KR20230118695A - Adenosine A2A receptor antagonists and uses thereof - Google Patents

Abstract

The present invention provides an adenosine A2A receptor antagonist, a pharmaceutical composition for preventing or treating adenosine A2A receptor-related diseases (eg, cancer) including the same, and methods for treating and preventing diseases using the same. The compound represented by Chemical Formula 1 of the present invention exhibits excellent antagonistic activity against adenosine A2A receptors and can effectively prevent or treat diseases (eg, cancer) related to adenosine A2A receptors.

Description

Adenosine A2A receptor antagonists and uses thereof

The present invention relates to a novel A2A receptor antagonist and its use, and more particularly, to a novel A2A receptor antagonist of Formula 1 and a pharmaceutical composition for cancer treatment containing the novel A2A receptor antagonist.

Adenosine is a purine nucleoside that regulates various physiological functions and belongs to the G protein-coupled receptor (GPCR) superfamily of adenosine A1, A2A, A2B and A3 receptors (A1R, A2AR, A2BR). and A3R) to show regulatory functions. Among them, adenosine A2A receptors (hereinafter referred to as A2ARs) have been studied as Parkinson's disease treatment drugs based on the functional interaction between A2AR and dopamine D2 in the basal ganglia. In addition, A2AR antagonism is known to be associated with therapeutic effects such as cognitive enhancement, neuroprotection and analgesia. Recently, it has been reported that A2AR plays an important role in life activities, such as regulating vasodilation, supporting the formation of new blood vessels, and protecting body tissues from inflammatory damage. Thus, inhibitors of A2AR may provide potent anti-cancer effects.

Hypoxia in tumor tissue induces the accumulation of higher concentrations of adenosine (~10 μM vs. ~20 nM at physiological levels). Activation of adenosine signaling causes sustained suppression of the innate immune response, which leads to uncontrolled growth of malignant tumors through immune tolerance. The binding of adenosine and A2AR in leukocytes such as lymphocytes, T lymphocytes, natural killer cells, and dendritic cells can suppress the immune function of these leukocytes. In addition, binding of adenosine and A2AR increases the expression of CD39, CD73 and CTLA4 (T cell checkpoint), resulting in more Treg cells with stronger immunosuppressive properties. Therefore, blocking the A2AR signaling pathway can induce a decrease in the suppressive effect on the immune system and an improvement in the immune function of T cells, so A2AR blockade is considered a promising negative feedback mechanism that can inhibit tumor growth.

Accordingly, an object of the present invention is to provide a novel A2AR antagonist exhibiting excellent antagonistic activity against adenosine A2A receptors, and using the same to restore or improve the immune response to have high efficacy in the treatment and prevention of cancer and other types of abnormal cell proliferation. is to achieve

An object of the present invention is to provide an A2AR antagonist represented by Formula 1.

Another object of the present invention is to provide a pharmaceutical composition comprising an A2AR antagonist represented by Formula 1 for preventing or treating diseases associated with A2AR.

Another object of the present invention is to provide a method for preventing or treating diseases associated with A2AR using the A2AR antagonist represented by Formula 1.

Each description and embodiment disclosed in this application can also be applied to each other description and embodiment. That is, all combinations of various elements disclosed in this application fall within the scope of this application. In addition, the scope of the present application is not to be construed as being limited by the specific descriptions described below.

One aspect of the present invention provides a compound represented by Formula 1, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof:

[Formula 1]

.

.

In Formula 1, G ¹ is -(CH ₂ ) _l -ring A, and G ² may be H or -(CH ₂ ) _m -pyridinyl. In this case, l and m are each independently an integer of 0, 1, 2 or 3. In one embodiment, l and m may each independently be an integer of 0, 1 or 2, preferably an integer of 0 or 1.

In one embodiment, G ¹ can be Ring A or -(CH ₂ )-Ring A.

The ring A is C _6-12 aryl; 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; 4-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S; and 4-6 membered cycloalkyl. In one embodiment, Ring A is C _6-10 aryl; 5- or 6-membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; 4-6 membered heterocyclyl containing 1 N; and 4-6 membered cycloalkyl. In one embodiment, Ring A can be selected from the group consisting of phenyl, furanyl, thiazolyl, pyrimidinyl, azetidinyl and cyclobutyl. In one embodiment, ring A is selected from the group consisting of phenyl, furan-2-yl, furan-3-yl, thiazol-5-yl, pyrimidin-5-yl, azetidin-1-yl and cyclobutyl It can be.

Ring A is selected from halogen, -CN, -OH, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkoxy, and NR ^A R ^B It may be substituted or unsubstituted with one or more substituents selected from the group consisting of In this case, R ^A and R ^B may each independently be H or C _1-6 alkyl. In one embodiment, ring A is halogen, -CN, -OH, C _1-4 alkyl, C _1-4 alkyl substituted with halogen, C _1-4 alkoxy, C _1-4 alkoxy substituted with halogen, and NR It may be unsubstituted or substituted with one or two substituents selected from the group consisting of ^A R ^B . In this case, R ^A and R ^B may each independently be H or C _1-4 alkyl. In one embodiment, ring A may be unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, -CN, -OH, -NH ₂ and C _1-4 alkyl.

For example, G ¹ is tolyl, cyanotolyl, cyanophenyl, phenyl, furanyl, furanylmethyl, thiazolyl, methylthiazolyl, pyrimidinyl, azetidinyl, aminoazetidinyl, cyclobutyl, or cyclobutyl substituted with one or more halogens, but is not limited thereto. For example, G ¹ is 3-cyano-o-tolyl, furan-2-yl, furan-3-yl, furan-2-ylmethyl, 2-methylthiazol-5-yl, pyrimidine-5- 1, 3-amino-azetidin-1-yl or 3,3-difluorocyclobutyl, but is not limited thereto.

In one embodiment, G ² can be H or pyridinyl. For example, G ² can be H or pyridin-4-yl, but is not limited thereto.

In one embodiment, G 2 may be bonded to position 5 of the pyrimidine ring to which G ¹ and G ² are bonded in Formula 1, and ^{G 1 may} be bonded to the remaining substitutable carbon atoms of the pyrimidine ring. For example, the G ² may be bonded to a para (para: p-) position or 1,4 position based on the amino group bonded to the pyrimidine ring, and the G ¹ may be the remaining substituents of the pyrimidine ring. can be bonded to carbon atoms.

In one embodiment, G ¹ is -(CH ₂ ) _l -Ring A, and G ² can be H. In another embodiment, G ¹ is -(CH ₂ ) _l -Ring A and G ² can be -(CH ₂ ) _m -pyridinyl. In this case, l and m may each independently be 0 or 1. For example, the -(CH ₂ ) _l -ring A may be -(CH ₂ ) _l -furanyl. For example, the -(CH ₂ ) _l -furanyl may be furan-2-yl, furan-3-yl or furan-2-ylmethyl. For example, the -(CH ₂ ) _m -pyridinyl may be pyridin-4-yl or pyridin-4-ylmethyl.

In one embodiment, X ¹ and X ² are each independently C or N, X ³ is CR' or N, and X ⁴ is CH, N or NH, wherein X ¹ , X ² , X ³ and X ⁴ are 1 to 3 may be N or NH, and R' may be H or -(CH ₂ ) _n -pyridinyl. In this case, n is an integer of 0, 1, 2 or 3. Also, n may be an integer of 0, 1 or 2, preferably an integer of 0 or 1. In one embodiment, R' can be pyridinyl or -(CH ₂ )-pyridinyl. For example, R' can be pyridin-4-yl or pyridin-4-ylmethyl.

은 벤조트리아졸일, [1,2,4]트리아졸로[4,3-a]피리딘일, [1,2,3]트리아졸로[1,5-a]피리딘일, [1,2,4]트리아졸로[1,5-a]피리딘일, 인다졸릴, 벤즈이미다졸릴, 인돌릴 및 이소인돌릴로 이루어진 군으로부터 선택될 수 있다.In one embodiment,

is benzotriazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,4] triazolo[1,5-a]pyridinyl, indazolyl, benzimidazolyl, indolyl and isoindolyl.

은 하기 군으로부터 선택될 수 있다:

,

,

,

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.In one embodiment,

may be selected from the group:

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,

and

.

은

이고, l 및 m은 0 또는 1일 수 있다.In one embodiment, G ¹ is -(CH ₂ ) _l -Ring A, G ² is H or -(CH ₂ ) _m -pyridinyl;

silver

And, l and m may be 0 or 1.

은

,

,

또는

이고, R'은 H, 피리딘일 또는 -(CH₂)-피리딘일일 수 있다. 이 경우, 고리 A는 퓨란일일 수 있다.

이

인 경우, R'은 피리딘일 또는 -(CH₂)피리딘일일 수 있다.In one embodiment, G ¹ is Ring A and G ² is H;

silver

,

,

or

, and R' may be H, pyridinyl or -(CH ₂ )-pyridinyl. In this case, ring A may be furanyl.

this

, R' may be pyridinyl or -(CH ₂ )pyridinyl.

R is -OH, -O-(CH ₂ ) _o -R ¹ , -(CH ₂ ) _p -OR ² , -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r -O- CO-R ⁴ or -CO-R ⁵ . In this case, o and p are each independently an integer of 0, 1, 2, 3, 4 or 5, and q and r are each independently an integer of 0, 1, 2 or 3. In one embodiment, o and p may each independently represent an integer of 0, 1, 2 or 3, and q and r may each independently represent an integer of 0 or 1.

In one embodiment, R may be bonded to a carbon atom not adjacent to a 5-membered ring comprising X ¹ to X ⁴ . In this case, the compound of Formula 1 may be represented by any one of the following structural formulas:

Wherein R ¹ and R ² are each independently C _4-6 cycloalkyl; 5-6 membered heteroaryl containing 1 to 3 N or O; 5-6 membered heterocyclyl containing 1 to 2 N; and C _6-12 aryl. In one embodiment, R ¹ and R ² are each independently C _4-6 cycloalkyl; 5-6 membered heteroaryl containing 1-2 N and optionally 1 O; 5-6 membered heterocyclyl containing 1 N; and phenyl. In one embodiment, R ¹ and R ² may each independently be selected from the group consisting of cyclopentyl, pyridinyl, pyrazolyl, oxadiazolyl, imidazolyl, piperidinyl and phenyl.

The R ¹ and R ² are each independently halogen; cyano; OH; amino; nitro; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO-(C _1-6 alkyl); C _1-6 alkyl optionally interrupted by 1-2 O; C _1-6 alkoxy optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO-(C _1-6 alkyl); C _6-12 aryl optionally substituted with R″; and a 5-6 membered heterocyclyl containing 1-2 N, O or S optionally substituted with R'''. In one embodiment, R ¹ and R ² are each independently halogen; cyano; OH; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO-(C _1-6 alkyl); C _1-6 alkyl optionally interrupted by 1-2 O; C _1-6 alkoxy; phenyl optionally substituted with R″; and a 5-6 membered heterocyclyl containing 1-2 Ns optionally substituted with R''', such as pyrrolidinyl optionally substituted with R'''. there is.

Wherein R″ and R″″ are each independently selected from halogen, cyano, OH, amino, nitro, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl, and C _1-6 alkoxy can be selected from the group. In one embodiment, R″ and R″″ are each independently selected from the group consisting of halogen, cyano, OH, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl and C _1-6 alkoxy. can be selected from.

