtering out this solid, it was washed with water and dried. If additional purification was necessary, the precipitated solid was filtered using ethyl acetate and n-hexane and dried to prepare 1.2 g of the target compound (yield 90.7%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.44 (br s, 1H), 10.60 (br s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.14 (br d, J = 8.1 Hz) , 1H), 7.73 (m, 1H), 7.64 (m, 1H), 6.30 (br s, 1H), 2.01 (m, 1H), 1.04-0.91 (m, 2H), 0.83-0.67 (m, 2H)

MS(ES): m/z 342.02 [M+H]+

Example 105

(1-(4- ((5-cyclopropyl-1H-pyrazol-3-yl) amino) benzo [4, 5] thieno [3, 2-d] pyrimidin-2-yl) piperidin-4-yl) methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine (40 mg, 0.12 mmol) After dissolving methylpyrrolidone in 1.5 mL, piperidin-4-ylmethanol (40 mg, 0.35 mmol) was added, and the mixture was stirred in a microwave reactor at 180°C for 2 hours. After cooling the reaction to room temperature, ethyl acetate was added, and the organic layer was washed several times with a saturated aqueous ammonium chloride solution. The product obtained by drying with anhydrous magnesium sulfate, filtering and concentrating was purified through preparative thin layer chromatography to prepare 33 mg of the target compound (yield 67.1%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.20 (br s, 1H), 9.74 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H ), 7.58 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 6.26 (br s, 1H), 4.80 (br d, J = 12.9 Hz, 2H), 4.48 (t , J = 5.3 Hz, 1H), 3.30 (br t, J = 5.7 Hz, 3H), 2.91 (br t, J = 11.7 Hz, 2H), 1.97 (m, 1H), 1.78-1.71 (m, 2H) , 1.71 (m, 1H), 1.20-1.07 (m, 2H), 0.97 (br d, J = 6.6 Hz, 2H), 0.72-0.63 (m, 2H)

MS(ES): m/z 421.43 [M+H]+

In Examples 106 to 110 below, the compounds were synthesized in the same manner as in Example 105, or were prepared using appropriate reactants in consideration of Scheme 2-7 and the structure of the compound to be prepared.

Example 106

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl) propan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperi din-4-yl) propan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.31 (br s, 1H), 10.17 (br s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.61 (m, 1H), 6.31 (br s, 1H), 3.86 (br s, 1H), 3.33-3.32 (m, 6H), 2.22-2.06 (m, 2H), 1.98 (m, 1H), 1.83-1.70 (m, 2H), 1.64 (br d, J = 12.1 Hz, 1H), 1.55-1.40 (m, 3H), 1.37 (m, 1H) , 0.97 (br d, J = 7.9 Hz, 2H), 0.74 (br d, J = 4.9 Hz, 2H)

MS(ES): m/z 449.10 [M+H]+

Example 107

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl) acetonitrile

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperi din-4-yl) acetonitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (br s, 1H), 9.78 (br s, 1H), 8.19 (br dd, J = 7.8, 3.6 Hz, 1H), 7.99 (br dd, J = 8.0, 4.1 Hz, 1H), 7.53-7.75 (m, 1H), 7.47 (td, J = 7.4, 4.1 Hz, 1H), 6.34 (m, 1H), 4.81 (br d, J = 12.6 Hz, 2H) ), 3.05-2.89 (m, 2H), 2.57-2.53 (m, 2H), 2.00-1.86 (m, 3H), 1.86-1.75 (m, 2H), 1.24 (br s, 3H), 1.02-0.91 ( m, 2H), 0.73-0.63 (m, 2H)

MS(ES): m/z 430.19 [M+H]+

Example 108

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl) ethan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperi din-4-yl) ethane-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (br s, 1H), 9.73 (br s, 1H), 8.18 (br d, J = 7.4 Hz, 1H), 7.99 (br d, J = 7.9 Hz, 1H), 7.65 (m, 1H), 7.52 (m, 1H), 6.31 (br s, 1H), 5.76 (s, 1H), 4.64 (br d, J = 12.3 Hz, 2H), 4.46 (m , 1H), 3.59-3.50 (m, 2H), 2.99 (br t, J = 10.9 Hz, 1H), 2.76-2.64 (m, 2H), 1.97-1.83 (m, 2H), 1.76-1.58 (m, 2H), 1.54-1.33 (m, 3H), 1.23 (m, 1H), 0.96 (br d, J = 6.5 Hz, 2H), 0.77-0.66 (m, 2H)

MS(ES): m/z 435.11 [M+H]+

Example 109

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl) -2-methylpropan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperi din-4-yl) -2-methylpropan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.19 (br s, 1H), 9.72 (br s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.63 (m, 1H), 7.47 (t, J = 7.5 Hz, 1H), 6.29 (br s, 1H), 5.76 (s, 1H), 4.90 (br d, J = 12.5 Hz, 2H), 4.47 (t, J = 5.3 Hz, 1H), 3.19 (dd, J = 9.9, 5.3 Hz, 3H), 2.80 (br t, J = 11.8 Hz, 2H), 1.98 (m, 1H), 1.71 (br d , J = 11.6 Hz, 2H), 1.57 (br t, J = 12.0 Hz, 1H), 1.25-1.14 (m, 2H), 0.97 (br d, J = 6.9 Hz, 2H), 0.77 (s, 6 H) ), 0.73-0.65 (m, 2H)

MS(ES): m/z 463.28 [M+H]+

Example 110

2-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2 -d]pyrimidin-4-amine

2-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno [3,2 -d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.20 (br s, 1H), 9.83 (br s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 6.35 (br s, 1H), 5.76 (s, 1H), 4.66 (br s, 2H), 2.02 (m, 1H), 1.85-1.66 (m, 4H), 1.50 (br d, J = 6.9 Hz, 4H), 0.98 (br d, J = 6.9 Hz, 2H), 0.84-0.62 (m, 2H)

MS(ES): m/z 403.03 [M+H]+

Example 111

2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

[Scheme 2-8]

Reagents and conditions: (a) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60 °C, 15 h; (b) piperidin-4-ylmethanol, methylpyrrolidone, 180 °C, microwave reactor, 2 h

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.31 (br s, 1H), 10.17 (br s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.61 (m, 1H), 6.31 (br s, 1H), 3.86 (br s, 1H), 3.33-3.32 (m, 6H), 2.22-2.06 (m, 2H), 1.98 (m, 1H), 1.83-1.70 (m, 2H), 1.64 (br d, J = 12.1 Hz, 1H), 1.55-1.40 (m, 3H), 1.37 (m, 1H) , 0.97 (br d, J = 7.9 Hz, 2H), 0.74 (br d, J = 4.9 Hz, 2H)

MS(ES): m/z 422.19 [M+H]+

Example 112

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl)ethan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

[Scheme 2-9]

Reagents and conditions: (a) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60 °C, 15 h; (b) piperidin-4-ylmethanol, methylpyrrolidone, 180 °C, microwave reactor, 2 h

Production example 22

2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzofuro[3,2-d]pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzofuro[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.31 (br s, 1H), 10.80 (br s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.86 (m, 1H), 7.78 ( m, 1H), 7.58 (m, 1H), 6.36 (s, 1H), 2.00 (m, 1H), 1.00-0.93 (m, 2H), 0.77-0.70 (m, 2H)

MS(ES): m/z 326 [M+H]+

Production example 23

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl)ethan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Ethan-1-ol

^1H NMR (400 MHz, DMSO- d6 ) δ 12.24 (m, 1H), 10.05 (m, 1H), 7.97 ₍ d, J = 7.8 Hz, 1H), 7.69-7.57 (m, 2H), 7.47 ( m, 1H), 6.33 (br s, 1H), 4.59 (br dd, J = 3.9, 8.6 Hz, 2H), 4.47 (m, 1H), 3.57-3.50 (m, 3H), 3.01-2.88 (m, 2H), 2.73-2.61 (m, 2H), 1.96-1.81 (m, 2H), 1.75-1.57 (m, 2H), 1.53-1.33 (m, 3H), 1.21 (m, 1H), 0.98-0.91 ( m, 2H), 0.72-0.66 (m, 2H)

MS(ES): m/z 419.35 [M+H]+

In Examples 113 to 116 below, the compounds were synthesized in the same manner as in Example 112, or were prepared using appropriate reactants in consideration of Scheme 2-9 and the structure of the compound to be prepared.

Example 113

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.85-10.08 (m, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.75-7.53 (m, 2H) , 7.49 (m, 1H), 6.42 (m, 1H), 4.72 (br d, J = 12.8 Hz, 2H), 4.48 (t, J = 5.3 Hz, 1H), 3.31-3.27 (m, 2H), 2.94 -2.84 (m, 2H), 1.91 (ddd, J = 5.1, 8.5, 13.2 Hz, 1H), 1.74 (br d, J = 12.6 Hz, 2H), 1.70 (m, 1H), 1.21-1.08 (m, 2H), 1.02-0.89 (m, 2H), 0.72-0.61 (m, 2H)

MS(ES): m/z 405.30 [M+H]+

Example 114

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d] pyrimidin-2-yl)piperidin-4-yl)acetonitrile

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Acetonitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (br s, 1H), 9.88-10.12 (m, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.73-7.56 (m, 2H) , 7.41 (t, J = 7.4 Hz, 1H), 6.29 (br s, 1H), 4.73 (br d, J = 12.8 Hz, 2H), 2.93 (br t, J = 12.5 Hz, 2H), 2.55 (br d, J = 6.4 Hz, 2H), 1.98-1.85 (m, 2H), 1.80 (br d, J = 12.1 Hz, 2H), 1.33-1.19 (m, 3H), 0.96 (br d, J = 7.6 Hz) , 2H), 0.73-0.61 (m, 2H)

MS(ES): m/z 414.18 [M+H]+

Example 115

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d] pyrimidin-2-yl)piperidin-4-yl)propan-1-ol

2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl) propan-1-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.91 (br s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.77-7.56 (m, 2H), 7.40 (t, J = 7.1 Hz, 1H), 6.32 (br s, 1H), 4.77 (br d, J = 12.4 Hz, 2H), 4.41 (t, J = 5.2 Hz, 1H), 3.32-3.26 (m , 2H), 2.87-2.76 (m, 2H), 1.96 (m, 1H), 1.71-1.56 (m, 3H), 1.43 (td, J = 6.2, 12.3 Hz, 1H), 1.34-1.12 (m, 3H) ), 0.96 (br d, J = 6.6 Hz, 2H), 0.82 (d, J = 6.9 Hz, 3H), 0.71-0.64 (m, 2H)

MS(ES): m/z 433.22 [M+H]+

Example 116

2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzofuro [3,2-d]pyrimidin-4-amine

2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzofuro [3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, Methanol- d ₄ ) δ 8.08 (d, J = 7.6 Hz, 1H), 7.65-7.55 (m, 2H), 7.39 (ddd, J = 1.4, 6.7, 7.9 Hz, 1H), 7.33-7.16 (m, 6H), 6.34 (br s, 1H), 4.75 (br d, J = 13.1 Hz, 2H), 3.00-2.88 (m, 2H), 2.60 (d, J = 7.3 Hz, 2H) , 1.99-1.82 (m, 3H), 1.79-1.70 (m, 2H), 1.41-1.25 (m, 7H), 1.04-0.97 (m, 2H), 0.76-0.69 (m, 2H)

MS(ES): m/z 465.36 [M+H]+

Example 117

3-Cyclopentyl-3- (4- (4- ((5-cyclopropyl-1H-pyrazol-3-yl) amino) benzo [4, 5-b] thieno [3, 2-d] pyrimidine-2-yl) -1H-pyrazol-1-yl) propanenitrile

3-Cyclopentyl-3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidine-2 -yl)-1H-pyrazole-1-yl)propanenitrile

[Scheme 2-10]

Reagents and conditions: (a) boronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate, 1,4-dioxane, water, 130 °C, microwave reactor, 1 h.

2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine (50 mg, 0.15 mmol), 3-Cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile ( 92 mg, 0.29 mmol), sodium carbonate (47 mg, 0.44 mmol), and Pd (PPh ₃ ) ₄ (8 mg, 0.007 mmol) were placed in a sealed tube, filled with nitrogen gas, and then 1,4-dioxane 1 mL and 0.3 mL of water were added. The mixture was stirred in a microwave reactor at 130° C. for 1 hour. After the reaction was cooled to room temperature, ethyl acetate was added, and the organic layer was washed with water. The product obtained by drying with anhydrous magnesium sulfate, filtering and concentrating was purified through preparative thin layer chromatography to prepare 40 mg of the target compound (yield 55.3%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.29 (br s, 2H), 10.14 (br s, 2H), 8.53 (s, 2H), 8.38 (d, J = 7.6 Hz, 2H), 8.24- 8.06 (m, 4H), 7.75 (m, 1H), 7.64-7.53 (m, 2H), 6.52 (br s, 2H), 4.57 (td, J = 9.5, 4.3 Hz, 2H), 3.26-3.19 (m , 2H), 2.48 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.60-1.50 (m, 2H), 1.50 (m, 1H), 1.40- 1.29 (m, 2H), 1.29-1.16 (m, 2H), 1.00 (br d, J = 6.6 Hz, 2H), 0.79 (br d, J = 3.5 Hz, 4H)

MS(ES): m/z 495.29 [M+H]+

Example 118

(S) -N- (5-cyclopropyl-1H-pyrazol-3-yl) -2- (3-fluoropyrrolidin-1-yl) benzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl)benzo [4,5]thieno[3,2- d]pyrimidin-4-amine

[Scheme 2-11]

Reagents and conditions: a) (S)-3-fluoropyrrolidine, methylpyrrolidone, 180 °C, microwave reactor, 2 h

2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) benzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine (40 mg, 0.12 mmol) was reacted with methylpyrrolidone. After dissolving in 1.5 mL, (S)-3-fluoropyrrolidine (31 mg, 0.35 mmol) was added. The mixture was stirred in a microwave reactor at 180° C. for 2 hours and then cooled to room temperature. Ethyl acetate was added, and the organic layer was washed several times with a saturated aqueous ammonium chloride solution. The product obtained by drying with anhydrous magnesium sulfate, filtering and concentrating was purified through PTLC to prepare 20 mg of the target compound (yield 43.3%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.20 (m, 1H) _, 9.93 (m, 1H), 8.19 (br dd, J = 7.4, 3.4 Hz, 1H), 8.00 (br dd, J = 7.4 , 3.8 Hz, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 6.55 (m, 1H), 3.95-3.84 (m, 2H), 2.60-2.40 (m, 4H), 2.33-2.25 ( m, 3H), 2.23-2.13 (m, 2H), 1.96-1.88 (m, 2H), 0.99-0.90 (m, 3H), 0.72 (br d, J = 2.1 Hz, 2H)

MS(ES): m/z 395.21 [M+H]+

In Examples 119 to 132 below, the compounds were synthesized in the same manner as in Example 118, or were prepared using appropriate reactants in consideration of Scheme 2-11 and the structure of the compound to be prepared.

Example 119

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-ol

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)p Rolidin-3-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.80 (br s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.01 (m, 1H), 7.58 ( t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 6.47 (br s, 1H), 4.96 (br d, J = 3.1 Hz, 1H), 4.47 (m, 1H), 3.71-3.55 (m, 5H), 2.11 (m, 1H), 1.92 (ddd, J = 13.4, 8.5, 5.3 Hz, 2H), 1.00-0.92 (m, 2H), 0.74-0.67 (m, 2H)

MS(ES): m/z 392.94 [M+H]+

Example 120

(S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3- yl)methanol

(S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl) Pyrrolidin-3-yl)methanol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.79 (br s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.00 (br d, J = 8.0 Hz) , 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 6.48 (br s, 1H), 5.76 (s, 1H), 4.24 (br s, 1H) , 3.76 (m, 1H), 3.66-3.56 (m, 2H), 3.53-3.43 (m, 2H), 2.06-1.96 (m, 3H), 1.96-1.86 (m, 2H), 0.99-0.88 (m, 2H), 0.81-0.68 (m, 2H)

MS(ES): m/z 407.25 [M+H]+

Example 121

(R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-ol

(R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)p Rolidin-3-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.79 (br s, 1H), 8.18 (br d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.0 Hz) , 1H), 7.58 (br t, J = 7.4 Hz, 1H), 7.52 (m, 1H), 6.60 (m, 1H), 4.96 (br d, J = 3.0 Hz, 1H), 4.42 (br s, 1H) ), 3.75-3.54 (m, 5H), 2.12 (m, 1H), 1.98-1.87 (m, 2H), 0.96 (br d, J = 7.4 Hz, 2H), 0.71 (br d, J = 4.4 Hz, 2H)

MS(ES): m/z 393.13 [M+H]+

Example 122

(R)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

(R)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d ]Pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.81 (br s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.67 (m, 1H), 7.52 (m, 1H), 6.48 (br s, 1H), 5.76 (s, 1H), 4.13 (m, 1H), 3.73-3.68 (m, 3H), 3.64- 3.54 (m, 2H), 3.33-3.28 (m, 3H), 2.13-2.06 (m, 2H), 1.96 (m, 1H), 0.99-0.92 (m, 2H), 0.73-0.67 (m, 2H)

MS(ES): m/z 408.20 [M+H]+

Example 123

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d ]Pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.81 (br s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 6.56 (m, 1H), 4.11 (br t, J = 3.8 Hz, 1H), 3.76-3.66 (m, 4H), 3.63-3.54 (m, 2H), 3.31 (br d, J = 0.75 Hz, 3H), 2.13-2.06 (m, 2H), 1.95 (m, 1H), 0.96 (br d, J = 7.0 Hz, 2H), 0.73-0.67 (m, 2H)

MS(ES): m/z 408.34 [M+H]+

Example 124

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin- 4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thieno[3 ,2-d]pyrimidine-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (br s, 1H), 9.89 (br s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 6.45 (br s, 1H), 4.18 (m, 1H), 4.07-3.93 (m, 2H) , 3.88 (m, 1H), 3.70 (td, J = 7.0, 10.4 Hz, 1H), 3.09 (s, 3H), 2.47-2.40 (m, 2H), 1.96 (m, 1H), 0.95 (br d, J = 6.6 Hz, 2H), 0.76-0.68 (m, 2H)

MS(ES): m/z 455.27 [M+H]+

Example 125

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidine-3-carbonitrile

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)p Rolidine-3-carbonitrile

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.90 (br s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 6.42 (br s, 1H), 3.96 (br dd, J = 7.1, 10.8 Hz, 1H), 3.89 (m, 1H), 3.81 (m , 1H), 3.73 (m, 1H), 3.59 (td, J = 6.4, 12.6 Hz, 1H), 2.45-2.24 (m, 2H), 1.97 (m, 1H), 1.00-0.92 (m, 2H), 0.76-0.68 (m, 2H)

MS(ES): m/z 402.21 [M+H]+

Example 126

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin -4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)benzo[4,5]thieno [3,2-d]pyrimidine-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (br s, 1H), 9.96 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H ), 7.60 (t, J = 7.2 Hz, 1H), 7.53 (m, 1H), 6.42 (br s, 1H), 5.63 (m, 1H), 5.47 (m, 1H), 4.13-3.98 (m, 2H) ), 3.85-3.71 (m, 2H), 1.98 (m, 1H), 1.21 (m, 1H), 1.01-0.92 (m, 2H), 0.75-0.69 (m, 2H)

MS(ES): m/z 413.30 [M +H]+

Example 127

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidine-3-carboxamide

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)p Rollidine-3-carboxamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.82 (br s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.63-7.44 (m, 3H), 6.99 (br s, 1H), 6.50 (br s, 1H), 3.90 (m, 1H), 3.80 (m, 1H), 3.66-3.53 (m, 3H) , 3.07 (d, J = 7.7 Hz, 1H), 2.25-2.06 (m, 2H), 1.96 (m, 1H), 0.95 (br d, J = 7.0 Hz, 2H), 0.76-0.66 (m, 2H)

MS(ES): m/z 420.23 [M+H]+

Example 128

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)-N,N- dimethylpyrrolidine-3-carboxamide

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)- N,N-Dimethylpyrrolidine-3-carboxamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.74-9.98 (m, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 8.0 Hz) , 1H), 7.62 (m, 1H), 7.53 (m, 1H), 6.46 (br s, 1H), 3.94 (m, 1H), 3.80 (m, 1H), 3.69-3.51 (m, 3H), 3.20 -3.08 (m, 3H), 2.91-2.83 (m, 3H), 2.26-2.05 (m, 2H), 1.96 (m, 1H), 1.02-0.91 (m, 2H), 0.80-0.62 (m, 2H)

MS(ES): m/z 448.41 [M+H]+

Example 129

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)benzo[4,5] thieno[3,2-d]pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)benzo[4,5] thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (br s, 1H), 9.78 (br s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.99 (br d, J = 7.9 Hz) , 1H), 7.57 (br t, J = 7.4 Hz, 1H), 7.52 (m, 1H), 6.52 (br s, 1H), 3.61 (br s, 4H), 2.03-1.85 (m, 5H), 0.96 (br d, J = 6.6 Hz, 2H), 0.80-0.61 (m, 2H)

MS(ES): m/z 377.25 [M+H]+

Example 130

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-phenylpyrrolidin-1-yl)benzo [4,5]thieno[3,2-d]pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-phenylpyrrolidin-1-yl)benzo [4,5]thieno[3,2-d]pyrimidine- 4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.81 (br s, 1H), 8.19 (br d, J = 7.9 Hz, 1H), 7.99 (br d, J = 8.0 Hz, 1H), 7.58 (br t, J = 7.5 Hz, 1H), 7.50 (m, 1H), 7.42-7.33 (m, 4H), 7.31 (m, 1H), 6.51 (br s, 1H), 4.29 (m, 1H), 4.01 (m, 1H), 3.75 (m, 1H), 3.62-3.49 (m, 2H), 2.46 (m, 1H), 2.23 (m, 1H), 2.01 (m, 1H), 1.00-0.85 (m, 2H), 0.66 (br s, 2H)

MS(ES): m/z 453.07 [M+H]+

Example 131

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)pyrrolidine-3-carboxylic acid

1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3 -carboxylic acid

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.31 (br s, 2H), 9.84 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H ), 7.58 (t, J = 7.2 Hz, 1H), 7.51 (m, 1H), 6.44 (s, 1H), 3.87-3.59 (m, 4H), 3.28 (m, 1H), 2.29-2.13 (m, 2H), 1.91 (tt, J = 5.0, 8.4 Hz, 1H), 1.00-0.90 (m, 2H), 0.77-0.65 (m, 2H)

MS(ES): m/z 421.18 [M+H]+

Example 132

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methylpyrrolidin-1-yl)benzo [4,5]thieno[3,2-d]pyrimidin-4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methylpyrrolidin-1-yl)benzo[4,5]thieno[3,2-d ]Pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (br s, 1H), 9.78 (br s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.59 Hz, 1H), 7.52 (m, 1H), 6.56 (m, 1H), 3.90-3.67 (m, 2H), 3.63 (m, 1H), 3.13 (dd, J = 7.75, 10.51 Hz, 1H), 2.43 (m, 1H), 2.19 (m, 1H), 1.95 (m, 1H), 1.62 (qd, J = 8.48, 11.96 Hz, 1H), 1.12 (d, J = 6.63Hz, 3H), 1.02-0.88 (m, 2H), 0.80-0.60 (m, 2H)

MS(ES): m/z 391.05 [M+H]+

Example 133

(1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol

[Scheme 2-12]

Reagents and conditions: a) 5-cyclopropyl-1H-thiazol-3-amine, diisopropylethylamine, dimethylformamide, 60° C., 15 h; b) Piperidin-4-ylmethanol, methylpyrrolidone, 180 °C, microwave reactor, 2 h

Manufacturing example 24

2-chloro-N-(5-cyclopropylthiazol-2-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

2-Chloro-N-(5-cyclopropylthiazol-2-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.00 (br s, 1H), 8.30 (d, J = 7.75 Hz, 1H), 8.15 (d, J = 8.13 Hz, 1H), 7.70 (dt, J = 1.19, 7.60 Hz, 1H), 7.64 (m, 1H), 7.25 (m, 1H), 5.76 (s, 1H), 2.07 (m, 1H), 1.00-0.93 (m, 2H), 0.78-0.72 ( m, 2H)

MS(ES): m/z 359.78 [M+H]+

Production example 25

(1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol

(1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol

17 mg of the target compound was prepared in the same manner (yield 46.5%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.21 (m, 1H), 8.22 (d, J = 7.38 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.61 (td, J = 7.57, 1.25 Hz, 1H), 7.52 (m, 1H), 7.53 (m, 1H), 7.16 (s, 1H), 4.95 (br d, J = 13.0 Hz, 2H), 4.50 (t, J = 5.3 Hz) , 1H), 3.44-3.38 (m, 2H), 3.33-3.29 (m, 2H), 3.13-2.96 (m, 2H), 2.09 (m, 1H) , 1.80 (br d, J = 12.76 Hz, 2H) , 1.77 (m, 1H), 1.00-0.93 (m, 2H), 0.73-0.66 (m, 2H)

MS(ES): m/z 438.32 [M+H]+

In Examples 134 to 136 below, the compounds were synthesized in the same manner as in Example 133, or were prepared using appropriate reactants in consideration of Scheme 2-12 and the structure of the compound to be prepared.

Example 134

N-(5-cyclopropylthiazol-2-yl)-2-(pyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

N-(5-cyclopropylthiazol-2-yl)-2-(pyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 11.89-12.17 (m, 1H), 8.20 (d, J = 7.75 Hz _, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.60 (dt, J = 1.13, 7.57 Hz, 1H), 7.54 (m, 1H), 7.14 (s, 1H), 3.72 (br s, 3H), 3.65 (m, 1H), 2.08-1.95 (m, 5H), 1.02- 0.89 (m, 2H), 0.76-0.66 (m, 2H)

MS(ES): m/z 394.08 [M+H]+

Example 135

(S)-1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)pyrrolidin-3-ol

(S)-1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d] pyrimidin-2-yl)pyrrolidine- 3-all

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.28 (m, 1H), 12.26 (m, 1H), 8.21 (d, J = 7.38 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H) , 7.60 (t, J = 7.61Hz, 1H), 7.50 (t, J = 7.52Hz, 1H), 7.20 (m, 1H), 5.00 (br s, 1H), 4.46 (br s, 1H), 3.92- 3.62 (m, 4H), 2.23 (m, 1H), 2.05-1.95 (m, 2H), 1.05-0.83 (m, 2H), 0.78-0.65 (m, 2H)

MS(ES): m/z 410.34 [M+H]+

Example 136

(S)-N-(5-cyclopropylthiazol-2-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

(S)-N-(5-cyclopropylthiazol-2-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo [4,5]thieno[3,2- d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.03-12.31 (m, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.9 Hz _, 1H), 7.71 (m, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 4.24-4.05 (m, 3H), 4.04-3.76 (m, 2H), 3.18-3.00 (m, 3H), 2.12 (m, 1H) , 1.05-0.84 (m, 2H), 0.81-0.62 (m, 2H)

MS(ES): m/z 472.29 [M+H]+

[Scheme 1-6]

Reagents and conditions: a) methyl 2-mercaptoacetate, KOtBu, dimethylformamide, 0 °C to rt, 2 h; b) sulfurisocyanatidic chloride, dichloromethane, 0 °C to rt, 2 h; c) Sodium hydroxide, water, 70 °C, 6 h; d) POCl3, 120 °C, 24 h; e) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60° C., 15 h; f) Methylpyrrolidone, 180 °C, microwave reactor, 2 h

Example 137

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-fluorobenzo[4,5] thieno[3, 2-d]pyrimidin-2-yl)pyrrolidin- 3-ol

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-fluorobenzo[4,5] thieno[3,2-d]pyrimidine- 2-yl) pyrrolidin-3-ol

[Scheme 2-13]

Reagents and conditions: a) methyl 2-mercaptoacetate, KOtBu, dimethylformamide, 0 °C to rt, 2 h; b) sulfurisocyanatidic chloride, dichloromethane, 0 °C to rt, 2 h; c) Sodium hydroxide, water, 70 °C, 6 h; d) POCl3, 120 °C, 24 h; e) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60° C., 15 h; f) Methylpyrrolidone, 180 °C, microwave reactor, 2 h

Production example 26

Methyl 3-amino-7-fluorobenzo [b] thiophene-2-carboxylate

Methyl 3-amino-7-fluorobenzo[b]thiophene-2-carboxylate

2, 3-difluorobenzonitrile (1 g, 7.19 mmol) was dissolved in 13 mL of dimethylformamide, and then methyl 2-mercaptoacetate (0.68 mL, 7.55 mmol) was added. After cooling to 0°C, potassium tert-butoxide (760 mg, 7.91 mmol) was added little by little. The mixture was slowly raised from 0°C to room temperature and stirred for 2 hours, and then an excess amount of water was added. The precipitated solid was filtered, washed with water, and dried to prepare 1.54 g of the target compound (yield 95.1%).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.03 (dd, J = 0.81, 7.82Hz, 1H), _7.54-7.34 (m, 3H), 7.29 (s, 2H), 3.81 (s, 3H)

MS(ES): m/z 225.53 [M+H]+

Manufacturing Example 27

6-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidine-2, 4 (1H, 3H) -dione

6-fluorobenzo[4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Methyl 3-amino-7-fluorobenzo [b] thiophene-2-carboxylate (1 g, 4.43 mmol) was dissolved in 40 mL of dichloromethane, and then sulfurisocyanatidic chloride (0.5 mL, 5.77 mmol) was slowly added thereto under nitrogen gas at 0°C. . The mixture was stirred for 2 hours while slowly rising from 0°C to room temperature and then concentrated. 30 mL of water was added, stirred at 70°C for 4 hours, and then cooled to room temperature. Sodium hydroxide (3.55 g, 88.79 mmol) was added and stirred again at 70°C for 2 hours. After the reaction was completed, it was cooled to room temperature and the pH was adjusted to 6 or less with 1 N hydrochloric acid. The precipitated solid was filtered, washed with distilled water and methanol, and dried to prepare 1.11 g of the target compound (yield 100%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.81 (br s, 1H), 7.85 (d, J = 7.75 Hz, 1H), 7.45-7.29 (m, 2H)