Wherein R ³ , R ⁴ and R ⁵ are each independently -NH-C _6-12 aryl; -NH-(5-6 membered heteroaryl containing 1-2 N, O or S); and -NR ^a R ^b . In this case, R ^a and R ^b together with the N to which they are attached form a 5-6 membered heterocyclyl optionally further containing 1 N, wherein the 5-6 membered heterocyclyl is optionally -(CH ₂ ) _s - It may be substituted with C _6-12 aryl or fused with C _6-12 aryl. In this case, s is an integer of 0, 1, 2 or 3. In one embodiment, R ³ , R ⁴ and R ⁵ are each independently -NH-phenyl; -NH-(5-6 membered heteroaryl containing 1 N, O or S); and NR ^a R ^b , wherein R ^a and R ^b together with the N to which they are bonded form piperazinyl or piperidinyl, wherein the piperazinyl or piperidinyl is optionally -(CH ₂ ) _s -Can be substituted with phenyl or fused with phenyl. In this case, s may be an integer of 0 or 1.

For example, R ³ can be -NH-phenyl, or piperazinyl optionally substituted with phenyl or -(CH ₂ )-phenyl, but is not limited thereto. For example, R ⁴ can be —NH-thiophenyl or tetrahydroisoquinolinyl, but is not limited thereto. For example, R ⁵ can be -(CH ₂ )-phenyl or piperazinyl optionally substituted with phenyl, but is not limited thereto.

Wherein R ³ , R ⁴ and R ⁵ are each independently halogen, cyano, OH, amino, nitro, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl, and C _1-6 alkoxy; It may be optionally substituted with a substituent selected from the group.

은

일 수 있다. 이 경우, R은 -OH, -O-(CH₂)_o-R¹, -(CH₂)_p-O-R², -O-(CH₂)_q-CO-R³, -(CH₂)_r-O-CO-R⁴ 또는 -CO-R⁵일 수 있고, R¹ 내지 R⁵, o, p, q 및 r은 전술한 바와 같다. 예를 들어, R은 -OH, -O-(CH₂)_o-R¹ 또는 -(CH₂)_p-O-R²일 수 있고(o 및 p는 각각 0 또는 1), 상기 R¹ 및 R²는 각각 독립적으로 C_4-6 사이클로알킬일 수 있다. 상기 R¹ 및 R²는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C_1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C_1-6 알킬)로 임의로 치환된 C_1-6 알킬; 또는 임의로 1~2개의 O에 의해 중단된 C_1-6 알킬로 임의로 치환될 수 있다.In one embodiment, G ¹ in Formula 1 is furanyl or -CH ₂ -furanyl, G ² is H, pyridinyl or -CH ₂ -pyridinyl;

silver

can be In this case, R is -OH, -O-(CH ₂ ) _o -R ¹ , -(CH ₂ ) _p -OR ² , -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r It may be -O-CO-R ⁴ or -CO-R ⁵ , and R ¹ to R ⁵ , o, p, q and r are as described above. For example, R may be -OH, -O-(CH ₂ ) _o -R ¹ or -(CH ₂ ) _p -OR ² (o and p are each 0 or 1), wherein R ¹ and R ² Each may independently be C _4-6 cycloalkyl. The R ¹ and R ² are each independently halogen; cyano; OH; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO-(C _1-6 alkyl); or C _1-6 alkyl optionally interrupted by 1-2 O.

은

이고, R'은 피리딘일 또는 -(CH₂)-피리딘일일 수 있다. 이 경우, R은 -OH, -O-(CH₂)_o-R¹, -(CH₂)_p-O-R², -O-(CH₂)_q-CO-R³, -(CH₂)_r-O-CO-R⁴ 또는 -CO-R⁵일 수 있고, R¹ 내지 R⁵, o, p, q 및 r은 전술한 바와 같다. 예를 들어, R은 -OH, -O-(CH₂)_o-R¹ 또는 -(CH₂)_p-O-R²일 수 있고(o 및 p는 각각 0 또는 1), R¹ 및 R²는 각각 독립적으로 1개의 N을 포함하는 5-6원 헤테로사이클릴일 수 있다. 상기 R¹ 및 R²는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C_1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C_1-6 알킬)로 임의로 치환된 C_1-6 알킬; 또는 임의로 1~2개의 O에 의해 중단된 C_1-6 알킬로 임의로 치환될 수 있다.In one embodiment, G ¹ in Formula 1 is furanyl or -CH ₂ -furanyl, G ² is H,

silver

And, R' may be pyridinyl or -(CH ₂ )-pyridinyl. In this case, R is -OH, -O-(CH ₂ ) _o -R ¹ , -(CH ₂ ) _p -OR ² , -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r It may be -O-CO-R ⁴ or -CO-R ⁵ , and R ¹ to R ⁵ , o, p, q and r are as described above. For example, R can be -OH, -O-(CH ₂ ) _o -R ¹ or -(CH ₂ ) _p -OR ² (o and p are each 0 or 1), and R ¹ and R ² are Each independently may be a 5-6 membered heterocyclyl containing 1 N. The R ¹ and R ² are each independently halogen; cyano; OH; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO-(C _1-6 alkyl); or C _1-6 alkyl optionally interrupted by 1-2 O.

은

일 수 있다. 이 경우, R은 -OH, -O-(CH₂)_o-R¹, -(CH₂)_p-O-R², -O-(CH₂)_q-CO-R³, -(CH₂)_r-O-CO-R⁴ 또는 -CO-R⁵일 수 있고, R¹ 내지 R⁵, o, p, q 및 r은 전술한 바와 같다. 예를 들어, R은 -OH, -O-(CH₂)_o-R¹ 또는 -(CH₂)_p-O-R²(o 및 p는 각각 0 또는 1)일 수 있고, R¹ 및 R²는 각각 독립적으로 페닐일 수 있다. 상기 R¹ 및 R²는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C_1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C_1-6 알킬)로 임의로 치환된 C_1-6 알킬; 또는 임의로 1~2개의 O에 의해 중단된 C_1-6 알킬로 임의로 치환될 수 있다.In one embodiment, G ¹ in Formula 1 is furanyl or -CH ₂ -furanyl, G ² is H,

silver

can be In this case, R is -OH, -O-(CH ₂ ) _o -R ¹ , -(CH ₂ ) _p -OR ² , -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r It may be -O-CO-R ⁴ or -CO-R ⁵ , and R ¹ to R ⁵ , o, p, q and r are as described above. For example, R can be -OH, -O-(CH ₂ ) _o -R ¹ or -(CH ₂ ) _p -OR ² (o and p are each 0 or 1), and R ¹ and R ² are may each independently be phenyl. The R ¹ and R ² are each independently halogen; cyano; OH; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO-(C _1-6 alkyl); or C _1-6 alkyl optionally interrupted by 1-2 O.

은

일 수 있다. 이 경우, R은 OH일 수 있다. 이 경우, 상기 고리 A는 C_6-12 아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택될 수 있다. 또한, 상기 고리 A는 페닐; N 및 S로부터 선택되는 1~2개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; 1개의 N을 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택될 수 있다. 예를 들어, 상기 고리 A는 티아졸릴, 피리미딜, 아제티딘일, 사이클로부틸, 또는 페닐일 수 있지만, 이에 제한되지 않는다. 상기 고리 A의 치환기는 전술한 바와 같다.In one embodiment, G ¹ of Formula 1 is ring A, G ² is H,

silver

can be In this case, R may be OH. In this case, the ring A is C _6-12 aryl; 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; 4-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S; and 4-6 membered cycloalkyl. In addition, the ring A is phenyl; 5- or 6-membered heteroaryl containing 1-2 heteroatoms selected from N and S; 4-6 membered heterocyclyl containing 1 N; and 4-6 membered cycloalkyl. For example, the ring A may be thiazolyl, pyrimidyl, azetidinyl, cyclobutyl, or phenyl, but is not limited thereto. Substituents of the ring A are as described above.

Among the compounds of Formula 1, compounds in which R is OH can be easily prepared based on the technical knowledge of a person skilled in the art by referring to Preparation Examples and Examples herein.

Among the compounds of Formula 1, compounds in which R is -O-(CH ₂ ) _o -R ¹ or -O-(CH ₂ ) _q -CO-R ³ can be prepared according to Scheme A below.

[Scheme A]

(In the above Scheme A, R ^A is -(CH ₂ ) _o -R ¹ or -(CH ₂ ) _q -CO-R ³ .)

According to Scheme A above, compounds of Formula 1 can be prepared by reacting R ^A -Br or R ^A -Cl with a compound in which R is OH.

The reaction may be suitably carried out in a suitable solvent (e.g., DMSO, DMF, THF, t-BuOK, etc.) for several tens of minutes to several hours within the range of 5 ° C. to 150 ° C., 20 ° C. to 120 ° C., or room temperature to 110 ° C. there is. Optional reagents or bases (eg, CuI, K ₃ PO ₄ , K ₂ CO ₃ , Cs ₂ CO ₃ , 1,10-phenanthroline, etc.) may be added during the reaction as needed.

Optionally, R ^A -Br protected with an appropriate protecting group (e.g., THP (tetrahydropyranyl), Boc (tert-butoxycarbonyl) ^, etc.) instead of R A -Br or R ^A -Cl in Scheme A above. Alternatively, the compound of Formula 1 may be prepared by reacting R ^A -Cl and subjecting to hydrolysis or protecting group removal in an appropriate solvent (MeOH and H ₂ O, TFA and DCM, etc.).

In addition, suitable chemical reactions for reacting R ^A' -Br or R ^A' -Cl instead of R ^A -Br or R ^A -Cl in Scheme A above and transforming R ^A ' into R ^A , such as CH ₃ MgBr The compound of Formula 1 can be prepared by forming an alcohol from an ester using a Grignard reagent such as, for example, basic hydrolysis of the ester in the presence of LiOH.

Among the compounds of Formula 1, the compound in which R is -(CH ₂ ) _p -OR ² or -(CH ₂ ) _r -O-CO-R ⁴ is replaced with the compound in which R is OH in Scheme A, where R is -(CH ₂ ) It can be prepared by using a compound of _p -OH or -(CH ₂ ) _r -OH as a starting material by appropriately changing reaction conditions and reagents.

Among the compounds of Formula 1, a compound in which R is -CO-R ⁵ can be prepared by using a compound in which R is -COOH as a starting material instead of a compound in which R is OH in Reaction Scheme A, and changing reaction conditions and reagents appropriately.

As the starting material, a compound in which R is -(CH ₂ ) _p -OH, -(CH ₂ ) _r -OH or -COOH can be easily prepared based on the technical knowledge of those skilled in the art with reference to Preparation Examples and Examples herein. there is.

In one embodiment, the compound represented by Formula 1 may be selected from the following group:

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.

As used herein, the term "furan" in "furanyl" refers to a heterocyclic group consisting of a 5-membered aromatic ring composed of 4 carbon atoms and 1 oxygen atom.

The term "alkyl" refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon. The alkyl may be a substituted or unsubstituted alkyl group. The C _1-6 alkyl may be an alkyl group of C ₁ to C ₅ , C ₁ to C ₄ , C ₁ to C ₃ , or C ₁ to C ₂ . Non-limiting examples of the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl. there is.

The alkyl group may include an alkyl interrupted by 1 to 2 oxygen atoms. Alkyl interrupted by 1 to 2 oxygen atoms means that an oxygen atom is inserted between the carbon atom-carbon bond of the alkyl (including the case where the alkyl ends with OH). For example, a C ₄ alkyl (ie butyl) can form a eg methoxyethoxymethyl (CH ₃ O(CH ₂ ) ₂ OCH ₃ -) group when interrupted by two oxygens.

The term "alkoxy" refers to an alkyl bonded to an oxygen atom. The C ₁ to C ₆ alkoxy group may be C ₁ to C ₅ , C ₁ to C ₄ , C ₁ to C ₃ , or C ₁ to C ₂ alkoxy.