MS(ES): m/z 236.63 [M+H]+

Manufacturing Example 28

2, 4-dichloro-6-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidine

2,4-dichloro-6-fluorobenzo[4,5]thieno[3,2-d]pyrimidine

A mixture of 6-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidine-2, 4 (1H, 3H)-dione (500 mg, 2.12 mmol) and phosphoryl chloride (9.89 mL, 105.83 mmol). N,N-dimethylformamide (3 drops) was added and stirred at 120°C overnight. The reaction product was concentrated, diluted with ethyl acetate, and washed several times with potassium hydrogen carbonate. The product obtained by drying with anhydrous magnesium sulfate, filtering and concentrating was used in the next reaction without purification (138 mg, yield 23.9%).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.36 (dd _, J = 1.2, 7.7 Hz, 1H), 7.88-7.77 (m, 2H)

MS(ES): m/z 275.08 [M+H]+

Manufacturing Example 29

2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) -6-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluorobenzo[4,5] thieno[3,2-d]pyrimidin-4-amine

It was prepared in the same manner (yield 97.4%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.50 (br s, 1H), 10.96 (m, 1H), 8.14 ( _dd , J = 1.3, 7.3 Hz, 1H), 7.70-7.57 (m, 2H) , 6.30 (br s, 1H), 2.09 (m, 1H), 1.08-0.91 (m, 2H), 0.82-0.68 (m, 2H)

MS(ES): m/z 359.79 [M+H]+

Production example 30

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-fluorobenzo[4,5] thieno[3, 2-d]pyrimidin-2-yl)pyrrolidin- 3-ol

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-fluorobenzo[4,5] thieno[3,2-d]pyrimidine- 2-yl) pyrrolidin-3-ol

15 mg of the target compound was prepared in the same manner (yield 32.9%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (br s, 1H), 9.96 (br s, 1H), 8.03 (d, J = 7.38 Hz, 1H), 7.58-7.43 (m, 2H), 6.50 (br s, 1H), 4.96 (d, J = 3.38 Hz, 1H), 4.47 (m, 1H), 3.76-3.51 (m, 5H), 2.13 (m, 1H), 1.98-1.86 (m, 2H) ), 0.97 (br d, J = 6.38 Hz, 2H), 0.78-0.65 (m, 2H)

MS(ES): m/z 411.09 [M+H]+

In Example 138 below, it was synthesized in the same manner as Example 137, or was prepared using appropriate reactants in consideration of Scheme 2-13 and the structure of the compound to be prepared.

Example 138

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin -4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[ 3,2-d]pyrimidine -4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.19 (br s, 1H), 9.99 (br s, 1H), _8.03 (dd, J = 0.81, 7.6 Hz, 1H), 7.57-7.44 (m, 2H) ), 6.47 (br s, 1H), 4.19 (m, 1H), 3.78-3.66 (m, 3H), 3.65 (m, 1H), 3.31-3.27 (m, 3H), 2.15-2.06 (m, 2H) , 2.02 (m, 1H), 1.04-0.90 (m, 2H), 0.77-0.66 (m, 2H)

MS(ES): m/z 425.09 [M+H]+

Example 139

N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2- (pyrrolidin-1-yl)benzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(pyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyri Mydin-4-amine

[Scheme 2-14]

Reagents and conditions: a) methyl 2-mercaptoacetate, potassium carbonate, dimethylformamide, 0 °C to rt, 5 h; b) sulfurisocyanatidic chloride, dichloromethane, 0 °C to rt, 2 h; c) Sodium hydroxide, water, 70 °C, 6 h; d) POCl3, 120 °C, 24 h; e) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60° C., 15 h; f) pyrrolidine, methylpyrrolidone, 180 °C, microwave reactor, 2 h

Production example 31

Methyl 3-amino-5-fluorobenzo [b] thiophene-2-carboxylate

Methyl 3-amino-5-fluorobenzo[b]thiophene-2-carboxylate

2, 5-difluorobenzonitrile (1 g, 7.19 mmol) was dissolved in 13 mL of N, N -dimethylformamide, and then potassium carbonate (1.99 g, 14.38 mmol) was added. Methyl 2-mercaptoacetate (0.65 mL, 7.19 mmol) dissolved in 2 mL of N, N-dimethylformamide at 0 °C was slowly added under nitrogen gas. The mixture was stirred at 0°C for 3.5 hours and then at room temperature for 1.5 hours. After the reaction was completed, an excessive amount of water was added, and the precipitated solid was filtered and washed with water. The collected solid was dissolved in an excess of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The product was purified through medium pressure liquid chromatography to obtain the target compound. 392 mg was prepared (yield 24.2%).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.03 (dd, J = 2.4, 10.1 Hz, 1H), 7.89 (dd, J = 5.0, 8.9 Hz, 1H), 7.42 (dt _, J = 2.7, 8.9 Hz, 1H), 7.14 (s, 2H), 3.80 (s, 3H)

MS(ES): m/z 225.53 [M+H]+

Production example 32

8-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidine-2, 4 (1H, 3H) -dione

8-fluorobenzo[4,5]thieno[3,2-d]pyrimidine-2,4(1H, 3H)-dione

555 mg was prepared in the same manner as Preparation Example 28 (yield 100%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.77 (br s, 1H), 7.88 (dd, J = 4.9, 8.8 Hz, 1H), 7.73 (dd, J = 2.6, 9.5 Hz, 1H), 7.32 (dt, J = 2.8, 8.8 Hz, 1H)

MS(ES): m/z 237.07 [M+H]+

Production example 33

2, 4-dichloro-8-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidine

2,4-dichloro-8-fluorobenzo[4,5]thieno[3,2-d]pyrimidine

61 mg was prepared in the same manner as Preparation Example 28 (yield 52.8%).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.40 (dd, J = 4.6, 9.0 Hz, 1H), 8.26 (dd, J = 2.4, 8.6 Hz, 1H), 7.81 (dt _, J = 2.7, 9.0 Hz, 1H)

MS(ES): m/z 274.82 [M+H]+

Production example 34

2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) -8-fluorobenzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluorobenzo[4,5]thieno[3,2-d]pyrimidin-4-amine

52 mg was prepared in the same manner as Preparation Example 29 (yield 71.8%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.46 (br s, 1H), _10.69 (br s, 1H), 8.21 (br dd, J = 4.6, 8.7 Hz, 1H), 8.00 (dd, J = 2.6, 8.8 Hz, 1H), 7.60 (dt, J = 2.6, 8.9 Hz, 1H), 6.30 (br s, 1H), 2.03 (m, 1H), 0.11-0.88 (m, 2H), 0.86-0.70 ( m, 2H)

MS(ES): m/z 359.79 [M+H]+

Production example 35

N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2- (pyrrolidin-1-yl)benzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(pyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyri Mydin-4-amine

25 mg was prepared in the same manner as Preparation Example 30 (yield 57.0%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.14 (br s, 1H), 9.86 (br s, 1H) _, 8.05 (dd, J = 4.6, 8.8 Hz, 1H), 7.83 (dd, J = 2.6) , 8.9 Hz, 1H), 7.47 (dt, J = 2.6, 8.9 Hz, 1H), 6.51 (br s, 1H), 3.61 (br t, J = 6.4 Hz, 4H), 2.01-1.95 (m, 4H) , 1.95 (m, 1H), 0.95 (br d, J = 6.8 Hz, 2H), 0.76-0.65 (m, 2H)

MS(ES): m/z 394.77 [M+H]+

In Examples 140 to 142 below, the compounds were synthesized in the same manner as in Example 139, or were prepared using appropriate reactants in consideration of Scheme 2-14 and the structure of the compound to be prepared.

Example 140

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-8-fluorobenzo[4,5] thieno[3,2-d]pyrimidin-2-yl)pyrrolidin- 3-ol

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-8-fluorobenzo[4,5] thieno[3,2-d]pyrimidine- 2-yl) pyrrolidin-3-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.88 (br s, 1H), 8.12 (m, 1H), 7.84 (dd, J = 2.6, 8.9 Hz, 1H), 7.47 (dt, J = 2.7, 8.9 Hz, 1H), 6.50 (br s, 1H), 5.01 (m, 1H), 4.47 (m, 1H), 3.74-3.50 (m, 4H), 2.12 (m, 1H) ), 1.98-1.86 (m, 2H), 1.03-0.91 (m, 2H), 0.78-0.65 (m, 2H)

MS(ES): m/z 411.16 [M+H]+

Example 141

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin -4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[ 3,2-d]pyrimidine -4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.16 (br s, 1H), 9.90 ( _br s, 1H), 8.06 (dd, J = 4.7, 8.8 Hz, 1H), 7.85 (dd, J = 2.6) , 9.0 Hz, 1H), 7.47 (dt, J = 2.6, 8.9 Hz, 1H), 6.48 (br s, 1H), 4.18 (m, 1H), 3.77-3.65 (m, 3H), 3.65 (m, 1H) ), 3.32-3.28 (m, 3H), 2.14-2.01 (m, 2H), 1.94-1.86 (m, 2H), 0.96 (br d, J = 6.6 Hz, 2H), 0.76-0.66 (m, 2H)

MS(ES): m/z 425.09 [M+H]+

Example 142

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thieno[3,2- d]pyrimidin-4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5 ]thieno[3,2- d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.19 (br s, 1H), 9.99 (br s, 1H), 8.07 (dd, J = 4.7, 8.8 Hz, 1H), 7.97 (m, 1H), 7.58 (m, 1H), 6.43 (br s, 1H), 4.18 (m, 1H), 4.08-3.91 (m, 2H), 3.89 (m, 1H), 3.69 (td, J = 7.0, 10.4 Hz, 1H ), 3.09 (s, 3H), 2.49-2.39 (m, 2H), 1.98 (m, 1H), 1.06-0.89 (m, 2H), 0.80-0.63 (m, 2H)

MS(ES): m/z 473.30 [M +H]+

Example 143

(S)-1-(7-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5] thieno[3,2-d]pyrimidin-2-yl)pyrrolidin -3-ol

(S)-1-(7-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5] thieno[3,2-d]pyrimidine-2 -1) pyrrolidin -3-ol

[Scheme 2-15]

Reagents and conditions: a) methyl 2-mercaptoacetate, potassium carbonate, dimethylformamide, 0 °C to rt, 5 h; b) sulfurisocyanatidic chloride, dichloromethane, 0 °C to rt, 2 h; c) sodium hydroxide, water, 70 °C, 6 h; d) POCl3, 120 °C, 24 h; e) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, dimethylformamide, 60° C., 15 h; f) pyrrolidine, methylpyrrolidone, 180 °C, microwave reactor, 2 h

Production example 36

methyl 3-amino-6-chlorobenzo[b]thiophene-2-carboxylate

Methyl 3-amino-6-chlorobenzo[b]thiophene-2-carboxylate

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 1.9, 8.7 Hz, 1H) , 7.22 (s, 2H), 3.79 (s, 3H)

MS(ES): m/z 241.79 [M+H]+

Production example 37

7-c chlorobenzo[4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

7-Chlorobenzo[4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.23-8.16 (m, 2H), 7.53 (dd, J = 1.9, 8.6 Hz, 1H)

MS(ES): m/z 253.08 [M+H]+

Production example 38

2,4,7-trichlorobenzo[4,5]thieno[3,2-d]pyrimidine

2,4,7-trichlorobenzo[4,5]thieno[3,2-d]pyrimidine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.53 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 1.9, 8.5 Hz, 1H) , 4.03 (s, 1H)

MS(ES): m/z 290.96 [M+H]+

Production example 39

2,7-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

2,7-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5]thieno[3,2-d]pyrimidin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.60 (m, 1H), 10.83 (m, 1H), _8.45 (m, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.69 (m, 1H), 6.28 (br s, 1H), 2.03 (m, 1H), 1.03-0.92 (m, 2H), 0.80-0.69 (m, 2H)

MS(ES): m/z 376.24 [M+H]+

Production example 40

(S)-1-(7-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5] thieno[3,2-d]pyrimidin-2-yl)pyrrolidin -3-ol

(S)-1-(7-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5] thieno[3,2-d]pyrimidine-2 -1) pyrrolidin -3-ol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (br s, 1H), 9.88 (br s, 1H), 8.23-8.11 (m, 2H), 7.50 (dd, J = 1.9, 8.5 Hz, 1H ), 6.49 (br s, 1H), 4.95 (d, J = 3.5 Hz, 1H), 4.46 (m, 1H), 3.76-3.51 (m, 5H), 2.10 (m, 1H), 1.92 (tt, J = 5.0, 8.4 Hz, 2H), 0.96 (br d, J = 6.6 Hz, 2H), 0.78-0.64 (m, 2H)

MS(ES): m/z 427.29 [M+H]+

In Examples 144 to 145 below, the compounds were synthesized in the same manner as in Example 143, or were prepared using appropriate reactants in consideration of Scheme 2-15 and the structure of the compound to be prepared.

Example 144

(S)-7-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidin -4-amine

(S)-7-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3 ,2-d]pyrimidine -4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.13 (br s, 1H), 9.90 (s, 1H), 8.23-8.11 (m, 2H), 7.51 (dd, J = 1.9, 8.5 Hz, 1H) , 6.43 (br s, 1H), 4.19 (m, 1H), 3.81-3.65 (m, 3H), 3.64 (m, 1H), 3.31-3.28 (m, 3H), 2.13-2.00 (m, 2H), 1.98 (m, 1H), 1.00-0.90 (m, 2H), 0.78-0.63 (m, 2H)

MS(ES): m/z 441.16 [M+H]+

Example 145

(S)-7-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thieno[3,2- d]pyrimidin-4-amine

(S)-7-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5] Thieno[3,2- d]pyrimidin-4-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.21 (br s, 1H), 9.98 (br s, 1H), 8.34-8.12 (m, 2H), 7.60 (m, 1H), 6.43 (br s, 1H), 4.19-3.91 (m, 4H), 3.89 (m, 1H), 3.69 (td, J = 7.0, 10.6 Hz, 1H), 3.12-3.05 (m, 3H), 2.47-2.38 (m, 2H) , 2.02 (m, 1H), 0.95 (br d, J = 6.5 Hz, 2H), 0.81-0.63 (m, 2H)

MS(ES): m/z 489.31 [M+H]+

[Scheme 2-16]

Reagents and conditions: a) boronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate, 1,4-dioxane, water, 130 °C, microwave reactor, 1.5 h; b) 4 N hydrochloric acid 1,4-dioxane solution, 1,4-dioxane, 60 °C, 24 h

Example 146

Tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine -1(2H)-carboxylate

Tert-Butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl)-3 ,6-dihydropyridine -1(2H)-carboxylate

2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) benzo [4, 5] thieno [3, 2-d] pyrimidin-4-amine (50 mg, 0.15 mmol), tetrakis(tri Phenylphosphine)Palladium (0) (8.5 mg, 0.0073 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate ( 90 mg, 0.29 mmol) and sodium carbonate (31 mg, 0.29 mmol) were all placed in a vial, sealed, and charged with nitrogen gas. Then, 1,4-dioxane (1 mL) and water (0.33 mL) were added and stirred for 1 hour and 30 minutes at 130°C in a microwave reactor. Ethyl acetate was added to the mixture cooled to room temperature and washed with water and saturated sodium chloride. After drying, filtering and concentration, the obtained product was purified through preparative thin layer chromatography to prepare 56 mg of the target compound (yield 78%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.24 (br s, 1H), 10.12 (br s, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.73-7.51 (m, 2H), 7.20 (br s, 1H), 6.42 (br s, 1H), 5.76 (s, 1H), 4.15 (br s, 2H), 3.59 (br t, J = 5.5 Hz, 2H), 2.76 (br s, 2H), 2.02 (m, 1H), 1.46 (s, 9H), 1.03-0.93 (m, 2H), 0.78-0.69 (m, 2H)

MS(ES): m/z 489.18 [M+H]+

Example 147

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzothiopheno[3,2-d]pyrimidin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[4,5]thieno[3,2- d]pyrimidine-4 -amine

Tert-butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine Add 4 N hydrochloric acid 1,4-dioxane solution (0.12 mL) to a mixture of -1(2H)-carboxylate (45 mg, 0.092 mmol) dissolved in 1,4-dioxane (1 mL, 0.1 M) at room temperature. did. Afterwards, the reaction mixture was stirred at 60°C overnight. Ethyl acetate and saturated sodium bicarbonate were added, shaken, and the organic layer was discarded. An excessive amount of hydrochloric acid _: isopropyl alcohol = 3:1 solution was added to the remaining water layer and shaken several times, and the collected organic layers were dried and concentrated to prepare 20 mg of the target compound (yield 56%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.55 (m, 1H) _, 10.31 (m, 1H), 8.41 (m, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.71 (m, 1H), 7.62 (m, 1H), 7.24 (br s, 1H), 6.50 (m, 1H), 3.59-3.52 (m, 2H), 3.21 (m, 1H), 3.06-2.92 (m, 2H), 2.71-2.62 (m, 2H), 2.00 (m, 1H), 1.01-0.94 (m, 2H), 0.77-0.69 (m, 2H)

MS(ES): m/z 389.16 [M+H]+

[Scheme 1-7]

Reagents and conditions: (a) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, 80 °C, 24 h; (b) Tetrahydrofuran, 100 °C, sealed tube, 24 h.

Example 148

[Scheme 2-17]

Reagents and conditions: (a) 5-cyclopropyl-1H-pyrazol-3-amine, diisopropylethylamine, isopropyl alcohol, rt, 24 h; (b) Cyclohexanethiol, potassium carbonate, dimethylformamide, 180°C, 4h, microwave reactor

Production example 41

2-Chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) pyrrolo [2, 1-f] [1, 2, 4] triazin-4-amine

2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (300 mg, 1.60 mmol) was dissolved in 3 mL of isopropyl alcohol, then 5-cyclopropyl-1H-pyrazole. -3-amine (197 mg, 1.60 mmol) and diisopropylethylamine (0.47 mL, 2.71 mmol) were added and stirred at room temperature overnight. Water was added, and the resulting solid was filtered and dried to prepare 410 mg (1.49 mmol) of the target compound (yield 93.5%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.36 (br s, 1H), 10.96-11.10 (m, 1H), 7.74 (br s, 1H), 7.40 (m, 1H), 6.69 (br s, 1H), 6.53 (m, 1H), 1.97 (m, 1H), 1.00-0.93 (m, 2H), 0.77-0.69 (m, 2H)

MS(ES): m/z 338.4 [M+H]+.

Production example 42

2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.73 mmol) After dissolving in 4 mL of dimethylformamide, cyclohexanethiol (0.2 mL, 2.18 mmol) and potassium carbonate (201 mg, 1.46 mmol) were added and stirred in a microwave reactor at 180°C for 4 hours. Ethyl acetate and distilled water were added to the reaction mixture, stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified through medium pressure liquid chromatography, and 170 mg (0.48 mmol) of the target compound was prepared (yield 65.9%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.36 (m, 1H), 10.64 (m, 1H), _7.62 (m, 1H), 7.26 (m, 1H), 6.61 (m, 1H), 6.49 ( m, 1H), 3.76 (m, 1H), 2.05 (br s, 2H), 1.95 (m, 1H), 1.74 (br d, J = 4.3 Hz, 2H), 1.65 (m, 1H), 1.43 (br d, J = 8.8 Hz, 4H), 1.34 (m, 1H), 1.01-0.93 (m, 2H), 0.75-0.67 (m, 2H)

MS(ES): m/z 355.47 [M+H]+.

In Examples 149 to 174 below, the compounds were synthesized in the same manner as in Example 148, or were prepared using appropriate reactants in consideration of Scheme 2-17 and the structure of the compound to be prepared.

Example 149

2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazin-4-amine

2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.34 (m, 1H), 10.66 (m, 1H), _7.62 (m, 1H), 7.32 (m, 1H), 6.61-6.49 (m, 2H), 2.26 (s, 3H), 2.11-2.07 (m, 2H), 1.79-1.72 (m, 2H), 1.65 (m, 1H), 1.48-1.39 (m, 4H), 1.32-1.26 (m, 2H)

MS(ES): m/z 329.44 [M+H]+.

Example 150

2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4]triazin-4-amine

2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine- 4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.32 (m, 1H), 10.70 (m, 1H), _7.62 (m, 1H), 7.27 (m, 1H), 6.61-6.50 (m, 2H), 3.69-3.62 (m, 2H), 2.26 (s, 3H), 1.99-1.94 (m, 2H), 1.63-1.55 (m, 2H), 1.51-1.43 (m, 2H), 1.37-1.30 (m, 2H) ), 0.96-0.93 (m, 6 H)

MS(ES): m/z 357.49 [M+H]+.

Example 151

2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4]triazin-4-amine

2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]tri Azine-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.33 (m, 1H), 10.68 (m, 1H), 7.64 ( _m , 1H), 7.32 (m, 1H), 6.64 (m, 1H), 6.55 ( m, 1H), 3.87 (m, 1H), 3.66 (m, 1H), 2.26 (s, 5H), 2.13-1.93 (m, 4H), 1.75-1.64 (m, 2H)

MS(ES): m/z 365.42 [M+H]+.

Example 152

2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazin-4-amine

2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazin-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.35 (m, 1H), 10.67 (m, 1H), 7.63 (m, 1H), 7.28 (m, 1H,) 6.64-6.48 (m, 2H), 3.79-3.68 (m, 2H), 2.68-2.61 (m, 4H), 2.12-2.04 (m, 2H), 1.78-1.70 (m, 2H,) 1.65 (m, 1H), 1.49-1.37 (m, 4H) ), 1.29-1.18 (m, 5H)

MS(ES): m/z 343.46 [M+H]+.

Example 153

N-(5-methyl-1H-pyrazol-3-yl)-2-((4-phenylcyclohexyl)thio)pyrrolo[2,1-f][1,2,4]triazin-4-amine

N-(5-methyl-1H-pyrazol-3-yl)-2-((4-phenylcyclohexyl)thio)pyrrolo[2,1-f][1,2,4]triazine-4- amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.29 (m, 1H), 10.64 (m, 1H,) 7.64 (m, 1H), 7.33-7.15 (m, 7 H), 6.62-6.51 (m, 2H), 4.29 (m, 1H), 2.27 (s, 3H), 2.12-1.99 (m, 4H), 1.82-1.72 (m, 5H)

MS(ES): m/z 405.53 [M+H]+.

Example 154

2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo[2,1-f][1,2,4]triazin-4-amine

2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo[2,1-f][1,2,4]triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.50 (m, 1H), 11.39 (m, 1H), _8.62 (m, 1H), 8.04 (m, 1H), 6.67 (m, 1H), 2.26 ( br s, 3H), 2.09 (s, 3H), 1.77-1.71 (m, 2H), 1.67 (m, 1H), 1.44 (br d, J = 9.8 Hz, 5H). 1.34-1.24 (m, 2H)

MS(ES): m/z 374.43 [M+H]+.

Example 155

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((4,4-dimethylcyclohexyl) thio)pyrrolo[2,1-f][1,2,4]triazin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((4,4-dimethylcyclohexyl)thio)pyrrolo[2,1-f][1,2,4]triazine -4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.42 (m, 1H), 10.71 (m, 1H), _7.69 (m, 1H), 7.35 (m, 1H), 6.68 (m, 1H), 6.47 ( m, 1H), 1.99-1.89 (m, 3H), 1.63-1.53 (m, 2H), 1.51-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.93 (br d, J = 4.0 Hz , 9H), 0.86-0.54 (m, 3H)

MS(ES): m/z 383.53 [M+H]+.

Example 156

2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.03 (br s, 1H), 10.61 (m, 1H), _7.61 (m, 1H), 7.30-7.14 (m, 3H), 6.70-6.61 (m, 2H), 6.57 (m, 1H), 5.88 (m, 1H), 5.59-5.44 (m, 2H), 2.22-2.12 (m, 3H)

MS(ES): m/z 338.4 [M+H]+.

Example 157

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenyl) -4-(4-methylpiperazin-1-yl)benzamide

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenyl)-4-(4-methylpiperazin-1-yl)benzamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (m, 1H), 10.68 (m, 1H), 10.23 (m, 1H), 7.95 (br d, J = 8.5 Hz, 2H), 7.91-7.86 (m, 2H), 7.62-7.57 (m, 3H), 7.26 (m, 1H), 7.07-7.02 (m, 2H), 6.62 (m, 1H), 5.70 (m, 1H), 2.26-2.23 (m , 3H), 2.05-2.01 (m, 3H), 1.24-1.03 (m, 4H), 0.85-0.71 (m, 4H)

MS(ES): m/z 540.65 [M+H]+.

Example 158

2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo [2,1-f][1,2,4]triazin-4-amine

2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo[2,1-f][1,2,4]triazine -4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.25 (m, 1H), 11.22 (m, 1H), 7.93 (br s, 1H), 8.52 (s, 1H), 7.25 (d, J = 8.5 Hz , 2H), 6.65 (d, J = 8.6 Hz, 2H), 5.78 (m, 1H), 5.62 (s, 2H), 2.24-2.13 (m, 3H)

MS(ES): m/z 383.4 [M+H]+.

Example 159

2-((4-aminophenyl)thio)-N-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((4-aminophenyl)thio)-N-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 10.76 (m, 1H), 7.57 (m, 1H), _7.46 (m, 1H), 7.26-7.21 (m, 2H), 7.20 (m, 1H), 6.65-6.60 (m, 2H), 6.58 (m, 1H), 6.20 (m, 1H), 5.55-5.46 (m, 2H), 5.76 (s, 1H), 3.80-3.74 (m, 3H)

MS(ES): m/z 338.4 [M+H]+.

Example 160

2-((4-aminophenyl)thio)-N-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((4-aminophenyl)thio)-N-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 10.63 (m, 1H), 8.35 (m, 1H), _7.76 (m, 1H), 7.69 (m, 1H), 7.59 (m, 1H), 7.44 ( m, 1H), 7.31-7.25 (m, 2H), 7.09 (m, 1H), 6.70-6.63 (m, 3H), 5.68-5.60 (m, 2H), 1.24 (s, 3H)

MS(ES): m/z 335.4 [M+H]+.

Example 161

2-((3-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((3-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.09 (m, 1H), 10.65 (m, 1H), _7.64 (m, 1H), 7.26 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.84 (s, 1H), 6.76 (m, 1H), 6.69 (m, 1H), 6.62 (m, 1H), 5.86 (m, 1H), 5.34-5.23 (m, 2H), 2.17-2.10 (m, 3H)

MS(ES): m/z 338.4 [M+H]+.

Example 162

2-((2-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((2-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 13.05 (m, 1H), 10.52 (m, 1H), _7.80 (m, 1H), 6.99-6.86 (m, 2H), 6.77 (m, 1H), 6.62 (m, 1H), 6.48 (m, 1H), 5.05 (s, 2H), 2.14 (s, 3H)

MS(ES): m/z 338.4 [M+H]+.

Example 163

2-chloro-N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl) thio)phenyl)acetamide

2-chloro-N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2 -1) Thio)phenyl)acetamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.1 (m, 1H), _10.7-10.5 (m, 2H), 7.8-7.7 (m, 2H), 7.7-7.6 (m, 3H), 7.3 (m) , 1H), 6.6 (m, 1H), 5.7 (m, 1H), 4.3-4.2 (m, 2H), 2.1-2.0 (m, 3H)

MS(ES): m/z 414.88 [M+H]+.

Example 164

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenyl) cyclohexanecarboxamide

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio ) phenyl) cyclohexanecarboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.10 (m, 1H), 10.69 (m, 1H), _10.12 (m, 1H), 7.79-7.72 (m, 2H), 7.61-7.51 (m, 3H) ), 7.27 (m, 1H), 6.61 (m, 1H), 5.64 (m, 1H), 2.39 (m, 1H), 2.06-1.97 (m, 3H), 1.84-1.75 (m, 4H), 1.73 ( m, 1H), 1.48-1.39 (m, 2H), 1.34-1.16 (m, 3H)

MS(ES): m/z 448.56 [M+H]+.

Example 165

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenyl) benzamide

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenyl)benzamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (m, 1H), 10.70 (m, 1H), 10.55 (m, 1H), 8.00-7.93 (m, 5H), 7.70-7.48 (m, 7H) ), 7.28 (m, 1H), 6.64 (m, 1H), 5.69 (m, 1H), 2.05 (s, 3H)

MS(ES): m/z 442.51 [M+H]+.

Example 166

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenyl) -2-phenylacetamide

N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio ) phenyl) -2-phenylacetamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.08 (m, 1H), 10.66 (m, 1H), 10.49 (m, 1H), 7.73 (s, 2H), 7.57 (s, 3H), 7.39- 7.32 (m, 4H), 7.31-7.15 (m, 2H), 6.57 (br d, J = 3.8 Hz, 1H), 5.62 (m, 1H), 3.72-3.65 (m, 2H), 1.89 (s, 3H) )

MS(ES): m/z 456.53 [M+H]+.

Example 167

N-(3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenyl) -2-phenylacetamide

N-(3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio ) phenyl) -2-phenylacetamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.11 (m, 1H), 10.70 (m, 1H), _10.33 (s, 1H), 7.87 (s, 2H), 7.60 (d, J = 0.75 Hz, 1H), 7.45 (m, 1H), 7.30 (s, 5H), 7.26-7.20 (m, 2H), 6.62 (m, 1H), 5.64 (m, 1H), 3.67-3.60 (m, 2H), 2.02 -1.94 (m, 3H)

MS(ES): m/z 456.53 [M+H]+.

Example 168

2-((3-methoxyphenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((3-methoxyphenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4- amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (m, 1H), 10.72 (m, 1H), 7.64 (m, 1H), 7.43 (m, 1H), 7.22 (br d, J = 1.3 Hz , 3H), 7.12 (m, 1H), 6.65 (m, 1H), 5.81 (m, 1H), 3.77 (s, 3H), 2.09 (s, 3H)

MS(ES): m/z 353.41 [M+H]+.