The term “cycloalkyl” refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group. Cycloalkyl groups can contain 4 to 10, 4 to 8, 4 to 6, or 5 carbon atoms. A monocycloalkyl group can be, for example, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl, and the like. Bicycloalkyl groups include, for example, bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, or bicyclo[2.2. 2] octylyl and the like. A tricycloalkyl group can be, for example, adamantyl.

The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom. Heterocyclyl groups can contain 4 to 10, 4 to 8, 4 to 6, or 5 or 6 ring atoms. The hetero atoms may be any one or more selected from the group consisting of N, O and S, preferably 1 to 3. The heterocyclyl may include one or two heteroatoms selected from N, O or S. The heteroatom may be 1 or 2 N. The heteroatom may be one N.

The heterocyclyl group may be a single ring group, two ring groups, or three ring groups. The two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group. As an example, the heterocyclyl is aziridinyl, azetidinyl tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl, thiazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydroisoquinolinyl, and the like, but are not limited thereto.

The term "aryl" refers to an aromatic hydrocarbon ring of 6 to 12 carbon atoms, and also includes groups in which an aromatic ring is fused to one or more carbon rings. The C ₆ to C ₁₂ aryl group may be, for example, a C ₆ to C ₁₀ or C ₆ to C ₈ aryl group. Non-limiting examples of aryl include phenyl, naphthyl, or tetrahydronaphthyl, and the like.

The term “heteroaryl” refers to a monocyclic or bicyclic aromatic compound containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the remaining ring atoms are carbon. The heteroaryl group may include, for example, 1 to 5, 1 to 3, or 1 or 2 heteroatoms. The heteroaryl group may include 5 to 10, 5 to 7, or 5 or 6 ring elements. The heteroaryl may be a 5-6 membered heteroaryl containing 1 or 2 N, O or S. The heteroaryl may be a 5-6 membered heteroaryl containing 1 or 2 N and optionally 1 O.

The heteroaryl group may be a single ring group, two ring groups, or three ring groups. The two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group. Non-limiting examples of “heteroaryl” include pyridinyl, thienyl, thiophenyl, pyrimidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl group, 1,2,3-thiadiazolyl, 1,2,4 -Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxa Zol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4- Triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazolyl, p Lead-2-yl, pyrid-3-yl, 2-pyrazin-2-yl, pyrazin-4-yl, pyrazin-5-yl, 2-pyrimidin-2-yl, 4-pyrimidin-2-yl, 5-pyrimidin-2-yl, isoquinolinyl, etc. are mentioned.

The term "halogen" atom refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, iodine, and the like.

The term "cyano" is -CN, and refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

The term "hydroxy" refers to the -OH functional group (hydroxyl group).

The term "nitro" refers to -NO ₂ .

The term "amino" refers to -NH ₂ .

The term "substitution" of the above "substituted" refers to an introduction instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and "substituent" refers to an introduced atomic group. Substituents include, for example, a hydroxyl group (eg, propanol, ethanol), a halogen atom, a C ₁ to C ₂₀ alkyl group substituted with a halogen atom (eg, CCF ₃ , CHCF ₂ , CH ₂ F, CCl ₃ , etc.), C ₁ to C 20 C ₂₀ alkoxy (eg, methoxy, ethoxy), C ₂ to C ₂₀ alkoxyalkyl (eg, methoxyethoxymethyl), hydroxyl group, nitro group, cyano group, amide group (eg acetamide), amino group , amidino group, hydrazine, hydrazone, carbonyl group, carboxyl group or its salt (eg, acetate, propanoic acid, carbamate), sulfonyl group, sulfamoyl group, sulfonic acid group or its salt, phosphoric acid or its salt, or C ₁ to C ₂₀ alkyl group (eg, methyl), C ₂ to C ₂₀ alkenyl group, C ₂ to C ₂₀ alkynyl group, C ₁ to C ₂₀ heteroalkyl group (eg pyrrolidine, piperidine), C ₆ to C 20 C ₂₀ aryl group (eg phenyl, benzyl, benzoic acid), C ₆ to C ₂₀ arylalkyl group, C ₆ to C ₂₀ heteroaryl group (eg pyridinyl), C ₇ to C ₂₀ heteroarylalkyl group, C ₆ to C ₂₀ heteroaryloxy group, and a C ₆ to C ₂₀ heteroaryloxyalkyl group, a C ₆ to C ₂₀ heteroarylalkyl group, or a combination thereof.

In addition, the substituent is halogen; cyano; OH; amino; nitro; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO-(C _1-6 alkyl); C _1-6 alkyl optionally interrupted by 1-2 O; C _1-6 alkoxy optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO-(C _1-6 alkyl); C _6-12 aryl; or a 5-6 membered heterocyclyl. In addition, the substituent may be further substituted with substituents such as halogen, cyano, OH, amino, nitro, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl, C _1-6 alkoxy.

"Isomer" of the term "stereoisomer" refers to a compound having the same molecular formula but not the same connection method or spatial arrangement of constituent atoms in a molecule. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomers may be diastereomers or enantiomers. Enantiomers refer to isomers that do not overlap with their mirror images, such as the relationship between left and right hands, and are also called optical isomers. Enantiomers are classified as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents differ from each other on the chiral central carbon. Diastereomers are stereoisomers that are not mirror images, and are isomers that result from differences in the arrangement of atoms in space. The diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.

The term "solvate" refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.

The term "salt" refers to inorganic and organic acid addition salts of a compound. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The inorganic acid salt may be a hydrochloride, bromate, phosphate, sulfate, or bisulfate salt. The organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edisyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate may be an acid salt. The metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.

The compound of Formula 1 may be an antagonist for adenosine A2A receptors. The adenosine A2A receptor may be a protein belonging to a G protein-coupled receptor (GPCR) having 7 transmembrane alpha helices. The adenosine A2A receptor may also be called ADORA2A, adenosine _A2A receptor, A2AR, ADORA2, or RDC8. The adenosine A2A receptor is Uniprot No. It may be a protein comprising the amino acid sequence of P29274.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating adenosine A2A receptor-related diseases, including the compound of Formula 1, a stereoisomer, solvate or pharmaceutically acceptable salt thereof according to one aspect. .

The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, and adenosine A2A receptors are as described above.

The disease associated with the adenosine A2A receptor may be selected from the group consisting of cancer, inflammation, sickle cell sepsis, septic shock, meningitis, peritonitis, arthritis, hemolytic urethral syndrome, glaucoma, ocular hypertension, and Parkinson's disease.

The cancer may be a solid cancer or a non-solid cancer. Solid cancer refers to cancerous tumors that have occurred in organs such as the liver, lungs, breast, and skin. Non-solid cancer is cancer that develops in the blood, and is also called hematological cancer. The cancer may be carcinoma, sarcoma, hematopoietic cell-derived cancer, germ cell tumor, or blastoma. The cancer is, for example, breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, stomach cancer, ovarian cancer, prostate cancer, bladder cancer, urethral cancer, liver cancer, kidney cancer, clear cell sarcoma, melanoma, cerebrospinal tumor , brain cancer, thymoma, mesothelioma, esophageal cancer, biliary tract cancer, testicular cancer, germ cell tumor, thyroid cancer, parathyroid cancer, cervical cancer, endometrial cancer, lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, acute leukemia , chronic leukemia, multiple myeloma, Hodgkin's disease, endocrine cancer, and sarcoma.

The pharmaceutical composition may further include other anticancer agents. The anti-cancer agent may be an immuno-anticancer agent. The immuno-anticancer agent may be an immune checkpoint inhibitor, an immune cell therapy agent, a therapeutic antibody, an anti-cancer vaccine, or a combination thereof. The immune checkpoint inhibitor is PD-1 (programmed death 1), PD-L1 (programmed death ligand 1), CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), VISTA (V-domain Ig suppressor of T cell activation ), PD-L2 (programmed death ligand 2), IDO (indoleamine 2,3-dioxygenase), arginase, B7 family inhibitory ligand B7-H3, B7 family inhibitory ligand B7-H4, LAG3 (lymphocyte activation gene 3), 2B4, BTLA (B and T lymphocyte attenuator), TIM3 (T cell membrane protein 3), CD39, and CD73. The immune checkpoint inhibitor is ipilimumab, tremelimumab, nivolumab, pembrolizumab, pidilizumab, MEDI-0680, REGN2810, AMP-224 , BMS-936559/MDX-1105, MPDL3280A/RG7446/atezolizumab, MSB0010718C/avelumab, or MEDI4736/durvalumab. The pharmaceutical composition may be a single composition or separate compositions. For example, the compound of Formula 1 may be a composition for oral dosage form, and the anticancer agent may be a composition for parenteral dosage form.

The term "prevention" refers to all activities that suppress or delay the onset of diseases associated with adenosine A2A receptors by administration of the pharmaceutical composition. The term "treatment" refers to all activities that improve or beneficially change symptoms of adenosine A2A receptor-related diseases by administration of the pharmaceutical composition.

The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used as a meaning including an excipient, diluent or auxiliary agent. Such carriers include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl fibre, It may be selected from the group consisting of Rolidone, water, physiological saline, a buffer such as PBS, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, or combinations thereof.

The pharmaceutical composition may be prepared in any dosage form according to conventional methods. The composition may be formulated as, for example, an oral dosage form (eg, powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (eg, injection). In addition, the composition may be prepared as a systemic formulation or topical formulation.

In the pharmaceutical composition, the solid preparation for oral administration may be tablets, pills, powders, granules, or capsules. The solid formulation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the oral liquid formulation may be a suspension, internal solution, emulsion, or syrup. The liquid formulation may include water or liquid paraffin. The liquid formulation may contain excipients such as wetting agents, sweetening agents, flavoring agents, or preservatives. In the pharmaceutical composition, preparations for parenteral administration may be sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried or suppositories. Non-aqueous solvents or suspensions may include vegetable oils or esters. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin fat, or glycerogelatin.

The pharmaceutical composition includes the compound according to one aspect, a stereoisomer, solvate or pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition. "Active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (eg, anti-cancer).

The pharmaceutical composition may contain an effective amount of the compound according to one aspect, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. The term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need of such prevention or treatment. The effective amount can be appropriately selected by those skilled in the art depending on the cell or organism to be selected. A preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the subject, the severity of the disease, the type of drug, the route and period of administration, but can be appropriately selected by those skilled in the art. However, the compound, its stereoisomer, solvate or pharmaceutically acceptable salt may be used in an amount of, for example, from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg. It may be divided into 1 to 24 times a day, 1 to 7 times every 2 days to 1 week, or 1 to 24 times every 1 month to 12 months. In the pharmaceutical composition, the compound, its stereoisomer, solvate or pharmaceutically acceptable salt is contained in an amount of about 0.0001% to about 10% by weight, or about 0.001% to about 1% by weight based on the total weight of the composition. can

The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The composition may be administered systemically or topically, and may be administered alone or in combination with other pharmaceutically active compounds.

Another aspect of the present invention is a method for preventing or treating diseases associated with adenosine A2A receptors, comprising administering to a subject a compound of Formula 1, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof according to one aspect. to provide.

The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, adenosine A2A receptor-related diseases, prevention, and treatment are as described above.

The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject may be an individual suffering from, or highly likely to suffer from, symptoms associated with a disease associated with adenosine A2A receptors.

The method may further include administering to the subject a known active ingredient having an effect of preventing or treating a disease related to the adenosine A2A receptor. The known active ingredient may be administered to the subject simultaneously, separately or sequentially with the compound according to one aspect, a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The pharmaceutical composition may be administered systemically or topically, and may be administered alone or in combination with other pharmaceutically active compounds.

A preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and period of administration, but can be appropriately selected by those skilled in the art. The dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg on an adult basis. can be The administration may be administered once a day, multiple times a day, or once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks to once a year.

Another aspect of the present invention provides the use of the compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to one aspect, for use in preventing or treating diseases associated with adenosine A2A receptors.

Another aspect of the present invention provides the use of the compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to one aspect for the preparation of a medicament for preventing or treating a disease associated with the adenosine A2A receptor do.

The adenosine A2A receptor-related diseases, prevention, treatment, compounds of Formula 1, stereoisomers, solvates, and pharmaceutically acceptable salts are as described above.

The compound of Formula 1 of the present invention exhibits excellent antagonistic activity against adenosine A2A receptors.

According to the adenosine A2A receptor antagonist of the present invention, a pharmaceutical composition for preventing or treating adenosine A2A receptor-related diseases (e.g., cancer) comprising the same, and a method for treating and preventing diseases using the same, adenosine A2A receptor-related diseases , for example, cancer can be effectively prevented or treated.

It will be described in more detail through the following examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Preparation Example 1: Methyl 3-(6-bromopyridin-2-yl)benzoate (Compound A)

3-(methoxycarbonyl)phenylboronic acid (3.00 g, 16.7 mmol) and 2,6-dibromopyridine (3.90 g, 16.7 mmol) were mixed with H ₂ O:1,4-dioxane (1:5, 120 mL) and added Pd(dppf)Cl ₂ CH ₂ Cl ₂ (2.00 g, 2.50 mmol) and K ₂ CO ₃ (6.90 g, 50.0 mmol). The resulting mixture was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and the solution was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give methyl 3-(6-bromopyridin-2-yl)benzoate (Compound A; 1.7 g, 32.1%) as off-white (off -white) was obtained as a solid. MS m/z: 292 [M+H] ⁺ .

Preparation Example 2: 2-Bromo-6-[(2-methoxyethoxy)methyl]pyridine (Compound B)

To a stirred solution of 2-methoxyethanol (303 mg, 3.98 mmol) in DMF (8.00 mL) was added NaH (159 mg, 3.98 mmol, 60% dispersion in mineral oil) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To this mixture was added 2-bromo-6-(bromomethyl)pyridine (500 mg, 1.99 mmol) at 0°C. The resulting mixture was stirred at 25 °C for an additional hour. The reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL). The combined organic layers were washed with brine (3 x 25.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give 2-bromo-6-[(2-methoxyethoxy)methyl]pyridine (Compound B; 300 mg, 58.1%). Obtained as an off-white oil. MS m/z: 246/248 [M+H] ⁺ .

Preparation Example 3: 1-(6-bromopyridin-2-yl)pyrrolidin-3-ol (Compound C)

2,6-Dibromopyridine (2.00 g, 8.44 mmol) and pyrrolidin-3-ol hydrochloride (1.10 g, 9.28 mmol) were stirred and mixed in THF (30.0 mL), DBU (3.80 g, 25.3 mmol) ) was added. The resulting mixture was stirred at 70° C. for 2 h, and the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure, eluted with PE/EtOAc (2:1) and purified by silica gel column chromatography to obtain 1-(6-bromopyridin-2-yl)pyrrolidin-3-ol (Compound C; 1.00 g). , 48.3%) as a yellow solid. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 7.29-7.27 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.64 -4.60 (m, 1H), 3.65-3.52 (m, 4H), 2.18-2.08 (m, 2H); MS m/z: 243/245 [M+H] ⁺ .

Preparation Example 4: Methyl 2-(3-bromo-4-fluorophenyl)-2-methylpropanoate (Compound D)

Step 1: Synthesis of methyl 2-(3-bromo-4-fluorophenyl)acetate

To a mixture of (3-bromo-4-fluorophenyl)acetic acid (5.00 g, 21.5 mmol) stirred in MeOH (50 mL) was added SOCl ₂ (4.00 g, 33.6 mmol) at 0 °C. The resulting mixture was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with aqueous NaHCO ₃ solution. The mixture was poured into water (500 mL) and extracted with ethyl acetate (500 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography to obtain methyl 2-(3-bromo-4-fluorophenyl)acetate (4.00 g, 68.7%). ) was obtained as a yellow solid.

Step 2: Synthesis of methyl 2-(3-bromo-4-fluorophenyl)-2-methylpropanoate (Compound D)

The compound obtained in step 1 above (4.00 g, 16.2 mmol) was mixed by stirring in DMF (30.0 mL) and NaH (777 mg, 32.4 mmol, 60% dispersion in mineral oil) was added at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and at 0 °C Mel (4.60 g, 32.4 mmol) was added. The resulting mixture was stirred at 25° C. for 3 h under a nitrogen atmosphere and the reaction was quenched with water/ice at 0° C. The mixture was added to water (500 mL) and extracted with ethyl acetate (500 mL), the combined organic layers were washed with brine (2 x 500 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography to obtain methyl 2-(3-bromo-4-fluorophenyl)-2-methylpropanoate (Compound D; 3.00 g, 57.3%) was obtained as a colorless oil. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 7.59-7.52 (m, 1H), 7.36-7.29 (m, 2H), 3.58 (s, 3H), 1.48 (s, 6H).

Preparation Example 5: 2-[2-[(3-bromo-5-methylphenyl)methoxy]ethoxy]oxane (Compound E)

To a mixture of (3-bromo-5-methylphenyl)methanol (1.00 g, 4.97 mmol) stirred in DMF (10.0 mL) was added NaH (300 mg, 7.50 mmol, 60% dispersion in mineral oil) at 0 °C. . The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the mixture was added 2-(2-bromoethoxy)oxane (1.00 g, 4.78 mmol). The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction was quenched with water/ice (90.0 mL). The resulting mixture was extracted with EtOAc (90.0 mL), and the combined organic layers were washed with brine (2 x 80.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (5:1) and purified by silica gel column chromatography to give 2-[2-[(3-bromo-5-methylphenyl)methoxy]ethoxy] Oxane (compound E; 660 mg, 37.5%) was obtained as a colorless solid.

Preparation Example 6: 2-chloro-N-phenylacetamide (Compound F)

Aniline (1.00 g, 10.7 mmol) and TEA (3.26 g, 32.2 mmol) were mixed by stirring in DCM (10.0 mL), and chloroacetyl chloride (2.43 g, 21.5 mmol) was added at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 1 hour under a nitrogen atmosphere and the reaction was quenched with water (50 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 50.0 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 2-chloro-N-phenylacetamide (Compound F; 700 mg, 36.5%) as a yellow solid. was obtained with MS m/z: 170 [M+H] ⁺ .

Preparation Example 7: 2-chloro-1- (4-phenylpiperazin-1-yl) ethanone (Compound G)

After stirring and mixing phenylpiperazine (1.00 g, 6.16 mmol) and TEA (1.87 g, 18.5 mmol) in DCM (15.0 mL), chloroacetyl chloride (1.04 g, 9.24 mmol) was added dropwise at 0°C under a nitrogen atmosphere. did The resulting mixture was stirred at 25° C. for 1 hour under a nitrogen atmosphere and the reaction was quenched with water (50.0 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 50.0 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 2-chloro-1-(4-phenylpiperazin-1-yl)ethanone (Compound G 700 mg, 45.2%) as a pale yellow solid. MS m/z: 239 [M+H] ⁺ .

Preparation Example 8: 5-bromo-6-chloro-2- (methylsulfanyl) pyrimidin-4-amine (Compound H)

To a mixture of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (35.0 g, 199 mmol) stirred in DCM (500 mL) was added NBS (53.0 g, 299 mmol). The resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was filtered and the filter cake was collected and washed with DCM (3 x 800 mL) to obtain 5-bromo-6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (Compound H; 28.0 g, 52.0%) as a white solid. MS m/z: 254 [M+H] ⁺ .

Preparation Example 9: 6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-amine (Compound I)

6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (10.0 g, 56.9 mmol) and furan-2-yl boronic acid (12.7 g) in dioxane (300 mL) and H ₂ O (60.0 mL). , 114 mmol) were stirred to mix, and Pd(dppf)Cl ₂ (4.10 g, 5.69 mmol) and Cs ₂ CO ₃ (55.6 g, 171 mmol) were added. After stirring at 85[deg.] C. for 3 hours under a nitrogen atmosphere, the mixture was cooled to room temperature and the solution was partially concentrated under reduced pressure. The mixture was extracted with EtOAc (3 x 500 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-amine (Compound I; 4.10 g, 33.4%) as an off-white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.86-7.85 (m, 1H), 7.09-7.08 (m, 1H), 7.04 (s, 2H), 6.66-6.61 (m, 1H) ), 6.45 (s, 1H), 2.45 (s, 3H); MS m/z: 208 [M+H] ⁺ .

Preparation Example 10: 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1,2,3-benzotriazole (Compound J)

Step 1: Synthesis of 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine

NaH (15.8g, 658.57 mmol, 1.2 equiv, 60%) was added to 2,6-dichloropyrimidin-4-amine (90 g, 548.81 mmol, 1.00 equiv) stirred and mixed in THF (3 L) at 0 °C under a nitrogen atmosphere. added in portions. The resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. 1-Fluoro-4-methoxy-2-nitrobenzene (84.5 g, 493.93 mmol, 0.9 eq) was added to the above mixture at 0 °C. The resulting mixture was stirred at 25° C. for an additional 16 hours. The reaction was quenched by adding water (500 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 2 L), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexanes (3 x 1.5 L). The resulting solid was dried under infrared light to give 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (110 g, 34.79%) as a red solid. ¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 10.27 (s, 1H), 7.56-7.50 (m, 2H), 7.36-7.33 (m, 1H), 6.77 (s, 1H), 3.85 (s, 3H); MS m/z: 315 [M+H] ⁺ .

Step 2: Synthesis of N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine

The compound obtained in step 1 (110 g, 190.94 mmol, 1.00 equiv, 54.7%) and Fe (53 g, 954.74 mmol, 5.00 equiv) were stirred and mixed in EtOH (1.5 L) and H ₂ O (300 mL) and NH ₄ Cl (30 g, 572.84 mmol, 3.00 equiv) was added. The mixture was stirred at 80° C. for 16 hours and cooled to room temperature. After filtering the resulting mixture, the filter cake was washed with EtOAc (3 x 700 mL), and the filtrate was concentrated under reduced pressure to obtain N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1 ,2-diamine (90 g, 94.22%) was obtained as a red solid. ¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 6.14 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 5.12 (s, 2H), 3.66 (s, 3H); MS m/z: 285 [M+H] ⁺ .

Step 3: Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1,2,3-benzotriazole (Compound J)

The compound obtained in step 2 (90.0 g, 179.91 mmol, 1.00 equiv, 57%) was stirred mixed in AcOH (1.2 L) and H ₂ O (400 mL) at 0 °C and NaNO ₂ (13.6 g, 197.91 mmol, 1.10 equivalent) was added in portions. The resulting mixture was stirred at 25 °C for 30 min. The reaction was quenched by the addition of water (800 mL) at room temperature and the precipitated solid was collected by filtration and washed with HCL (4 M, 3 x 1.0 L) to give 1-(2,6-dichloropyrimidine-4 -yl)-5-methoxy-1,2,3-benzotriazole (Compound J; 40 g, 44.22%) was obtained as a brown solid. ¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.39 (s, 1H), 8.27-8.25 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); MS m/z: 296 [M+H] ⁺ _.