Example 169

2-((3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4- amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.20 (m, 1H), 10.75 (m, 1H), _7.65 (m, 1H), 7.57-7.47 (m, 3H), 7.41 (m, 1H), 7.30 (m, 1H), 6.64 (m, 1H), 5.70 (m, 1H), 2.10 (s, 3H)

Example 170

3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenol

3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenol

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.10 (m, 1H), 10.67 (m, 1H), 9.81 (m, 1H), 7.60 (br s, 1H), 7.28 (s, 2H), 7.03 (br d, J = 2.3 Hz, 2H), 6.93 (m, 1H), 6.62 (m, 1H), 5.74 (s, 1H), 2.15-2.09 (m, 3H)

MS(ES): m/z 339.39 [M+H]+.

Example 171

2-((4-amino-3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-((4-amino-3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]tri Azine-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.14 (m, 1H), 10.68 (m, 1H), _7.65 (m, 1H), 7.32-7.10 (m, 3H), 6.88-6.77 (m, 1H) ), 6.66 (m, 1H), 5.84 (m, 1H), 5.68-5.57 (m, 2H), 2.15 (s, 3H)

MS(ES): m/z 356.39 [M+H]+.

Example 172

(R)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-(2-fluoro-4-((4-((5-methyl-1H-pyrazol- 3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenyl)acetamide

(R)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-(2-fluoro-4-((4-( (5-methyl-1H-pyrazol-3)-yl)amino)pyrrolo[2,1-f][1,2,4] riazin-2-yl)thio)phenyl)acetamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.17 (m, 1H), 10.74 (m, 1H), _9.79 (m, 1H), 8.27 (m, 1H), 7.65-7.59 (m, 2H), 7.51 (m, 1H), 7.31 (m, 1H), 6.60 (br d, J = 2.5 Hz, 1H), 5.77 (m, 1H), 4.03 (m, 1H), 3.77-3.65 (m, 3H), 3.57-3.50 (m, 2H), 3.25 (m, 1H), 2.98 (m, 1H), 2.83-2.75 (m, 2H), 2.72-2.65 (m, 2H), 2.45-2.32 (m, 2H), 1.97 (m, 1H)

MS(ES): m/z 600.63 [M+H]+.

Example 173

4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenol

4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio)phenol

^1H NMR (400 MHz, DMSO- d6 ) δ 13.08 (m, 1H), 10.43 (m, 1H), _9.43 (m, 1H), 7.78 (m, 1H), 6.99-6.92 (m, 2H), 6.75 (m, 1H), 6.63-6.58 (m, 2H), 1.99 (s, 3H)

MS(ES): m/z 339.39 [M+H]+.

Example 174

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4] triazin-2-yl)pyrrolidin-3- ol

(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl) Pyrrolidin-3-ol

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazine-4-amine (50 mg, 0.18 mmol) and (3S)-pyrrolidin-3-ol (48 mg, 0.55 mmol) were dissolved in methylpyrrolidone (3 mL) and stirred in a microwave reactor at 150°C for 8 hours. Ethyl acetate and distilled water were added to the reaction mixture, stirred, and the organic layer was separated. The separated organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified through medium pressure liquid chromatography, and 12 mg (0.04 mmol) of the target compound was prepared (yield 20.3%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.22 (m, 1H), 10.28 (m, 1H), 7.37 (br s, 1H), 7.13 (m, 1H), 6.67 (m, 1H), 6.42 (m, 1H), 4.91 (br s, 1H), 4.43 (m, 1H), 4.17 (m, 1H), 3.58-3.50 (m, 3H), 2.06-1.83 (m, 3H), 1.01-0.92 ( m, 2H), 0.74-0.67 (m, 2H)

MS(ES): m/z 326.37 [M+H]+.

In Examples 175 to 187 below, the compounds were synthesized in the same manner as in Example 174 above, or were prepared using appropriate reactants in consideration of the structure of the compound to be manufactured.

Example 175

1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-3-ol

1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-3 -all

^1H NMR (400 MHz, DMSO- d6 ) δ 12.17 (m, 1H), 10.27 (m, 1H), _7.37 (s, 1H), 7.09 (m, 1H), 6.72 (m, 1H), 6.39 ( m, 1H), 4.96 (m, 1H), 4.39-4.30 (m, 2H), 3.58-3.50 (m, 3H), 3.41 (br s, 2H), 2.26 (s, 3H), 1.99 (s, 2H) ), 1.91 (m, 1H)

MS(ES): m/z 300.33 [M+H]+.

Example 176

(R)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4]triazin-4- amine

(R)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4 ]Triazine-4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.27 (m, 1H), 10.30 (m, 1H), 7.36 (t, J = 1.9 Hz, 1H), 7.05 (br d, J = 3.4 Hz, 1H ), 6.71 (m, 1H), 6.37 (dd, J = 4.4, 2.4 Hz, 1H), 3.62-3.51 (m, 5H), 3.18-3.12 (m, 2H), 2.29-2.24 (m, 3H), 2.08 (m, 1H), 1.94 (m, 1H), 1.73 (m, 1H), 1.24 (s, 2H)

MS(ES): m/z 299.35 [M+H]+.

Example 177

(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4- amine

(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4 ]Triazine-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.26 (m, 1H), 10.29 (m, 1H), _7.36 (s, 1H), 7.11 (m, 1H), 6.72 (m, 1H), 6.40 ( m, 1H), 3.63-3.45 (m, 5H), 3.17-3.08 (m, 2H), 2.25 (s, 3H), 2.07 (m, 1H), 1.73 (m, 1H)

MS(ES): m/z 299.35 [M+H]+.

Example 178

(S)-N-(5-methyl-1H-pyrazol-3-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin -4-amine

(S)-N-(5-methyl-1H-pyrazol-3-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1, 2,4]triazine- 4-amine

^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.22 (s, 1H), 7.40 (m, 1H), 7.08 (m, 1H), 6.64 (m, 1H), 6.42 (m, 1H), 3.68- 3.65 (m, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 2.20 (m, 1H), 1.90 (s, 3H)

MS(ES): m/z 313.37 [M+H]+.

Example 179

(S)-2-(3-fluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4- amine

(S)-2-(3-fluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.28 (m, 1H), 10.30 (m, 1H), 7.44 (m, 1H), 7.12 (m, 1H), 6.66 ( _m , 1H), 6.46 ( m, 1H), 5.53 (m, 1H), 3.82-3.65 (m, 6H), 2.25 (s, 6H)

MS(ES): m/z 302.32 [M+H]+.

Example 180

2-(3,3-difluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-(3,3-difluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4 ]Triazine-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.21 (m, 1H), 10.43 (m, 1H), _7.48 (m, 1H), 7.17 (m, 1H), 6.61 (m, 1H), 6.43 ( dd, J = 4.3, 2.4 Hz, 1H), 3.89-3.82 (m, 3H), 3.70 (br t, J = 7.3 Hz, 5H), 2.26 (s, 3H)

MS(ES): m/z 320.31 [M+H]+.

Example 181

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4- amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.21 (m, 1H), 10.29 (m, 1H), _7.42 (m, 1H), 7.13 (m, 1H), 6.64 (m, 1H), 6.43 ( m, 1H), 3.30-3.27 (m, 4H), 2.18 (br t, J = 7.8 Hz, 1H), 2.04 (br d, J = 1.75 Hz, 2H), 1.91 (br d, J = 6.75 Hz, 2H), 0.97-0.91 (m, 2H), 0.73-0.67 (m, 2H)

MS(ES): m/z 340.39 [M+H]+.

Example 182

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin -4-amine

(S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrrolo[2,1-f][ 1,2,4]triazine- 4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.24 (m, 1H), 10.39 (m, 1H), _7.46 (m, 1H), 7.17 (m, 1H), 6.58 (m, 1H), 6.44 ( m, 1H), 4.10 (m, 1H), 3.88-3.78 (m, 3H), 3.71-3.60 (m, 2H), 3.58-3.48 (m, 3H), 3.05 (s, 2H), 0.97-0.91 ( m, 2H), 0.73-0.65 (m, 2H)

MS(ES): m/z 388.46 [M+H]+.

Example 183

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4- amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.17 (m, 1H) _, 10.24 (m, 1H), 7.40 (m, 1H), 7.07 (m, 1H), 6.60 (m, 1H), 6.40 ( m, 1H), 1.93-1.91 (m, 4H), 1.24 (br s, 2H), 1.16-1.14 (m, 2H), 1.06-1.03 (m, 2H), 0.97-0.93 (m, 2H)

MS(ES): m/z 310.37 [M+H]+.

Example 184

2-(4-aminopiperidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

2-(4-aminopiperidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine- 4-amine

^1H NMR (400 MHz, DMSO- d6 ) δ 12.30 (m, 1H), 10.31 (m, 1H), _7.38 (s, 1H), 7.12 (s, 1H), 6.49-6.36 (m, 2H), 4.32-4.25 (m, 2H), 4.19 (m, 1H), 3.17 (br s, 2H), 2.96-2.87 (m, 2H), 2.26 (s, 3H),1.80-1.69 (m, 2H), 1.24 (s, 4H)

MS(ES): m/z 313.37 [M+H]+.

Example 185

N-(5-methyl-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

N-(5-methyl-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4 -Amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.20 (m, 1H), 10.27 (m, 1H), 7.43 (m, 1H), 7.12 (m, 1H), 6.48-6.40 (m, 2H), 3.54 (br s, 5H), 2.39 (br s, 4H), 2.25 (s, 3H), 2.21 (s, 3H)

MS(ES): m/z 313.37 [M+H]+.

Example 186

1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperidin-4-ol

1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperidine-4 -all

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.26 (m, 1H), 10.26 (m, 1H), 7.38 (t, J = 1.9 Hz, 1H), 7.08 (m, 1H), 6.41 (br dd , J = 4.3, 2.4 Hz, 2H), 4.73 (m, 1H), 4.14-4.04 (m, 2H), 3.73 (m, 1H), 3.13-3.07 (m, 2H), 2.29-2.24 (m, 3H) ), 1.83-1.75 (m, 2H), 1.41-1.30 (m, 2H)

MS(ES): m/z 314.36 [M+H]+.

Example 187

(1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperidin-4-yl)methanol

1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperidine-4 -1) Methanol

^1H NMR (400 MHz, DMSO- d6 ) δ 12.25 (m, 1H), 10.25 (m, 1H), 7.38 ( _s , 1H), 7.10 (m, 1H), 6.48-6.36 (m, 2H), 4.53 (m, 1H), 4.40 (br d, J = 12.9 Hz, 2H), 3.30-3.25 (m, 2H), 2.83-2.75 (m, 2H), 2.30-2.22 (m, 3H), 1.74-1.57 (m, 3H), 1.19- 1.08 (m, 2H)

MS(ES): m/z 328.38 [M+H]+.

Example 188

N- (5-cyclopropyl-1H-pyrazol-3-yl) -2- (1H-pyrazol-4-yl) pyrrolo [2, 1-f] [1, 2, 4] triazin-4-amine

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4 -Amine

[Scheme 2-18]

Reagents and conditions: (a) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, sodium carbonate, bis(triphenylphosphine)palladium ( II) Dichloride, 1,4-dioxane, distilled water, 130 °C, 0.5 h, microwave reactor

2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazine-4-amine (50 mg, 0.18 mmol) , 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (39 mg, 0.20 mmol), sodium carbonate (39 mg, 0.36 mmol), bis(triphenylphosphine)palladium(II) dichloride (6.4 mg, 0.0091 mmol) was dissolved in 1,4-1,4-dioxane mixed 2:1 and 3 mL of distilled water. The microwave reactor was stirred at 130° C. for 30 minutes. Ethyl acetate and distilled water were added to the reaction mixture, stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was subjected to medium pressure liquid chromatography to prepare 17 mg (0.05 mmol) of the target compound (yield 30.5%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.22 (m, 1H), 12.29 (m, 1H), 10.57 (m, 1H), 8.23-7.87 (m, 2H), 7.67 (br s, 1H) , 7.31 (m, 1H), 6.76-6.55 (m, 2H), 2.02 (m, 1H), 1.02-0.95 (m, 2H), 0.81-0.73 (m, 2H)

MS(ES): m/z 307.33 [M+H]+.

Example 189

[Scheme 2-19]

Reagents and conditions: (a) isopropyl alcohol, rt, 24 h; (b) methylamine, hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide I, diisopropylethylamine, dimethylformamide, rt; (c) Pyrrolidine, methylpyrrolidone, 180 °C, 2h, microwave reactor

Production example 43

2-chloro-4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] pyrrolo [2, 1-f] [1, 2, 4] triazine-7-carboxylic acid

2-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid

2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (680 mg, 2.93 mmol) was dissolved in 10 mL of isopropyl alcohol, then diisopropyl Ethylamine (1.02 mL, 5.86 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (361 mg, 2.93 mmol) dissolved in 10 mL of isopropyl alcohol were slowly added. The reaction mixture was stirred at 90 °C overnight. After the reaction was completed, the reaction mixture was concentrated, 5 mL of isopropyl alcohol was added and stirred for 30 minutes. The undissolved solid was filtered and dried to prepare 740 mg (2.32 mmol) of the target compound (yield 79.2%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.57 (m, 1H), 11.33 (m, 1H), 7.49 (m, 1H), _7.22 (m, 1H), 6.58 (m, 1H), 1.98 ( m, 1H), 0.98-0.93 (m, 2H), 0.77-0.68 (m, 2H)

MS(ES): m/z 275.07 [M+H]+.

Production example 44

2-chloro-4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] -N-methyl-pyrrolo [2, 1-f] [1, 2, 4] triazine-7-carboxamide

2-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-N-methyl-pyrrolo[2,1-f][1,2,4]triazine-7- Carboxamide

2-Chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (740 mg, 2.32 mmol) was dissolved in 10 mL of dimethylformamide, then 1-hydroxybenzotriazole hydrate (439 mg, 3.25 mmol), (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (668 mg) , 3.48 mmol), methylamine (0.22 mL, 2.55 mmol), and diisopropylethylamine (0.81 mL, 4.64 mmol) were added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, distilled water was added, and the resulting solid was filtered and dried to prepare 610 mg (1.83 mmol) of the target compound (yield 79.2%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.49 (m, 1H) _, 11.40 (m, 1H), 8.48 (m, 1H), 7.47 (m, 1H), 7.26 (m, 1H), 6.57 ( m, 1H), 2.95-2.90 (m, 3H), 2.01 (m, 1H), 1.02-0.93 (m, 2H), 0.78-0.69 (m, 2H)

MS(ES): m/z 332.76 [M+H]+.

Production example 45

4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino] -N-methyl-2-pyrrolidin-1-yl-pyrrolo [2, 1-f] [1, 2, 4] triazine-7- carboxamide

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2, 4]Triazine-7-carboxamide

2-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-N-methyl-pyrrolo[2,1-f][1,2,4]triazine-7- Carboxamide (250 mg, 0.75 mmol) was dissolved in 5 mL of methylpyrrolidone, and then pyrrolidine (0.19 mL, 2.26 mmol) was added and stirred in a microwave reactor at 180°C for 2 hours. Ethyl acetate and distilled water were added to the reaction mixture, stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified through medium pressure liquid chromatography to prepare 220 mg (0.60 mmol) of the target compound (yield 79.7%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.26 (s, 1H), 10.59 (s, 1H), _9.27 (s, 1H), 7.13-7.23 (m, 1H), 6.95 (m, 1H), 6.61 (m, 1H), 3.56-3.50 (m, 4H), 2.91 (d, J = 1.0 Hz, 3H), 2.01-1.89 (m, 5H), 1.00-0.92 (m, 2H), 0.73-0.67 ( m, 2H)

MS(ES): m/z 367.42 [M+H]+.