Preparation Example 11: 2-chloro-6- (3,3-difluorocyclobutyl) pyrimidin-4-amine (Compound K)

Step 1: Synthesis of 2,4-dichloro-6-(3,3-difluorocyclobutyl)pyrimidine

2,4-Dichloropyrimidine (50 g, 335.63 mmol, 1.00 equiv) and 3,3-difluorocyclobutane-1-carboxylic acid (36.5 g, 268.51 mmol, 0.8 equiv) were added to CH ₃ CN (400 mL) and H Stir mixed in ₂ O (400 mL), (NH ₄ ) ₂ S ₂ O ₈ (61.2 g, 268.51 mmol, 0.8 equiv) and AgNO ₃ (9.1 g, 53.70 mmol, 0.16 equiv) were added. The resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, filtered and the filter cake was washed with DCM (3 x 300 mL). The filtrate was partially concentrated under reduced pressure. The mixture was extracted with CH ₂ Cl ₂ (3 x 400 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1) to give 2,4-dichloro-6-(3,3-difluorocyclobutyl)pyrimidine (7.9 g, 9.55%) in light green color. Obtained as an oil. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.78 (s, 1H), 3.61-3.50 (m, 1H), 3.00-2.82 (m, 4H).

Step 2: Synthesis of 2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-amine (Compound K)

The compound obtained in step 1 (7.9g, 33.04 mmol, 1.00 equiv) and NH ₃ (g) were stirred and mixed in MeOH (7 M, 20 mL) and EtOH (20 mL) at 80° C. for 5 h under a nitrogen atmosphere. . After cooling the mixture to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (2:1) to give 2-chloro-6-(3,3-difluorocyclobutyl)pyridine. Midin-4-amine (Compound K; 2.3 g, 30.55%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.37 (s, 2H), 6.28 (s, 1H), 3.28-3.25 (m, 1H), 2.85-2.69 (m, 4H); MS m/z: 220 [M+H] ⁺ _.

Example 1: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-01)

Compound (Ex-01) was synthesized according to Scheme 1 below.

[Scheme 1]

Step 1: Synthesis of 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine

To a solution of 2,6-dichloropyrimidin-4-amine (1.00 g, 6.10 mmol) and 1-fluoro-4-methoxy-2-nitrobenzene (869 mg, 5.08 mmol) in DMF (10.0 mL) at 0 °C NaH (406 mg, 10.2 mmol, 60% dispersion in mineral oil) was added. The mixture was stirred at 25° C. for 3 hours. The mixture was added to water (50.0 mL) and ethyl acetate (70.0 mL), the organic layer was separated, washed with saturated brine (60.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give the crude product. . The product was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 - 5:1). Obtained 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (800 mg, 2.54 mmol, 50.0% yield) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 - 9.17 (m, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.37 (dd, J = 2.9, 8.9 Hz, 1H), 6.78 (s, 1H), 3.96 - 3.82 (m, 3H); MS m/z: 315.0 [M+H] ⁺ .

Step 2: Synthesis of N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine

To a solution of the compound obtained in step 1 (400 mg, 1.27 mmol) in EtOH (20.0 mL) was added Fe (708 mg, 12.7 mmol) and NH ₄ Cl (203 mg, 3.81 mmol). The mixture was stirred at 70 °C for 2 hours. The mixture was filtered and the cake was collected and dried in vacuo. N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine (500 mg, crude product) was obtained as a gray solid without purification. MS m/z: 315.0 [M+H] ⁺ .

Step 3: Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole

AcOH (12.0 mL) and conc. of the compound obtained in step 2 (500 mg, 1.75 mmol). To a solution in HCl (3.00 mL) at 0 °C was added NaNO ₂ (133 mg, 1.93 mmol) and the mixture was stirred at 25 °C for 2 h. The mixture was filtered and the cake was collected and dried in vacuo. 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole (250 mg, 844 μmol, 48.2% yield) was obtained without purification. Obtained as a white solid. MS m/z: 296 [M+H] ⁺ .

Step 4: Synthesis of 1-(2-chloro-6-(furan-2-yl)pyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole

The compound obtained in step 3 (144 mg, 742 μmol) and 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (200 mg, 675 μmol) in dioxane (10.0 mL) and H ₂ O (2.00 mL) were added K ₂ CO ₃ (186 mg, 1.35 mmol) and Pd(dppf)Cl ₂ (24.7 mg, 33.7 μmol); The mixture was stirred at 80 °C for 2 h. The mixture was added to water (40.0 mL) and ethyl acetate (40.0 mL) and the organic layer was separated, washed with saturated brine (40.0 mL), dried over Na ₂ SO ₄ and filtered and concentrated to give the crude product. The product was purified by silica gel column chromatography (petroleum ether: EtOAc = 100:1 - 5:1) to obtain 1-(2-chloro-6-(furan-2-yl)pyrimidin-4-yl)-5- Obtained methoxy-1H-benzo[d][1,2,3]triazole (150 mg, 457 μmol, 67.8% yield) as a white solid. MS m/z: 328.1 [M+H] ⁺ .

Step 5: Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyrimidin-2-amine

To a solution of the compound obtained in step 4 (140 mg, 427 μmol) in EtOH (200 μL) was added NH ₃ .H ₂ O (1.50 g, 8.54 mmol, 1.65 mL, 20% purity). The mixture was stirred at 90 °C for 12 hours. The mixture was concentrated to give a residue. 4-(furan-2-yl)-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyrimidin-2-amine without purification (130 mg, 421 μmol, 98.7% yield) as a white solid. MS m/z: 309.2 [M+H] ⁺ .

Step 6: 1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-ol (Ex-01 ) synthesis of

To a solution of the compound obtained in step 5 (120 mg, 389 μmol) in DCM (1.00 mL) was added BBr ₃ (292 mg, 1.17 mmol, 112 μL), and the mixture was stirred at -78 °C for 5 h and returned to 25 °C. was allowed to rise to The mixture was concentrated to give a residue. The crude product was purified by reverse phase HPLC under 0.1% HCl. 1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-ol (Ex-01; 5.00 mg , 16.5 μmol, 4.24% yield, 97.1% purity) as a white solid. ¹ H NMR (400 MHz DMSO-d ₆ ) δ 8.63 (d, J = 8.9 Hz, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H), 7.29 (s, 2H), 7.23 (d, J = 2.1, 9.0 Hz, 1H); MS m/z: 295.1 [M+H] ⁺ .

Example 2: 2-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl } oxy) pyridin-2-yl] propan-2-ol (Ex-02)

Compound (Ex-02) was synthesized according to Scheme 2 below.

[Scheme 2]

Step 1: Synthesis of 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine

NaH (6.47 g, 162 mmol, 60% dispersion in mineral oil) was added to 2,6-dichloropyrimidin-4-amine (34.0 g, 207 mmol) stirred and mixed in THF (700 mL) at 0 °C under a nitrogen atmosphere. added in portions. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. 1-Fluoro-4-methoxy-2-nitrobenzene (48.5 g, 270 mmol) was added portionwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional 16 hours. The reaction was quenched by the addition of water (500 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 1000 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to obtain 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (22 g, 30%) was obtained as a red solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 10.3 (s, 1H), 7.56-7.50 (m, 2H), 7.36-7.33 (m, 1H), 6.77 (s, 1H), 3.85 (s, 3H) ); MS m/z: 315 [M+H] ⁺ .

Step 2: Synthesis of N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine

The compound obtained in step 1 (22.0 g, 62.8 mmol), Fe (17.5 g, 314 mmol) and NH ₄ Cl (6.72 g, 126 mmol) were mixed with EtOH (250 mL), THF (250 mL) and H ₂ O ( 80.0 mL) and mixed by stirring at 80° C. for 2 hours. The mixture was cooled at room temperature. After filtering the resulting mixture, the filter cake was washed with EtOAc (3 x 300 mL) and the filtrate was concentrated under reduced pressure. The resulting mixture was washed with water (3 x 200 mL) to obtain N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine (16.0 g, 80.0%) in red color. Obtained as a solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 6.14 (d, J = 8.0 Hz, 1H) , 5.87(s, 1H), 5.12(s, 2H), 3.66(s, 3H); MS m/z: 285 [M+H] ⁺ .

Step 3: Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1,2,3-benzotriazole

The compound obtained in step 2 (16.0 g, 50.5 mmol) was stirred mixed in AcOH (60.0 mL) and H ₂ O (20.0 mL) at 0 °C and NaNO ₂ (3.83 g, 0.056 mmol) was added in portions. The resulting mixture was stirred at 25 °C for 30 min. The reaction was quenched by the addition of water (200 mL) at room temperature and the precipitated solid was collected by filtration and washed with ethanol (3 x 30.0 mL) to give 1-(2,6-dichloropyrimidin-4-yl) Obtained -5-methoxy-1,2,3-benzotriazole (8 g, 48%) as a red solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.39 (s, 1H), 8.27-8.25 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); MS m/z: 296 [M+H] ⁺ .

Step 4: Synthesis of 1-[2-chloro-6-(furan-2-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

The compound obtained in step 3 (8.00 g, 27.0 mmol) and tributyl(furan-2-yl)stannane (9.65 g, 27.0 mmol) were stirred and mixed in DMF (80.0 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (3.79 g, 5.40 mmol) was added. The resulting mixture was stirred at 25° C. for 16 hours under a nitrogen atmosphere. Water (300 mL) was added to quench the reaction and the resulting mixture was extracted with CH ₂ Cl ₂ (3 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (10:1) to obtain 1-[2-chloro-6-(furan-2-yl)pyrimidin-4-yl]-5 -Methoxy-1,2,3-benzotriazole (2.60 g, 27.9%) was obtained as a pale yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.48 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H), 7.71 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.30 ( m, 1H), 6.65-6.64 (m, 1H), 3.93 (s, 3H); MS m/z: 328 [M+H] ⁺ .

Step 5: Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine

The compound obtained in step 4 (2.00 g, 6.10 mmol) was stirred mixed in EtOH (20.0 mL) and NH ₃ (g) in MeOH (20.0 mL) was added. The resulting mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (1:2) to give 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazole-1 Obtained -yl)pyrimidin-2-amine (940 mg, 42.5%) as a pink solid. MS m/z: 309 [M+H] ⁺ _.

Step 6: Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (intermediate I)

A mixture of the compound obtained in step 5 (940 mg, 3.04 mmol) and BBr ₃ was stirred in DCM (1M, 40.0 mL) at 55° C. for 48 hours. The mixture was cooled at room temperature and MeOH (20.0 mL) was added at 0 °C. After the resulting mixture was concentrated under reduced pressure, it was poured into a saturated NaHCO ₃ aqueous solution. The precipitated solid was collected by filtration and washed with ethyl acetate to yield 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5 -ol (intermediate I; 450 mg, 42.6%) was obtained as a greenish-yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.61 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.66-7.64 (m, 1H), 7.42-7.21 (m, 2H), 6.76-6.74 (m, 1H), 6.75 (s, 1H); MS m/z: 295 [M+H] ⁺ .