In Examples 190 to 211 below, the compounds were synthesized in the same manner as in Example 189, or were prepared using appropriate reactants in consideration of Scheme 2-19 and the structure of the compound to be prepared.

Example 190

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) (pyrrolidin-1-yl)methanone

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine -7-yl)(pyrrolidin-1-yl)methanone

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.24 (m, 1H), 10.40 (m, 1H), 7.20 (m, 1H), 6.62-6.50 (m, 2H), 3.45 (br s, 10H) , 1.92 (br s, 10H), 0.99-0.90 (m, 2H), 0.74-0.65 (m, 2H)

MS(ES): m/z 407.48 [M+H]+.

Example 191

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) (piperazin-1-yl)methanone

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]tri azine-7-yl)(piperazine-1-yl)methanone

^1H NMR (400 MHz, DMSO- d6 ) δ 12.24 (m, 1H), 10.43 (m, 1H), _7.18 (m, 1H), 6.61-6.53 (m, 2H), 1.96-1.91 (m, 4H) ), 1.43 (m, 11H), 1.26-1.22 (m, 3H), 1.16 (m, 1H), 0.99-0.92 (m, 2H), 0.89-0.75 (m, 4H), 0.72-0.67 (m, 2H) )

MS(ES): m/z 422.5 [M+H]+.

Example 192

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1,2, 4]triazine-7-carboxamide

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)-N-methylpyrrolo[2,1 -f][1,2,4]triazine-7-carboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.28 (s, 1H), 10.66 (s, 1H), _9.20 (m, 1H), 7.25 (m, 1H), 6.98 (m, 1H), 6.58 ( s, 1H), 5.49 (d, J = 1.0 Hz, 1H), 3.90-3.67 (m, 4H), 3.63-3.53 (m, 3H), 2.92 (d, J = 4.6 Hz, 3H), 2.32 (m , 1H), 2.00 (m, 1H), 1.00-0.92 (m, 2H), 0.76-0.70 (m, 2H)

MS(ES): m/z 385.41 [M+H]+.

Example 193

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1,2, 4]triazine-7-carboxamide

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-N-methylpyrrolo[2,1 -f][1,2,4]triazine-7-carboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.27 (s, 1H), 10.62 (s, 1H), _9.27 (s, 1H), 7.11-7.22 (m, 1H), 6.98 (m, 1H), 6.62 (m, 1H), 5.03 (m, 1H), 4.46 (m, 1H), 3.65-3.56 (m, 3H), 3.50-3.43 (m, 2H), 2.93 (d, J = 1.0 Hz, 3H) , 2.11 (m, 1H), 1.98-1.89 (m, 2H), 1.01-0.94 (m, 2H), 0.75-0.69 (m, 2H)

MS(ES): m/z 383.42 [M+H]+.

Example 194

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl) pyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1 ,2,4]triazine-7-carboxamide

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-7-carboxamide

^1H NMR (400 MHz, DMSO- d ₆ ) 12.38 (m, 1H), 10.68 (m, 1H), 9.32 (m, 1H), 7.23 (m, 1H), 6.93 (d, J = 4.8 Hz, 1H ), 6.59 (m, 1H), 4.85 (m, 1H), 4.18 (m, 1H), 3.71 (m, 1H), 3.61 (m, 1H), 3.47-3.41 (m, 2H), 2.90 (d, J = 4.8 Hz, 3H), 2.08-1.89 (m, 5H), 0.93 (br dd, J = 8.5, 2.5 Hz, 2H), 0.77 (br d, J = 2.9 Hz, 2H)

MS(ES): m/z 397.45 [M+H]+.

Example 195

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl) pyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1 ,2,4]triazine-7-carboxamide

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1, 2,4]triazine-7-carboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.35 (m, 1H), 10.64 (m, 1H), _9.35 (m, 1H), 7.27 (m, 1H), 6.97 (m, 1H), 6.60 ( m, 1H), 4.82 (m, 1H), 4.17 (m, 1H), 3.71 (m, 1H), 3.61 (m, 1H), 3.47-3.40 (m, 2H), 2.90 (d, J = 4.8 Hz , 3H), 2.08-1.85 (m, 5H), 1.00-0.89 (m, 2H), 0.82-0.70 (m, 2H)

MS(ES): m/z 397.45 [M+H]+.

Example 196

(R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)(pyrrolidin-1-yl)methanone

(R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2, 4]triazine-7-yl)(pyrrolidin-1-yl)methanone

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.21 (br s, 1H), 10.37 (m, 1H), 7.17 (m, 1H), 6.56-6.50 (m, 2H), 4.73 (m, 1H) , 4.09 (m, 1H), 3.65 (m, 1H), 3.66 (m, 1H), 3.49-3.39 (m, 7H), 2.03 (m, 1H), 1.93-1.79 (m, 8H), 0.95-0.89 (m, 2H), 0.80-0.73 (m, 2H)

MS(ES): m/z 437.51 [M+H]+.

Example 197

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl) pyrrolidin-1-yl)-N,N-dimethylpyrrolo[2,1-f] [1,2,4]triazine-7-carboxamide

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N,N-dimethylpy Rolo[2,1-f][1,2,4]triazine-7-carboxamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.20 (br s, 1H), 10.34 (s, 1H), 7.17 (m, 1H), 6.55-6.49 (m, 2H), 4.72 (m, 1H) , 4.10 (m, 1H), 3.66 (m, 1H), 3.47-3.38 (m, 3H), 3.06-2.95 (m, 3H), 2.92-2.83 (m, 3H), 2.05-1.84 (m, 5H) , 0.95-0.89 (m, 2H), 0.80-0.71 (m, 2H)

MS(ES): m/z 411.47 [M+H]+.

Example 198

(R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone

(R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2, 4]triazine-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone

^1H NMR (400 MHz, DMSO- d6 ) δ 12.28 (m, 1H), 10.45 (m, 1H), _7.20 (m, 1H), 6.66 (m, 1H), 6.57 (m, 1H), 4.73 ( m, 1H), 4.12-4.04 (m, 2H), 3.99-3.87 (m, 2H), 3.77-3.68 (m, 2H), 3.66 (m, 1H), 3.49-3.36 (m, 4H), 2.06- 1.84 (m, 6H), 0.96-0.90 (m, 2H), 0.80-0.72 (m, 2H)

MS(ES): m/z 473.49 [M+H]+.

Example 199

(R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)(piperazin-1-yl)methanone

(R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2, 4]triazine-7-yl)(piperazin-1-yl)methanone

^1H NMR (400 MHz, DMSO- d6 ) δ 12.27 (m, 1H), 10.39 (m, 1H), _7.17 (m, 1H), 6.54-6.49 (m, 2H), 5.01 (m, 1H), 4.76-4.60 (m, 2H), 4.13-3.96 (m, 2H), 3.67-3.57 (m, 3H), 2.83-2.72 (m, 4H), 2.06-1.85 (m, 7H), 0.97-0.91 (m) , 2H), 0.80-0.75 (m, 2H)

MS(ES): m/z 452.52 [M+H]+.

Example 200

2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo[2,1-f][1,2 ,4]triazine-7-carboxamide

2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo[2, 1-f][1,2,4]triazine-7-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.30 (br s, 1H), 10.63 (m, 1H), 9.05 (m, 1H), 7.20 (m, 1H), 6.98 (m, 1H), 6.42 (m, 1H), 4.39-4.29 (m, 2H), 3.44-3.37 (m, 2H), 2.97-2.88 (m, 5H), 2.00 (m, 1H), 1.81-1.72 (m, 2H), 1.67 -1.51 (m, 3H), 1.39-1.30 (m, 2H), 1.23-1.11 (m, 2H), 1.00-0.92 (m, 2H), 0.72-0.65 (m, 2H)

MS(ES): m/z 448.54 [M+H]+.

Example 201

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)pyrrolo[2,1 -f][1,2,4]triazine-7-carboxamide

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1- 1) Pyrrolo[2,1- f][1,2,4]triazine-7-carboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.42 (m, 1H), 10.59 (m, 1H), 8.99 ( _m , 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.48 ( m, 1H), 4.42 (m, 1H), 3.64-3.37 (m, 9H), 2.88 (br d, J = 4.5 Hz, 3H), 2.11 (m, 1H), 1.04-0.88 (m, 2H), 0.77-0.60 (m, 2H)

MS(ES): m/z 450.55 [M+H]+.

Example 202

ethyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]triazine-6-carboxylate

Ethyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]tri Azine-6-carboxylate

^1H NMR (400 MHz, DMSO- d6 ) δ 12.33 (m, 1H), 10.45-10.63 (m, 1H), 7.85 (m, 1H), _7.67 (m, 1H), 6.64 (m, 1H), 4.22 (d, J = 7.1 Hz, 2H), 3.46 (br s, 4H), 1.96-1.87 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.00-0.88 (m, 2H), 0.75-0.63 (m, 2H)

MS(ES): m/z 382.43 [M+H]+.

Example 203

ethyl (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4] triazine-6-carboxylate

Ethyl (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4] Triazine-6-carboxylate

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.25 (br s, 1H), 10.61 (br s, 1H), 7.81 (m, 1H), 7.68 (m, 1H), 6.59 (m, 1H), 4.27-4.19 (m, 2H), 3.79-3.48 (m, 4H), 2.27-2.15 (m, 2H), 1.96-1.85 (m, 2H), 1.32-1.26 (m, 3H), 0.99-0.91 (m) , 2H), 0.77-0.66 (m, 2H)

MS(ES): m/z 400.42 [M+H]+.

Example 204

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine -6-carboxylic acid

^1H NMR (400 MHz, DMSO- d6 ) δ 12.28 (m, 1H), 10.56 (m, 1H), 7.68 (d _, J = 1.8 Hz, 1H), 7.53 (m, 1H), 6.59 (m, 1H), 3.49-3.43 (m, 4H), 1.98-1.84 (m, 5H), 0.99-0.90 (m, 2H), 0.74-0.64 (m, 2H)

MS(ES): m/z 354.38 [M+H]+.

Example 205

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine -6-carboxylic acid

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic acid

^1H NMR (400 MHz, DMSO- d6 ) δ 12.54 (m, 1H), 10.64 (m, 1H), _7.83 (m, 1H), 7.55 (m, 1H), 6.57 (m, 1H), 5.51 ( m, 1H), 3.79-3.49 (m, 5H), 2.31-2.12 (m, 2H), 1.97 (m, 1H), 0.98-0.92 (m, 2H), 0.75-0.69 (m, 2H)

MS(ES): m/z 372.37 [M+H]+.

Example 206

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl) (piperazin-1-yl)methanone

(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]tri azine-6-yl) piperazine-1-yl) methanone

^1H NMR (400 MHz, DMSO- d6 ) δ 12.32 (m, 1H), 10.48 (m, 1H), 7.57 (d _, J = 1.75 Hz, 1H), 7.36 (m, 1H), 6.61 (m, 1H), 3.60-3.53 (m, 5H), 2.76-2.70 (m, 4H), 1.92 (br d, J = 2.88 Hz, 6 H), 0.97-0.93 (m, 2H), 0.72-0.67 (m, 2H)

MS(ES): m/z 422.5 [M+H]+.

Example 207

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-6 -carboxamide

4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2, 4]Triazine-6-carboxamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.30 (m, 1H), 10.48 (m, 1H), 7.92 (br d, J = 4.6 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H) ), 7.38 (s, 1H), 6.58 (m, 1H), 3.45 (br s, 4H), 2.74 (d, J = 4.6 Hz, 3H), 2.51 (dt, J = 1.8, 3.6 Hz, 3H), 1.92 (br s, 6H), 0.98-0.92 (m, 2H),0.72-0.66 (m, 2H)

MS(ES): m/z 367.42 [M+H]+.

Example 208

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-7-carboxamide

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine -1-yl)-N-methylpyrrolo[2,1-f][1,2,4] triazine-7-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.28 (s, 1H,) 10.66 (s, 1H), 9.21 (s, 1H), ,7.24 (m, 1H), ,6.97 (m, 1H), ,6.59 (m, 1H), 4.08 (t, J = 1.0 Hz, 1H), 3.88-3.82 (m, 2H), 3.81-3.72 (m, 3H), 3.70-3.61 (m, 4H), 3.59-3.52 (m, 5H), 2.90 (br d, J = 4.1 Hz, 3H), 2.30 (m, 1H), 2.15 (m, 1H), 1.96 (m, 1H), 0.98-0.92 (m, 2H), 0.72 -0.65 (m, 2H)

MS(ES): m/z 500.52 [M+H]+.

Example 209

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)

pyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

(R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-6-carboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.27 (m, 1H) _, 10.43 (m, 1H), 7.95 (m, 1H), 7.85 (m, 1H), 7.45 (m, 1H), 6.55 ( m, 1H), 4.75 (m, 1H), 4.12 (m, 1H), 3.67 (m, 1H), 3.48-3.41 (m, 3H), 2.06-1.85 (m, 5H), 0.97-0.89 (m, 2H), 0.79-0.69 (m, 2H)

MS(ES): m/z 397.45 [M+H]+.

Example 210

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl) pyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide

(S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1, 2,4]triazine-6-carboxamide

^1H NMR (400 MHz, DMSO- d6 ) δ 12.28 (m, 1H), 10.43 (m, 1H), _7.95 (m, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.46 (m, 1H), 6.53 (m, 1H), 4.75 (m, 1H), 4.12 (m, 1H), 3.65 (m, 1H), 3.50-3.42 (m, 3H), 2.74 (d, J = 4.5 Hz, 3H) ), 2.04-1.84 (m, 5H), 0.95-0.88 (m, 2H), 0.79-0.71 (m, 2H)

MS(ES): m/z 397.45 [M+H]+.

Example 211

2-(4-(3-Cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo[2,1-f][1,2 ,4]triazine-6-carboxamide

2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo[2, 1-f][1,2,4]triazine-6-carboxamide

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.33 (m, 1H), 10.57 (m, 1H), 7.82 (m, 1H), 7.65 (m, 1H), 6.41 (m, 1H), 4.43- 4.36 (m, 2H), 3.76 (s, 3H), 2.88-2.77 (m, 2H), 2.22-2.14 (m, 2H), 1.95-1.87 (m, 3H), 1.75-1.67 (m, 2H), 1.65-1.57 (m, 2H), 1.56 (m, 1H), 1.36-1.29 (m, 2H), 1.17-1.05 (m, 2H), 1.01-0.93 (m, 2H), 0.70-0.63 (m, 2H) )

MS(ES): m/z 448.54 [M+H]+.

Example 212

6-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4]triazin-4-amine

6-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4] Triazine-4-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.20 (br s, 1H), 10.37 (m, 1H), 7.56 (m, 1H), 7.20 (m, 1H), 6.59 (m, 1H), 3.44 (br t, J = 6.1 Hz, 4H), 2.21 (m, 1H), 1.95-1.90 (m, 5H), 0.99-0.91 (m, 2H), 0.71-0.66 (m, 2H)

MS(ES): m/z 389.27 [M+H]+.