Step 7: 2-[6-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy Synthesis of )pyridin-2-yl]propan-2-ol (Ex-02)

The compound obtained in step 6 (70.0 mg, 0.230 mmol) and 2-(6-bromopyridin-2-yl)propan-2-ol (102 mg, 0.470 mmol) were stirred and mixed in DMSO (5.00 mL), CuI (45.0 mg, 0.230 mmol) and K ₃ PO ₄ (151 mg, 0.710 mmol) were added. The resulting mixture was stirred at 110° C. for 1 hour under a nitrogen atmosphere and cooled at room temperature. Water (20.0 mL) was added to quench the reaction and the resulting mixture was extracted with CH ₂ Cl ₂ (3 x 20.0 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (1:2). The crude product was purified by Prep-HPLC under the following conditions: column YMC-Actus Triart C ₁₈ , 30 mm x 150 mm, 5 μm; Mobile phase, ACN and water (50 mmol/L NH ₄ HC (38% Phase B, up to 58% in 7 min); detector, UV 254&220 nm. Collected fractions were lyophilized to give 2-[6-([1-[ 2-amino-6- (furan-2-yl) pyrimidin-4-yl] -1,2,3-benzotriazol-5-yl] oxy) pyridin-2-yl] propan-2-ol (Ex ^-02 _; 2H), 7.89-7.84(m, 1H), 7.66(s, 1H), 7.58-7.54(m, 1H), 7.41(d, J = 7.5 Hz, 1H), 7.36-7.35(m, 3H), 6.93 (d, J = 8.1 Hz, 1H), 6.75-6.74 (m, 1H), 5.18 (s, 1H), 1.27 (s, 6H); MS m/z: 430 [M+H] ⁺ .

Example 3: 3-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl }oxy)pyridin-2-yl]benzoic acid (Ex-03)

Compound (Ex-03) was prepared according to Scheme 3 below.

[Scheme 3]

Step 1: Methyl 3-[6-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy Synthesis of )pyridin-2-yl]benzoate

Same as in Step 7 of Example 2, except that Compound (A) of Preparation Example 1 was used instead of 2-(6-bromopyridin-2-yl)propan-2-ol in Step 7 of Example 2. method methyl 3-[6-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy) Pyridin-2-yl]benzoate (35.0 mg, 19.4%) was obtained as a pale yellow solid. MS m/z: 506 [M+H] ⁺ .

Step 2: 3-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl} Synthesis of oxy) pyridin-2-yl] benzoic acid (Ex-03)

The compound obtained in step 1 (35.0 mg, 0.069 mmol) was stirred and mixed in THF/MeOH (4/1) (5.00 mL), and a solution of NaOH (5.54 mg, 0.138 mmol) in H ₂ O (1.00 mL) was added. added. The resulting mixture was stirred at 25 °C for 2 h. The crude product was purified by Prep-HPLC with the following conditions: column, Xselect CSH OBD column 30x150 mm 5 μm, n; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (25% Phase B, up to 45% in 7 min); Detector, UV 254 & 220nm. The collected fractions were lyophilized to obtain 3-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole- Obtained 5-yl}oxy)pyridin-2-yl]benzoic acid (Ex-03; 9.10 mg, 26.7%) as an off-white solid. 1H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.89 (d, J = 9.0 Hz, 1H), 8.44 (s, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.03- 7.98 (m, 3H), 8.92 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.69-7.65 (m, 2H), 7.50-7.45 (m, 1H), 7.37 -7.36 (m, 3H), 7.11 (d, J = 8.1 Hz, 1H), 6.77-6.75 (m, 1H); MS m/z :492 [M+H] ⁺ .

Example 4: 4-(furan-2-yl)-6-[5-({6-[(2-methoxyethoxy)methyl]pyridin-2-yl]oxy)-1H-1,2,3 -benzotriazol-1-yl] pyrimidin-2-amine (Ex-04)

Same method as in Step 7 of Example 2, except that Compound (B) of Preparation Example 2 was used instead of 2-(6-bromopyridin-2-yl)propan-2-ol in Step 7 of Example 2. 4-(furan-2-yl)-6-[5-({6-[(2-methoxyethoxy)methyl]pyridin-2-yl]oxy)-1H-1,2,3-benzotria Zol-1-yl]pyrimidin-2-amine (Ex-04; 13.9 mg, 11.1%) was obtained as an off-white solid. 1H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.84 (d, J = 9.0 Hz, 1H), 8.00 (s, 2H), 7.94-7.88 (m, 1H), 7.67 (s, 1H) ), 7.58-7.54 (m, 1H), 7.36-7.35 (m, 3H), 7.21 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.76-6.75 (m, 1H), 4.38 (s, 2H), 3.60-3.56 (m, 2H), 3.47-3.45 (m, 2H), 3.23 (s, 3H); MS m/z: 460 [M+H] ⁺ .

Example 5: 1-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl } oxy) pyridin-2-yl] pyrrolidin-3-ol (Ex-05)

Same method as in Step 7 of Example 2, except that Compound (C) of Preparation Example 3 was used instead of 2-(6-bromopyridin-2-yl)propan-2-ol in Step 7 of Example 2. 1-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl}oxy)pyridine- 2-yl]pyrrolidin-3-ol (Ex-05; 6.60 mg, 6.08%) was obtained as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.82 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.58-7.52(m, 2H), 7.36-7.35(m, 3H), 6.76-6.74(m, 1H), 6.17(s, 1H), 6.14(s, 1H), 4.89(d) , J = 3.6 Hz, 1H), 4.28 (brs, 1H), 3.28-3.25 (m, 3H), 3.12-3.08 (m, 1H), 1.94-1.90 (m, 1H), 1.82-1.75 (m, 1H) ); MS m/z: 457 [M+H] ⁺ .

Example 6: 2-{6-[({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- yl}oxy)methyl]pyridin-2-yl}propan-2-ol (Ex-06)

Compound (Ex-06) was prepared according to Scheme 4 below.

[Scheme 4]

Step 1: Ethyl 6-[([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl])-1,2,3-benzotriazol-5-yl]oxy) Synthesis of methyl]pyridine-2-carboxylate

The compound prepared in step 6 of Example 2 (Intermediate I) (80.0 mg, 0.270 mmol) and ethyl 6-(chloromethyl)pyridine-2-carboxylate (108 mg, 0.540 mmol) were stirred in DMF (3.00 mL). were mixed, K ₂ CO ₃ (112 mg, 0.810 mmol) was added and the resulting mixture was stirred at 25° C. for 16 h. The reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL) and the combined organic layers were washed with brine (2 x 25.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain ethyl 6-[([1-[2-amino-6-(furan-2-yl) Obtained 40.0 mg, 30.6% of pyrimidin-4-yl])-1,2,3-benzotriazol-5-yl]oxy)methyl]pyridine-2-carboxylate as an off-white solid. MS m/z: 458 [M+H] ⁺ .

Step 2: 2-{6-[({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl}oxy Synthesis of )methyl]pyridin-2-yl}propan-2-ol (Ex-06)

The compound obtained in step 1 (40.0 mg, 0.087 mmol) was stirred mixed in THF (5.00 mL) and CH ₃ MgBr (80 μL, 0.694 mmol, 1M THF solution) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 16 hours under a nitrogen atmosphere. The reaction was quenched with water (25.0 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 25.0 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:2) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC with the following conditions: column, Xselect CSH OBD column 30x150 mm 5 μm, n; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (45% PhaseB, up to 65% in 7 min); Detector, UV 254 & 220 nm. The collected fractions were lyophilized to obtain 2-{6-[({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5 Obtained -yl}oxy)methyl]pyridin-2-yl}propan-2-ol (Ex-06; 9.80 mg, 25.3%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.73 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.87-7.80 (m, 2H), 7.64-7.63 ( m, 2H), 7.48-7.44(m, 2H), 7.34-7.33(m, 3H), 6.75-6.74(m, 1H), 5.31(s, 2H), 5.26(s, 1H), 1.47(s, 6H); MS m/z: 444 [M+H] ⁺ .

Example 7: 4-(furan-2-yl)-6-(5-phenoxy-1H-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine (Ex-07)

The compound prepared in step 6 of Example 2 (intermediate I) (110 mg, 0.370 mmol) and diphenyliodanium bromide (270 mg, 0.750 mmol) were stirred and mixed in THF (5.00 mL), and t-BuOK ( 125 mg, 1.12 mmol) was added. The resulting mixture was stirred at 40° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C ₁₈ , 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (64% PhaseB, up to 84% in 7 min); Detector, UV 254 & 220 nm. The collected fractions were freeze-dried to obtain 4-(furan-2-yl)-6-(5-phenoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine (Ex-07; 8.80 mg, 6.33%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.85 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H) , 7.54-7.41 (m, 3H), 7.35-7.34 (m, 3H), 7.23-7.20 (m, 1H), 7.18-7.10 (m, 2H), 6.76-6.74 (m, 1H); MS m/z: 371 [M+H] ⁺ .

Example 8: 4-[5-(benzyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-08 )

The compound prepared in step 6 of Example 2 (intermediate I) (80.0 mg, 0.270 mmol) and benzyl bromide (93.0 mg, 500 μmol) were mixed by stirring in DMF (2.00 mL), and Cs ₂ CO ₃ (265 mg , 0.810 mmol) was added. The resulting mixture was stirred at 25° C. for 16 h under a nitrogen atmosphere and the reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL), and the combined organic layers were washed with brine (3 x 25.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C ₁₈ , 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (64% PhaseB, up to 84% in 7 min); Detector, UV 254 & 220 nm. The collected fractions were freeze-dried to obtain 4-[5-(benzyloxy)-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 08; 10.2 mg, 9.74%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.72 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H) , 7.55-7.52 (m, 2H), 7.46-7.33 (m, 7H), 6.75-6.74 (m, 1H), 5.26 (s, 2H); MS m/z: 385 [M+H] ⁺ .

Example 9: 4-(furan-2-yl)-6-[5-[(1-methylpiperidin-3-yl)oxy]-1H-1,2,3-benzotriazol-1-yl ]Pyrimidine-2-amine (Ex-09)

4-(furan-2-yl)- 6-[5-[(1-methylpiperidin-3-yl)oxy]-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex-09; 9.00 mg, 3.36 %) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.69 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H) , 7.34-7.32(m, 4H), 6.77-6.74(m, 1H), 4.67-4.55(m, 1H), 2.90-2.85(m, 1H), 2.59-2.55(m, 1H), 2.20(s, 3H), 2.19-2.15 (m, 1H), 2.14-1.97 (m, 2H), 1.80-1.71 (m, 1H), 1.68-1.52 (m, 1H), 1.45-1.36 (m, 1H); MS m/z: 392 [M+H] ⁺ .

Example 10: Methyl 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- yl}oxy)pyridin-2-yl]acetate (Ex-10)

The compound prepared in step 6 of Example 2 (intermediate I) (300 mg, 1.01 mmol) and methyl 2-(3-bromopyridin-2-yl)acetate (703 mg, 3.05 mmol) were mixed with DMSO (10 mL). Stir in to mix, and add CuI (19.0 mg, 1.019 mmol), 1,10-phenanthroline (183 mg, 1.01 mmol) and Cs ₂ CO ₃ (830 mg, 2.54 mmol). The resulting mixture was stirred at 110° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Prep OBD C ₁₈ column, 19 x 250 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (41% PhaseB, up to 52% in 10 min); Detector, UV 254&220 nm. The collected fractions were lyophilized to obtain methyl 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5 Obtained -yl}oxy)pyridin-2-yl]acetate (Ex-10; 5.00 mg, 1.10%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.86 (d, J = 9.0 Hz, 1H), 8.36-8.34 (m, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.64(s, 1H), 7.51-7.48(m, 1H), 7.42-7.34(m, 5H), 6.75-6.74(m, 1H), 3.96(s, 2H), 3.57(s, 3H) ; MS m/z: 444 [M+H] ⁺ _.

Example 11: 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl } oxy) -4-fluorophenyl] -2-methyl propanoic acid (Ex-11)

Compound (Ex-11) was prepared according to Scheme 5 below.

[Scheme 5]

Step 1: Methyl 2-[3-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy Synthesis of )-4-fluorophenyl]-2-methyl propanoate

Methyl 2-[3-([1-[2- Amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)-4-fluorophenyl]-2-methyl propanoate ( 40.0 mg, 2.41%) as an off-white solid. MS m/z: 489 [M+H ⁺ ].

Step 2: 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl}oxy) Synthesis of -4-fluorophenyl] -2-methyl propanoic acid (Ex-11)

The compound obtained in step 1 (40.0 mg, 0.082 mmol) was stirred in THF (4.00 mL)/MeOH (1.00 mL), and a solution of LiOH (20.0 mg, 0.820 mmol) was added. The resulting mixture was stirred at 25° C. for 4 hours, and the crude product was purified by Prep-HPLC with the following conditions: column, SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (45% PhaseB, up to 65% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 2-[3-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5- Obtained yl]oxy)-4-fluorophenyl]-2-methyl propanoic acid (Ex-11; 8.50 mg, 21.7%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 12.50 (brs, 1H), 8.85 (d, J = 9.2 Hz, 1H), 7.99 (s, 1H), 7.64 (s, 1H) , 7.57-7.52 (m, 2H), 7.44-7.19 (m, 6H), 6.75-6.74 (m, 1H), 1.45 (s, 6H); MS m/z: 475 [M+H] ⁺ .

Example 12: 2-{[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- yl}oxy)-5-methylphenyl]methoxy}ethane-1-ol (Ex-12)

Compound (Ex-12) was prepared according to Scheme 6 below.

[Scheme 6]

Step 1: 4-(furan-2-yl)-6-[5-(3-methyl-5-[[2-(oxan-2-yloxy)ethoxy]methyl]phenoxy)-1,2, Synthesis of 3-benzotriazol-1-yl] pyrimidin-2-amine

4-(furan-2-yl)-6-[ 5-(3-methyl-5-[[2-(oxan-2-yloxy)ethoxy]methyl]phenoxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (25.0 mg, 1.58%) as an off-white oil. MS m/z:543 [M+H] ⁺ .

Step 2: 2-{[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl Synthesis of }oxy)-5-methylphenyl]methoxy}ethane-1-ol (Ex-12)

The compound obtained in step 1 (25.0 mg, 0.032 mmol) was mixed with MeOH (2.00 mL) and conc. It was dissolved in HCl (1.00 mL) and stirred at 25 °C for 1 hour. The crude product was purified by Prep-HPLC with the following conditions: Column, XSelect CSH Fluoro Phenyl, 30 mm X 150 mm, 5 μm; mobile phase, water (50 mmol/L NH ₄ HCO ₃ ) and ACN (40% PhaseB, up to 60% in 7 min); detector, UV. The collected fractions were lyophilized to obtain 2-{[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole Obtained -5-yl}oxy)-5-methylphenyl]methoxy}ethane-1-ol (Ex-12; 5.20 mg, 33.9%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.84 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.51-7.47 (m, 1H), 7.35-7.34 (m, 2H), 6.98 (s, 1H), 6.85-6.83 (m, 2H), 6.76-6.74 (m, 1H), 4.65 (br s, 1H), 4.46 (s, 2H), 3.54-3.51 (m. 4H), 2.30 (s, 3H); MS m/z: 459 [M+H] ⁺ .

Example 13: 2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl}oxy) -N-phenylacetamide (Ex-13)

2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl in the same manner as in Example 8, except that the compound (F) of Preparation Example 6 was used instead of benzyl bromide. Obtained ]-1H-1,2,3-benzotriazol-5-yl}oxy)-N-phenylacetamide (Ex-13; 15.2 mg, 10.4%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 10.18 (s, 1H), 8.76 (d, J = 9.3 Hz, 1H), 7.98 (s, 1H), 7.69-7.63 (m, 4H), 7.53-7.50 (m, 1H), 7.37-7.32 (m, 4H), 7.12-7.07 (m, 1H), 6.75-6.73 (m, 1H), 4.88 (s, 2H); MS m/z: 428 [M+H] ⁺ .

Example 14: 4-(furan-2-yl)-6-{5-[(5-phenyl-1,2,4-oxadiazol-3-yl)oxy]-1H-1,2,3- Benzotriazol-1-yl} pyrimidin-2-amine (Ex-14)

4-(furan-2-yl)-6-{5-[( 5-phenyl-1,2,4-oxadiazol-3-yl)oxy]-1H-1,2,3-benzotriazol-1-yl}pyrimidin-2-amine (Ex-14; 17.4 mg , 7.62%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.92 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.7 Hz , 2H), 7.99(s, 1H), 7.89-7.85(m, 1H), 7.75-7.73(m, 1H), 7.72-7.62(m, 3H), 7.38-7.35(m, 3H), 6.76-6.74 (m, 1H); MS m/z: 439 [M+H] ⁺ .

Example 15: 2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl}oxy) -1-(4-phenylpiperazin-1-yl)ethan-1-one (Ex-15)

2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl in the same manner as in Example 8, except that the compound (G) of Preparation Example 7 was used instead of benzyl bromide. ]-1H-1,2,3-benzotriazol-5-yl}oxy)-1-(4-phenylpiperazin-1-yl)ethan-1-one (Ex-15; 22.4 mg, 12.9%) was obtained as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.71 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.43-7.39 (m, 1H), 7.34-7.23 (m, 3H), 7.27-7.22 (m, 2H), 6.99 (d, J = 8.1 Hz, 2H), 6.85-6.80 (m , 1H), 6.75-6.74 (m, 1H), 5.07 (s, 2H), 3.66 (br s, 4H), 3.24 (br s, 2H), 3.15 (br s, 2H); MS m/z: 497 [M+H] ⁺ .

Example 16: 4-(furan-2-yl)-6-{5-[3-(1H-imidazol-1-yl)propoxy]-1H-1,2,3-benzotriazole-1- 1} Pyrimidine-2-amine (Ex-16)

4-(furan-2-yl)-6-{5- was prepared in the same manner as in Example 8, except that 1-(3-bromopropyl)imidazole (272 mg, 1.43 mmol) was used instead of benzyl bromide. [3-(1H-imidazol-1-yl)propoxy]-1H-1,2,3-benzotriazol-1-yl}pyrimidin-2-amine (Ex-16; 9.70 mg, 4.00%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.68 (d, J = 9.0 Hz, 1H), 7.98-7.97 (m, 1H), 7.63-7.62 (m, 2H), 7.34- 7.30(m, 4H), 6.75-6.73(m, 1H), 3.95-3.93(m, 2H), 2.99-2.95(m, 2H), 2.49-2.45(m, 2H), 1.88-1.84(m, 1H) ), 1.76-1.72 (m, 2H), 1.27-1.18 (m, 2H); MS m/z: 402 [M+H] ⁺ .

Example 17: 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 17)

4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazole was prepared in the same manner as in Example 8, except that bromocyclopentane (252 mg, 1.69 mmol) was used instead of benzyl bromide. Obtained -1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-17; 11.7 mg, 9.00%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.67 (d, J = 9.0 Hz, 1H), 7.98-7.97 (m, 1H), 7.62-7.60 (m, 2H), 7.33- 7.26 (m, 4H), 6.75-6.73 (m, 1H), 5.01-4.96 (m, 1H), 2.07-1.96 (m, 2H), 1.81-1.60 (m, 6H); MS m/z: 362 [M+H] ⁺ .

Example 18: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-1H-1,2,3-benzotriazol-1-yl}pyridine Midin-2-amine (Ex-18)

Compound (Ex-18) was prepared according to Scheme 7 below.

[Scheme 7]

Step 1: tert-Butyl 4-[([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy ) methyl] piperidine-1-carboxylate synthesis

tert-butyl 4-[( [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)methyl]piperidine-1-carboxyl Yield (80.0 mg, 21.0%) was obtained as a white solid; MS m/z: 491 [M+H] ⁺ .

Step 2: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-1H-1,2,3-benzotriazol-1-yl}pyrimidine Synthesis of -2-amine (Ex-18)

The compound obtained in step 1 above (80.0 mg, 0.160 mmol) was stirred and mixed in DCM (3.00 mL), and TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 3 hours and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C ₁₈ column, 30 x 150 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25B to 45B in 7 min, RT1: 5.52. The collected fractions were freeze-dried to obtain 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-1H-1,2,3-benzotriazole-1- 1} Obtained pyrimidin-2-amine (Ex-18; 13.2 mg, 22.0%) as a white solid. ^1H -NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.67 (d, J = 12.4 Hz, 1H), 7.98-7.97 (m, 1H), 7.63-7.62 (m, 2H), 7.40- 7.30(m, 4H), 6.75-6.73(m, 1H), 3.94(d, J = 8.4 Hz, 2H), 2.99-2.90(m, 2H), 2.60-2.51(m, 2H), 1.95-1.70( m, 3H), 1.30-1.10 (m, 2H); MS m/z: 391 [M+H] ⁺ .

Example 19: 1-[2-amino-6-(furan-3-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-19)

2-(furan-3-yl) instead of 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 4 of Example 1 1-[2-amino-6-(furan-3- yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-19; 7.40 mg, 16.0%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.08 (brs, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.55 (s, 1H), 7.84-7.83 (m, 1H), 7.65 (s, 1H), 7.36-7.35 (m, 1H), 7.23-7.12 (m, 3H), 7.04 (s, 1H); MS m/z: 295 [M+H] ⁺ .

Example 20: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-6-ol (Ex-20)

Steps 1 to 2 of Example 2, except that 2-fluoro-4-methoxy-1-nitrobenzene was used instead of 1-fluoro-4-methoxy-2-nitrobenzene in Step 1 of Example 2. 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-20; 9.70 mg, 0.42%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO) δ 7.99-7.97 (m, 3H), 7.59 (s, 1H), 7.32-7.31 (m, 1H), 7.21 (s, 2H), 7.09-7.06 (m, 1H), 6.74-6.73 (m, 1H); MS m/z: 295[M+H] ⁺ .

Example 21: 4-(furan-2-yl)-6-{6-[3-(imidazol-1-yl)propoxy]-1H-1,2,3-benzotriazol-1-yl} Pyrimidine-2-amine (Ex-21)

The compound of Example 20 (100 mg, 0.340 mmol) and 1-(3-bromopropyl)imidazole (96.0 mg, 0.510 mmol) were mixed by stirring in DMF (1.00 mL) and K ₂ CO ₃ ( 140 mg, 1.02 mmol) was added in portions. The resulting mixture was stirred at 100° C. for 1.5 h under a nitrogen atmosphere, and the mixture was cooled to room temperature. The desired product could be confirmed by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C ₁₈ column, 30x150, 5 μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow Rate: 60 mL /minute). The collected fractions were freeze-dried to obtain 4-(furan-2-yl)-6-{6-[3-(imidazol-1-yl)propoxy]-1,2,3-benzotriazol-1-yl } Obtained pyrimidin-2-amine (Ex-21; 10.7 mg, 7.00%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14-8.08 (m, 2H), 7.98 (s, 1H), 7.66-7.62 (m, 2H), 7.38-7.32 (m, 3H), 7.22-7.17 ( m, 2H), 6.90 (s, 1H), 6.74 (s, 1H), 4.24-4.19 (m, 2H), 4.15-4.11 (m, 2H), 2.33-2.23 (m, 2H); MS m/z: 403 [M+H] ⁺ .