Experimental Example: Evaluation of the ability of pyrimidine and triazine derivatives of the present invention to inhibit Fer kinase activity

The pyrimidine and triazine derivatives of the present invention prepared in the above preparation examples were evaluated for their ability to inhibit the activity of Fer kinase.

More specifically, the ability to inhibit Fer kinase activity of the derivatives of the present invention was evaluated using an enzyme-substrate reaction between Fer (human) recombinant protein and Poly (4:1 Glu:Tyr) synthetic peptide using Promega's ADP- Measurements were made using the Glo ^TM Kinase Assay Kit as follows.

ADP-Glo ^TM Kinase Assay is an analysis method that measures ADP formed through a kinase reaction, a type of enzyme. The formed ADP is converted to ATP and generates luminescence through a luciferase reaction. The generated luminescence was proportional to the kinase activity.

This assay is very suitable for measuring the effect of compounds on the activity of various kinases and is used for primary screening and kinase selectivity profiling.

Fer (human) recombinant protein used in this experimental example was purchased from Abnova, and Poly (4:1 Glu:Tyr) synthetic peptide was purchased from Signalchem.

Evaluation and analysis of the compound's ability to inhibit Fer kinase activity were conducted according to the following method.

Using the 5X kinase buffer included in the ADP-Glo ^TM Kinase Assay, 1X kinase buffer containing DTT (Dithiothreitol) at a final concentration of 50 μmol/L was prepared by diluting it in ultrapure water.

Afterwards, 10 mmol/L ATP and 1 mg/mL Poly (4:1 Glu:Tyr) synthetic peptide were diluted 1:40 and 1:1, respectively, in 1X kinase buffer, and 200 ng/μL Fer enzyme was added at 1.3 ng/μL. It was prepared by diluting.

The derivative compounds of the present invention were diluted in DMSO to have five times the final concentration of 2000 nmol/L, 400 nmol/L, 80 nmol/L, 16 nmol/L, and 3.2 nmol/L.

After mixing 5 μL of ATP, 5 μL of Poly (4:1 Glu:Tyr) synthetic peptide, and 5 μL of the compound of the present invention prepared above in a 96 well plate, 10 μL of Fer enzyme was added and reacted at 30°C for 40 minutes.

After 40 minutes of reaction, 25 μL of ADP-Glo was added and reacted at 30°C for another 40 minutes, then 50 μL of kinase detection reagent was added and reacted at room temperature for 5 minutes. After transferring 75 μL of the reaction material to a 96 well plate, luminescence was measured using a microplate reader.

Wells to which the derivative compound of the present invention was not added were regarded as 100% kinase activity, and wells to which neither the compound nor enzyme were added were regarded as 0% kinase activity. Afterwards, the % kinase activity of the compound was calculated at each treatment concentration, and the IC ₅₀ value (Inhibition concentration 50) was calculated using the Prism program (version 8.0, Graphpad Software, Inc.) to confirm the ability to inhibit Fer enzyme activity. The results were as shown in Table 2 below.

Example Enzyme IC ₅₀ Example Enzyme IC ₅₀ One B 2 A 3 B 4 C 5 C 6 C 7 A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 A 23 A 24 A 25 A 26 A 27 A 28 A 29 A 30 A 31 A 32 B 33 B 34 B 35 B 36 A 37 B 38 A 39 A 40 B 41 B 42 B 43 A 44 A 45 B 46 C 47 C 48 C 49 B 50 C 51 B 52 C 53 C 54 B 55 B 56 C 57 A 58 A 59 A 60 B 61 A 62 B 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 71 B 72 A 73 A 74 A 75 A 76 A 77 C 78 A 79 A 80 B 81 A 82 C 83 A 84 A 85 A 86 C 87 C 88 C 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 C 98 A 99 A 100 A 101 A 102 A 103 A 104 C 105 B 106 A 107 A 108 A 109 A 110 A 111 B 112 B 113 B 114 B 115 A 116 C 117 B 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 B 129 B 130 A 131 A 132 B 133 B 134 C 135 B 136 A 137 B 138 B 139 B 140 A 141 B 142 A 143 A 144 A 145 A 146 B 147 B 148 A 149 B 150 C 151 C 152 B 153 C 154 C 155 B 156 C 157 C 158 C 159 C 160 C 161 C 162 C 163 C 164 C 165 C 166 C 167 C 168 C 169 C 170 B 171 B 172 C 173 C 174 A 175 C 176 C 177 C 178 C 179 C 180 B 181 A 182 A 183 A 184 B 185 C 186 B 187 B 188 B 189 A 190 B 191 A 192 A 193 A 194 A 195 A 196 C 197 C 198 C 199 A 200 A 201 B 202 B 203 C 204 B 205 A 206 A 207 B 208 A 209 A 210 A 211 B 212 B < 50 nM: A, 50-500 nM: B, > 500 nM: C

As shown in Table 2, it can be seen that the pyrimidine and triazine derivatives according to the examples of the present invention have excellent inhibitory ability on the activity of Fer kinase, effectively treating various cancer diseases involving Fer kinase. It can be expected to prevent, treat or improve.

In the above, the description has been made focusing on the embodiments of the present invention, but this is only an example and does not limit the present invention, and those skilled in the art will understand the present invention without departing from the essential characteristics of the embodiments of the present invention. It will be apparent that various modifications and applications not illustrated above are possible. For example, each component specifically shown in the embodiments of the present invention can be modified and implemented. And these variations and differences in application should be construed as being included in the scope of the present invention as defined in the appended claims.

Claims (6)

A compound represented by the following formula (I-1) or (I-2), an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[Formula I-1]

[Formula I-2]

(In the above formulas I-1 and I-2,
X is C or N,
Y and Z are each independently C, S or O,
Ra and Rb are each independently hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _1-6 alkoxy, hydroxy, carbonyl, carboxyl or amide, or Ra and Rb are directly or indirectly connected to each other to form C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _{2- 8} Form a heteroaryl ring compound,
The Ra and Rb or the ring compound may each independently be unsubstituted or substituted,
A is C _6-10 aryl or C _2-8 heteroaryl,
R ₁ and R ₂ are each independently hydrogen, halogen, amide, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl, R ₁ and R ₂ are directly or indirectly connected to each other to form a ring compound of C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl,
The R ₁ and R ₂ or the ring compound may each independently be unsubstituted or substituted,
L ₁ is S or S(O) ₂ ,
R ₈ is C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _2-8 heteroaryl,
R ₈ may be unsubstituted or substituted,
L ₂ is N or C,
L ₂ , R ₉ and R ₁₀ together form a C _4-8 ring compound containing one or more heteroatoms among N and O,
The ring compound may be unsubstituted or substituted.) According to claim 1,
In the above formulas I-1 and I-2,
When X is C, Y is S or O, and when X is N, Y is C,
Z is C,
Ra and Rb are each independently hydrogen, bromo, methyl, ethyl, propyl, piperidinyl, piperidinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, pyrazolyl, tetrahydropyridinyl, phenyl, C _1-3 alkylene oxide, amide, nitro, hydroxy or carbonyl, or Ra and Rb are linked together to form hexane,
The Ra and Rb or the hexane are each independently unsubstituted or methyl, hydroxy, methoxy, ethoxy, fluoro, chloro, cyano, amino, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pipera may be substituted with one or more selected from the group consisting of zinyl, cyclopropyl, and phenyl,
A is azolyl, phenyl, or pyridinyl,
R ₁ and R ₂ are each independently cyclopropyl, methyl, ethyl, cyclopentyl, butyl, phenyl, furanyl, or amide, or R ₁ and R ₂ are directly or indirectly linked to each other to form tetrahydrothiophene, pyridine, or cyclohexane. or forms benzene,
The R ₁ and R ₂ or the ring compound may each independently be unsubstituted or substituted with one or more selected from the group consisting of methyl, cyclopropyl, and fluoro,
R ₈ is C _3-8 cycloalkyl or C _6-10 aryl,
R ₈ is unsubstituted or one or more selected from the group consisting of halogen, amino, amide, hydroxy, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, and C _2-8 heterocycloalkyl. It can be replaced with
L ₂ , R ₉ and R ₁₀ are one of the following formulas,

B is C, N or O,
D and D' are each independently absent or C _1-3 alkylene,
n is an integer from 0 to 4,
R ₁₁ is hydrogen, C _1-6 alkyl, hydroxy, C _3-8 cycloalkyl or C _2-8 heterocycloalkyl,
R ₁₂ is hydrogen, C _1-6 alkyl, hydroxy, cyano, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl or carbonyl,
R ₁₃ is hydrogen, halogen, C _1-6 alkyl, amino, nitro, cyano, C _1-6 alkoxy, hydroxy, carboxyl or amide,
Wherein R ₁₁ to R ₁₃ are each independently unsubstituted or C _1-6 alkyl, hydroxy, cyano, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, nitro, may be substituted with one or more selected from the group consisting of halogen, C _2-8 heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl and carbonyl,
B and R ₁₂ may be directly or indirectly connected to each other to form C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl.
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. According to clause 2,
In the above formulas I-1 and I-2,
Ra and Rb are expressed as one of the following formulas,

A is pyrazolyl, thiazolyl, phenyl, or pyridinyl,
A, R ₁ and R ₂ are one of the following formulas,

R ₈ is cyclopentyl, cyclohexyl, cycloheptyl or benzyl,
R ₈ may be unsubstituted or substituted with one or more selected from the group consisting of chloro, fluoro, methyl, cyclohexyl, phenyl, amino, pyrrolidinyl, amide, and hydroxy,
B is C or N,
n is an integer from 0 to 3,
R ₁₁ is hydrogen, methyl, hydroxy or pyrrolidinyl,
R ₁₂ is hydrogen, methyl, butyl, hydroxy, cyano, morpholinyl, pyrrolidinyl, phenyl, amino, fluoro, Boc (t-butyloxycarbonyl, tert-Butyloxycarbonyl), diazaspirodecane ), triazolyl, thiophenyl, thiazolyl, tetrahydrothiopyranyl, methoxy, sulfonyl, amide, carboxyl or carbonyl,
R ₁₁ and R ₁₂ are each independently unsubstituted or methyl, butyl, hydroxy, cyano, morpholinyl, pyrrolidinyl, phenyl, amino, fluoro, Boc, triazolyl, thiophenyl, thiazolyl, tetra. May be substituted with one or more selected from the group consisting of hydrothiopyranyl, methoxy, sulfonyl, amide, carboxyl and carbonyl.
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. According to clause 3,
One of the following compounds 1 to 212, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
(1) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol
(2) (1-(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) methanol
(3) (1-(4-((5-ethyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) methanol
(4) 1-(4-((4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)amino)thieno[3,2-d]pyrimidine-2 -1)piperidine-4-1)methanol
(5) (1-(4-((1H-pyrazolo[3,4-b]pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol
(6) (1-(4-((4,5,6,7-tetrahydro-1H-indazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)p Peridin-4-yl)methanol
(7) (1-(4-((5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidine-2- 1) piperidin-4-yl) methanol
(8) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) ethane-1-ol
(9) 1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) ethane-1-ol
(10) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Acetonitrile
(11) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3-yl )methanol
(12) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-3 -1) ethane-1-ol
(13) (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine -3-day) methanol
(14) (R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidine -3-day) methanol
(15) (S)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)p peridin-4-yl)ethan-1-ol
(16) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Propan-1-ol
(17) (R)-1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)p peridin-4-yl)ethan-1-ol
(18) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Propane Nitrile
(19) 1-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Propan-2-ol
(20) 1-(1-(4-((5-cyclopropylthiazol-2-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl) Propane-2-ol
(21) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -yl)-2-methylpropan-1-ol
(22) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-3 -1) ethane-1-ol
(23) (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidine -3-day) methanol
(24) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Propan-1-ol
(25) 3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazine-1- 1) Propan-1-ol
(26) 4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1)Butanenitrile
(27) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1)Butan-1-ol
(28) (R)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidine -3-day) methanol
(29) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,8-diazaspiro[4.5]decan-8-yl)thieno[3,2-d]pyri Mydin-4-amine
(30) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-morpholinopiperidin-1-yl)thieno [3,2-d]pyrimidine-4- amine
(31) 1-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazine-1- 1) Propane-2-ol
(32) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)-3-methylp peridin-4-yl)ethane-1-ol
(33) 4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Butan-2-ol
(34) 2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl) thieno[3,2-d]pyrimidin-4-amine
(35) 3-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperidin-4 -yl)-2-methylpropan-1-ol
(36) 2-(4-(2-aminoethyl)piperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyri Mydin-4-amine
(37) 3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazine-1- 1) Propane Nitrile
(38) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3,2-d]pyri Mydin-4-amine
(39) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl) thieno [3,2-d]pyri Mydin-4-amine
(40) 2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(41) 2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl) thieno[3,2-d]pyrimidine-4- amine
(42) 2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine
(43) 2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(44) 2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(45) 2-(cyclohexylthio)-N-(5-cyclopentyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(46) 2-(cyclohexylthio)-N-(1,5-dimethyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(47) N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine
(48) 2-(cyclohexylthio)-N-(4-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine
(49) 2-(cyclohexylthio)-N-(5-(cyclopropylmethyl)-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine
(50) N-(5-cyclohexyl-1H-pyrazol-3-yl)-2-(cyclohexylthio)thieno[3,2-d] pyrimidin-4-amine
(51) 2-(cyclohexylthio)-N-(5-isopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(52) 2-(cyclohexylthio)-N-(5-phenyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(53) 2-(cyclohexylthio)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(54) 2-(cyclohexylthio)-N-(5-(1-methylcyclopropyl)-1H-pyrazol-3-yl) thieno[3,2-d]pyrimidin-4-amine
(55) 2-(cyclohexylsulfonyl)-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(56) 2-(cyclohexylthio)-N-(1H-indazol-3-yl)thieno[3,2-d]pyrimidin-4-amine
(57) 2-((cyclohexylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno [3,2-d] pyrimidin-4-amine
(58) 2-(cycloheptylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(59) 2-(benzylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d] pyrimidin-4-amine
(60) 2-((1-cyclohexylethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine
(61) 2-((cyclopentylmethyl)thio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno [3,2-d]pyrimidin-4-amine
(62) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperidin-1-yl)methyl)thieno[3, 2-d]pyrimidin-2-yl)piperidin-4-yl)methanol
(63) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((4,4-difluoropiperidin-1-yl)methyl)thi no[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol
(64) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyri midin-2-yl)piperidin-4-yl)methanol
(65) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-((3,3-difluoropyrrolidin-1-yl)methyl)thi no[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol
(66) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)piperidine -4-day) methanol
(67) (1-(6-bromo-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperi din-4-yl)methanol
(68) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylthieno [3,2-d] pyrimidin-2-yl)p peridin-4-yl)ethane-1-ol
(69) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]pyrimidin-2- yl)piperidin-4-yl)methanol
(70) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-phenylthieno[3,2-d]pyrimidin-2-yl)piperidine -4-day) methanol
(71) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(4-(trifluoromethyl)phenyl)thieno[3,2-d] Pyrimidin-2-yl)piperidin-4-yl)methanol
(72) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)thi no[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol
(73) (1-(6-(4-aminophenyl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidine-2- 1) piperidin-4-yl) methanol
(74) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(piperidin-4-yl)-1H-pyrazol-4- I) thieno [3,2- d] pyrimidin-2-yl) piperidin-4-yl) methanol
(75) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4- I) thieno [3,2- d] pyrimidin-2-yl) piperidin-4-yl) methanol
(76) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4- 1) thieno [3,2-d] pyrimidin-2-yl) piperidin-4-yl) methanol
(77) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl) Thieno[3,2-d] pyrimidin-2-yl)piperidin-4-yl)methanol
(78) 2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno [3,2-d]pyrimidin-6-yl)-1H-pyrazole -1-yl)acetonitrile
(79) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)thieno[ 3,2-d]pyrimidin-2-yl)piperidin-4-yl)methanol
(80) 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl) benzonitrile
(81) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl)propan-2-ol
(82) tert-Butyl 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2- d]pyrimidin-2-yl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate
(83) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2 -d]pyrimidin-2-yl)pyrrolidin-3-ol
(84) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-morpholinopiperidin-1-yl)thieno[3,2-d ]pyrimidin-6-yl)propan-2-ol
(85) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(morpholinomethyl)piperidin-1-yl)thieno[3 ,2-d]pyrimidin-6-yl)propan-2-ol
(86) 2-(2-(4-((1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)-4-((5-cyclopropyl-1H- pyrazol-3-yl) amino) thieno [3,2-d] pyrimidin-6-yl) propan-2-ol
(87) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiophen-2-ylmethyl)piperidin-1-yl)thi no[3,2-d]pyrimidin-6-yl)propan-2-ol
(88) 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(thiazol-2-ylmethyl)piperidin-1-yl)thi no[3,2-d]pyrimidin-6-yl)propan-2-ol
(89) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2- d]pyrimidin-6-yl)methanol
(90) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl) ethane-1-ol
(91) 3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl)oxetan-3-ol
(92) Cyclopropyl (4-((5-cyclopropyl-1H-pyrazol-3-yl) amino) -2- (4- (hydroxymethyl) piperidin-1-yl) thieno [3, 2-d]pyrimidin-6-yl)methanol
(93) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl) propan-1-ol
(94) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl)-2-phenylethan-1-ol
(95) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-methoxypropan-2-yl)thieno[3,2-d] Pyrimidin-2-yl)piperidine-4-yl)methanol
(96) 2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2- d]pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile
(97) 4-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-(2-hydroxypropan-2-yl)thieno[3,2- d]pyrimidin-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide
(98) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N-methylthieno[3 ,2-d]pyrimidine-6-carboxamide
(99) Methyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2- d]pyrimidine-6-carboxylate
(100) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3, 2-d]pyrimidin-6-yl)ethane-1-one
(101) (S)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[ 3,2-d]pyrimidin-6-yl)(3-fluoropyrrolidin-1-yl)methanone
(102) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)thieno[3,2- d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone
(103) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(4-(hydroxymethyl)piperidin-1-yl)-N,N-dimethylthieno [3,2-d]pyrimidine-6-carboxamide
(104) 2-((2-chloro-6-(2-hydroxypropan-2-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-N-methylbenzamide
(105) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)p Peridin-4-yl)methanol
(106) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl ) piperidin-4-yl) propan-1-ol
(107) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl ) piperidin-4-yl) acetonitrile
(108) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl ) piperidin-4-yl) ethane-1-ol
(109) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidin-2-yl ) piperidin-4-yl) -2-methylpropan-1-ol
(110) 2-((1s,4s)-7-azabicyclo[2.2.1]heptan-7-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5 ]thieno[3,2-d]pyrimidin-4-amine
(111) 2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzo[4,5] thieno[3,2-d]pyrimidin-4-amine
(112) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4 -1) ethane-1-ol
(113) (1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4-yl )methanol
(114) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Acetonitrile
(115) 2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzofuro[3,2-d]pyrimidin-2-yl)piperidin-4 -1) Propan-1-ol
(116) 2-(4-benzylpiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl) benzofuro[3,2-d]pyrimidin-4-amine
(117) 3-cyclopentyl-3-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl) amino) benzo [4,5] thieno [3,2-d] pyri midin-2-yl)-1H-pyrazol-1-yl) propanenitrile
(118) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-fluoropyrrolidin-1-yl)benzo [4,5]thieno[3 ,2-d]pyrimidin-4-amine
(119) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidine-2- 1) Pyrrolidin-3-ol
(120) (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidine-2 -yl)pyrrolidin-3-yl)methanol
(121) (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidine-2- 1) Pyrrolidin-3-ol
(122) (R)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3, 2-d]pyrimidin-4-amine
(123) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thieno[3, 2-d]pyrimidin-4-amine
(124) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4,5]thi No[3,2-d]pyrimidin-4-amine
(125) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidine-2- 1) Pyrrolidine-3-carbonitrile
(126) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)benzo[4,5 ]thieno[3,2-d]pyrimidin-4-amine
(127) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidine-2- 1) Pyrrolidine-3-carboxamide
(128) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno [3,2-d]pyrimidine-2- I)-N,N-methylpyrrolidine-3-carboxamide
(129) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)benzo[4,5] thieno[3,2-d]pyrimidine- 4-amine
(130) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-phenylpyrrolidin-1-yl)benzo [4,5]thieno[3,2-d] Pyrimidin-4-amine
(131) 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)pyrroli Din-3-carboxylic acid
(132) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methylpyrrolidin-1-yl)benzo [4,5] thieno [3, 2-d]pyrimidin-4-amine
(133) (1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)piperidine- 4-day) methanol
(134) N-(5-cyclopropylthiazol-2-yl)-2-(pyrrolidin-1-yl)benzo[4,5]thieno [3,2-d]pyrimidin-4-amine
(135) (S)-1-(4-((5-cyclopropylthiazol-2-yl)amino)benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)p Rolidin-3-ol
(136) (S)-N-(5-cyclopropylthiazol-2-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl) benzo[4,5]thieno[3 ,2-d]pyrimidin-4-amine
(137) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6-fluorobenzo [4,5]thieno[3,2-d] Pyrimidin-2-yl)pyrrolidin-3-ol
(138) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5] Thieno[3,2-d]pyrimidin-4-amine
(139) N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(pyrrolidin-1-yl) benzo[4,5]thieno[3,2- d]pyrimidin-4-amine
(140) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-8-fluorobenzo [4,5]thieno[3,2-d] Pyrimidin-2-yl)pyrrolidin-3-ol
(141) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-methoxypyrrolidin-1-yl)benzo[4,5] Thieno[3,2-d]pyrimidin-4-amine
(142) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-8-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[ 4,5]thieno[3,2- d]pyrimidin-4-amine
(143) (S)-1-(7-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5]thieno[3,2-d]pyri midin-2-yl)pyrrolidin-3-ol
(144) (S)-7-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl)benzo[4,5]thi No[3,2-d]pyrimidine-4-amine
(145) (S)-7-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)benzo[4 ,5]thieno[3,2- d]pyrimidin-4-amine
(146) Tert-Butyl 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)benzo[4,5] thieno[3,2-d]pyrimidin-2-yl )-3,6-dihydropyridine-1(2H)-carboxylate
(147) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[4,5]thieno[3 ,2-d]pyrimidine-4 -amine
(148) 2-(cyclohexylthio)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine
(149) 2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazine-4-amine
(150) 2-((4,4-dimethylcyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2,4] Triazine-4-amine
(151) 2-((4,4-difluorocyclohexyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2, 4]triazine-4-amine
(152) 2-(cyclohexylthio)-N-(5-ethyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4] triazine-4-amine
(153) N-(5-methyl-1H-pyrazol-3-yl)-2-((4-phenylcyclohexyl)thio)pyrrolo[2,1-f] [1,2,4]triazine -4-amine
(154) 2-(cyclohexylthio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo[2,1-f][1,2,4]triazine- 4-amine
(155) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-((4,4-dimethylcyclohexyl)thio)pyrrolo[2,1-f][1,2,4 ]Triazine-4-amine
(156) 2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine- 4-amine
(157) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2- 1)thio)phenyl)-4-(4-methylpiperazin-1-yl)benzamide
(158) 2-((4-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)-6-nitropyrrolo [2,1-f][1,2,4 ]Triazine-4-amine
(159) 2-((4-aminophenyl)thio)-N-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine- 4-amine
(160) 2-((4-aminophenyl)thio)-N-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine
(161) 2-((3-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine- 4-amine
(162) 2-((2-aminophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine- 4-amine
(163) 2-chloro-N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f] [1,2,4]tri azine-2-yl)thio)phenyl)acetamide
(164) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2- I)thio)phenyl)cyclohexanecarboxamide
(165) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2- I)thio)phenyl)benzamide
(166) N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2- I)thio)phenyl)-2-phenylacetamide
(167) N-(3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2- I)thio)phenyl)-2-phenylacetamide
(168) 2-((3-methoxyphenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine -4-amine
(169) 2-((3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4]triazine -4-amine
(170) 3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenol
(171) 2-((4-amino-3-fluorophenyl)thio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1,2, 4]triazine-4-amine
(172) (R)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-(2-fluoro-4-(( 4-((5-methyl-1H-pyrazol-3)-yl)amino)pyrrolo[2,1-f][1,2,4] riazin-2-yl)thio)phenyl)acetamide
(173) 4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thio )phenol
(174) (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-2 -1) pyrrolidin-3-ol
(175) 1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrroli din-3-ol
(176) (R)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1, 2,4]triazine-4-amine
(177) (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo [2,1-f][1, 2,4]triazine-4-amine
(178) (S)-N-(5-methyl-1H-pyrazol-3-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4]triazine-4-amine
(179) (S)-2-(3-fluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine
(180) 2-(3,3-difluoropyrrolidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl) pyrrolo[2,1-f][1, 2,4]triazine-4-amine
(181) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-methoxypyrrolidin-1-yl) pyrrolo[2,1-f][1 ,2,4]triazine-4-amine
(182) (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrrolo[2,1- f][1,2,4]triazine-4-amine
(183) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4]triazine -4-amine
(184) 2-(4-aminopiperidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f] [1,2,4] Triazine-4-amine
(185) N-(5-methyl-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)pyrrolo[2,1-f] [1,2,4]tri Azine-4-amine
(186) 1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperi din-4-ol
(187) 1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperi din-4-yl)methanol
(188) N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]tri Azine-4-amine
(189) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1 ,2,4]triazine-7 -carboxamide
(190) Cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f] [1,2,4]triazine-7- 1)(pyrrolidin-1-yl)methanone
(191) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2, 4]triazine-7-yl)(piperazine-1-yl)methanone
(192) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-7-carboxamide
(193) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-N-methylpyrrolo[ 2,1-f][1,2,4]triazine-7-carboxamide
(194) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methyl Pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide
(195) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methyl Pyrrolo[2,1-f][1, 2,4]triazine-7-carboxamide
(196) (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)(pyrrolidin-1-yl)methanone
(197) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N,N -Dimethylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide
(198) (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone
(199) (R)-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)(piperazine-1-yl)methanone
(200) 2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo [2,1-f][1,2,4]triazine-7-carboxamide
(201) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(2-(pyrrolidin-1-ylmethyl)pyrrolidine -1-yl) pyrrolo[2,1- f][1,2,4]triazine-7-carboxamide
(202) ethyl 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2, 4]Triazine-6-carboxylate
(203) Ethyl (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1 -f][1,2,4] triazine-6-carboxylate
(204) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2,4 ]Triazine-6-carboxylic acid
(205) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid
(206) (4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(pyrrolidin-1-yl)pyrrolo [2,1-f][1,2, 4]triazine-6-yl)(piperazine-1-yl)methanone
(207) 4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methyl-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1 ,2,4]triazine-6 -carboxamide
(208) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl) Pyrrolidin-1-yl)-N-methylpyrrolo[2,1-f][1,2,4] triazine-7-carboxamide
(209) (R)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methyl Pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide
(210) (S)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-methyl Pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide
(211) 2-(4-(3-cyanopropyl)piperidin-1-yl)-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-N-methylpyrrolo [2,1-f][1,2,4]triazine-6-carboxamide
(212) 6-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2 ,4]triazine-4-amine A pharmaceutical composition for the prevention or treatment of cancer comprising the compound of any one of claims 1 to 4, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. A method for producing pyrimidine and triazine derivatives comprising steps according to one of Schemes 1 to 5 below.
[Scheme 1]

(a) reacting the compound 1-1 with the compound a) to obtain the compound 1-2; and
(b) reacting the compound 1-2 with the compound b) to obtain the compound 1-3
[Scheme 2]

(a) reacting the compound 2-1 with the compound a) to obtain the compound 2-2; and
(b) reacting the compound 2-2 with the compound b) to obtain the compound 2-3
[Scheme 3]

(a) reacting the compound 3-1 with the compound a) to obtain the compound 3-2; and
(b) reacting the compound 3-2 with the compound b) to obtain the compound 3-3
[Scheme 4]

(a) reacting the compound 4-1 with the compound a) to obtain the compound 3-2; and
(b) reacting the compound 4-2 with the compound b1) or b2) to obtain the compound 4-3 or 4-4
(In Schemes 1 to 5 above,
Ra and Rb are each independently hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _1-6 alkoxy, hydroxy, carbonyl, carboxyl or amide, or Ra and Rb are directly or indirectly connected to each other to form C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _{2- 8} Form a heteroaryl ring compound,
The Ra and Rb or the ring compound may each independently be unsubstituted or substituted,
R ₁ , R ₂ and R ₃ are each independently hydrogen, halogen, amide, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _2-8 hetero It is aryl, or two or more of R ₁ to R ₃ are directly or indirectly connected to each other to form a ring compound of C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, or C _2-8 heteroaryl. do,
The R ₁ , R ₂ and R ₃ or the ring compound may each independently be unsubstituted or substituted,
R ₄ is hydrogen, C _1-6 alkyl, hydroxy or C _2-8 heterocycloalkyl,
R ₅ , R ₆ and R ₇ are each independently hydrogen, C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 heteroaryl , C _1-6 alkoxy, sulfonyl, amide, carboxyl or carbonyl,
Wherein R ₅ , R ₆ and R ₇ are each independently unsubstituted or C _1-6 alkyl, hydroxy, cyano, C _2-8 heterocycloalkyl, C _6-10 aryl, amino, halogen, C _2-8 may be substituted with one or more selected from the group consisting of heteroaryl, C _1-6 alkoxy, sulfonyl, amide, carboxyl and carbonyl,
R ₈ is hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl, C _2-8 heteroaryl, amino, nitro, C _1-6 alkoxy , hydroxy, carbonyl, carboxyl or amide,
R ₈ may be unsubstituted or substituted,
L ₁ is S or S(O) ₂ ,
R ₉ is C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocycloalkyl, C _6-10 aryl or C _2-8 heteroaryl,
R ₉ may be unsubstituted or substituted,
Z is C, N or O,
n is an integer from 0 to 4,
m is an integer from 0 to 3,
Q is S, N or O.)