Example 22: 4-[6-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 22)

4-[6-(cyclopentyloxy)-1H-1,2,3-benzo was prepared in the same manner as in Example 21, except that bromocyclopentane was used instead of 1-(3-bromopropyl)imidazole. Obtained triazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-22; 10.9 mg, 8.78%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13(s, 1H), 8.13(d, J = 3.2 Hz, 1H), 8.04(s, 1H), 7.62(s, 1H), 7.33(s, 3H), 7.14-7.11(m, 1H), 7.14-7.11(m, 1H), 6.75-6.76(m, 1H), 5.15-5.11(m, 1H), 2.33-2.32(m, 2H), 2.09- 2.00 (m, 4H), 1.79-1.71 (m, 1H); MS m/z: 363 [M+H] ⁺ .

Example 23: 4-(furan-2-yl)-6-{6-[2-(piperidin-4-yl)ethoxy]-1H-1,2,3-benzotriazol-1-yl } Pyrimidine-2-amine (Ex-23)

Compound (Ex-23) was prepared according to Scheme 8 below.

[Scheme 8]

Step 1: tert-Butyl 4-[2-([3-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl Synthesis of ]oxy)ethyl]piperidine-1-carboxylate

The compound of Example 20 (100 mg, 0.340 mmol) and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (148 mg, 0.510 mmol) were stirred in DMF (1.00 mL). Mixed and added K ₂ CO ₃ (140 mg, 1.02 mmol) portionwise at room temperature. The resulting mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere, and the mixture was cooled to room temperature. The desired product could be confirmed by LCMS. Water (3.00 mL) was added to the resulting mixture, the resulting mixture was extracted with CH ₂ Cl ₂ (3 x 3.00 mL), the combined organic layers were washed with water (3 x 2.00 mL), anhydrous Na ₂ SO ₄ dried with After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain tert-butyl 4-[2-([3-[2-amino-6-(furan- 2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)ethyl]piperidine-1-carboxylate (100 mg, 58.0%) as a yellow solid obtained. MS m/z: 506 [M+H] ⁺ .

Step 2: 4-(furan-2-yl)-6-{6-[2-(piperidin-4-yl)ethoxy]-1,2,3-benzotriazol-1-yl}pyrimidine Synthesis of -2-amine (Ex-23)

The compound obtained in step 1 (100 mg, 0.240 mmol) was stirred in DCM (1.0 0 mL), and TFA (0.330 mL) was added dropwise to the solution at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be confirmed by LCMS. The crude product was purified under the following conditions (Column: Kinetex EVO C ₁₈ column, 30x150, 5 μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow Rate: 60 mL/min). The collected fractions were freeze-dried to obtain 4-(furan-2-yl)-6-{6-[2-(piperidin-4-yl)ethoxy]-1,2,3-benzotriazole-1- 1} Obtained pyrimidin-2-amine (Ex-23; 7.80 mg, 7.78%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13(s, 1H), 8.13(d, J = 3.2Hz, 1H), 8.04(s, 1H), 7.62(s, 1H), 7.33(s, 3H) ), 7.14-7.11 (m, 1H), 7.14-7.11 (m, 1H), 6.75-6.76 (m, 1H), 5.15-5.11 (m, 1H), 2.33-2.32 (m, 2H), 2.09-2.00 (m, 4H), 1.79-1.71 (m, 1H); MS m/z: 406 [M+H] ⁺ .

Example 24: 4-[5-(4-benzylpiperazine-1-carbonyl)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidine -2-amine (Ex-24)

Compound (Ex-24) was prepared according to Scheme 9 below.

[Scheme 9]

Steps 1 to 5: Synthesis of methyl 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylate

Steps 1 to 2 of Example 2, except that methyl 4-fluoro-3-nitrobenzoate was used instead of 1-fluoro-4-methoxy-2-nitrobenzene in Step 1 of Example 2. Methyl 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylate (800 mg, 35.5%) as a pink solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.88 (d, J = 8.0 Hz, 1H), 8.75 (s, 1H), 8.22-8.19 (m, 1H), 7.97 (s, 1H), 7.61 (s, 1H), 7.36 (s, 2H), 7.34-7.33 (m, 1H), 6.74-6.72 (m, 1H), 3.92 (s, 3H); MS m/z: 337 [M+H] ⁺ .

Step 6: Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylic acid

The compound obtained in step 5 above (2.00 g, 5.94 mmol) was stirred mixed in THF (20.0 mL) and LiOH (1.40 g, 58.5 mmol) in H ₂ O (4.00 mL) was added. The resulting mixture was stirred at 25° C. for 16 h and concentrated in vacuo. The crude product was purified by reverse phase column chromatography (column, C ₁₈ silica gel, 80 g, 40-60 μm, 60 A; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (0% ACN, max. in 30 min). up to 100%); detector, UV 220&254 nm). The collected fractions were concentrated to obtain 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylic acid (900 mg, 42.3 %) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.66 (d, J = 8.0 Hz, 1H), 8.57 (s, 1H), 8.28-8.25 (m, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.32 (s, 2H), 6.73-6.10 (m, 1H); MS m/z: 323 [M+H] ⁺ .

Step 7: 4-[5-(4-Benzylpiperazine-1-carbonyl)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin- Synthesis of 2-amine (Ex-24)

The compound obtained in step 6 (110 mg, 0.340 mmol) and benzylpiperazine (72.0 mg, 0.410 mmol) were mixed by stirring in DMF (3.00 mL), HATU (456 mg, 1.19 mmol) and DIEA (132 mg). , 1.02 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The mixture was poured into water (50.0 mL) and the resulting mixture was extracted with EtOAc (60.0 mL). The combined organic layers were washed with brine (50.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C18, 30 mm X 150 mm, 5 μm; mobile phase, water (50 mmol/L NH ₄ HCO ₃ ) and ACN (48% PhaseB, up to 68% in 7 min); Detector, UV 254&220 nm. Product fractions were freeze-dried to obtain 4-[5-(4-benzylpiperazine-1-carbonyl)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl) Pyrimidin-2-amine (Ex-24; 9.10 mg, 5.33%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.86 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.65(s, 1H), 7.36-7.25(m, 8H), 6.75-6.74(m, 1H), 3.76-3.68(m, 2H), 3.52(s, 2H), 3.39-3.31 (m, 2H), 2.49-2.32 (m, 4H) MS m/z: 481 [M+H] ⁺ .

Example 25: {1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl}methyl N-(thiol) Ofen-3-yl)carbamate (Ex-25)

Compound (Ex-25) was prepared according to Scheme 10 below.

[Scheme 10]

Step 1: Synthesis of [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methanol

The compound obtained in step 5 of Example 24 (500 mg, 1.48 mmol) and LiAlH ₄ (110 mg, 2.90 mmol) were stirred in THF (10.0 mL) under a nitrogen atmosphere at room temperature for 15 minutes. The reaction was quenched with water/ice at room temperature. The mixture was poured into water (90.0 mL) and extracted with CH ₂ Cl ₂ (80 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methanol (300 mg, 60.9%) as a white solid. MS m/z: 309 [M+H] ⁺ .

Step 2: [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methyl N-(thiophen-3 Synthesis of -yl)carbamate (Ex-25)

The compound obtained in step 1 (50.0 mg, 0.160 mmol) and 3-isocyanatothiophene (44.0 mg, 0.350 mmol) were stirred and mixed in DMF (2.00 mL), and DIEA (68.0 mg, 0.520 mmol) was added. added. The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The mixture was poured into water (80.0 mL) and extracted with EtOAc (80.0 mL), the combined organic layers were washed with brine (80.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; Mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (44% PhaseB, up to 64% in 7 min). Product fractions were lyophilized to [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methyl N-(thiol). Offen-3-yl)carbamate (Ex-25; 5.50 mg, 7.67%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.13 (s, 1H), 8.83 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 7.99-7.98 (m, 1H), 7.81-7.78(m, 1H), 7.65(s, 1H), 7.45-7.43(m, 1H), 7.35-7.34(m, 3H), 7.24(s, 1H), 7.03-7.02(m, 1H), 6.75-6.74 (m, 1H), 5.36 (s, 2H); MS m/z: 434 [M+H] ⁺ .

Example 26: [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl]methyl3,4- Dihydro-1H-isoquinoline-2-carboxylate (Ex-26)

The compound obtained in step 1 of Example 25 (100 mg, 0.320 mmol), CDI (105 mg, 0.648 mmol) and TEA (131 mg, 1.29 mmol) were mixed by stirring in DMF (3.00 mL) and the resulting mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. Tetrahydroisoquinoline (86.0 mg, 0.640 mmol) was added and the resulting mixture was stirred at 60° C. for 1 hour under a nitrogen atmosphere and the mixture was cooled to room temperature. The mixture was poured into water (60.0 mL) and extracted with EtOAc (60.0 mL), the combined organic layers were washed with brine (60.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C ₁₈ , 30 mm×150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (59% PhaseB, up to 79% in 7 min); Detector, UV 254&220 nm. Product fractions were lyophilized to [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methyl 3,4- Dihydro-1H-isoquinoline-2-carboxylate (Ex-26; 14.4 mg, 9.40%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.21 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.65(s, 1H), 7.34-7.33(m, 3H), 7.19-7.17(m, 4H), 6.75-6.74(m, 1H), 5.34(s, 2H), 4.68-4.57 (m, 2H), 3.75-3.63 (m, 2H), 2.84-2.81 (m, 2H); MS m/z: 468 [M+H] ⁺ .

Example 27: 1-[2-amino-6-(furan-2-yl)-5-(pyridin-4-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole- 5-ol (Ex-27)

Compound (Ex-27) was prepared according to Scheme 11 below.

[Scheme 11]

Steps 1 to 3: Synthesis of 1-[5-bromo-6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

Same as steps 1 to 3 of Example 2, except that Compound (H) (26.5 g, 104 mmol) of Preparation Example 8 was used instead of 2,6-dichloropyrimidin-4-amine in Step 1 of Example 2. Method 1-[5-bromo-6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole (20.0 g, 62.0%) was obtained as a brownish solid. MS m/z: 386 [M+H] ⁺ .

Step 4: 1-[6-chloro-2-(methylsulfanyl)-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole synthesis

The compound obtained in step 3 (20.0 g, 51.7 mmol) and pyridin-4-yl boronic acid (5.09 g, 41.4 mmol) were mixed in dioxane (300 mL) and H ₂ O (50.0 mL), K ₂ CO ₃ (21.6 g, 156 mmol) and Pd(dppf)Cl ₂ (7.57 g, 10.3 mmol) were added. The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 600 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EA/PE (1/2) to give 1-[6-chloro-2-(methylsulfanyl)-5-(pyridin-4-yl)pyrimidine-4- yl]-5-methoxy-1,2,3-benzotriazole (3.00 g, 14.0%) was obtained as a purple solid. MS m/z: 385 [M+H] ⁺ .

Step 5: 1-[6-(furan-2-yl)-2-(methylsulfanyl)-5-(pyridin-4-yl))pyrimidin-4-yl]-5-methoxy-1,2 Synthesis of ,3-benzotriazole

The compound obtained in step 4 (3.00 g, 7.79 mmol) and furan-2-yl boronic acid (872 mg, 7.79 mmol) were mixed in dioxane (50.0 mL) and H ₂ O (10.0 mL) and Cs ₂ CO ₃ (7.61 g, 23.4 mmol), Xphos (743 mg, 1.56 mmol) and XPhos Pd G3 (659 mg, 0.780 mmol) were added. The resulting mixture was stirred at 8° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (60.0 mL) and extracted with EtOAc (3 x 80.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc/PE (1/2) to give 1-[6-(furan-2-yl)-2-(methylsulfanyl)-5-(pyridin-4-yl) ) Pyrimidin-4-yl] -5-methoxy-1,2,3-benzotriazole (1.20 g, 35.1%) was obtained as a yellow solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.83-8.81 (m, 2H), 8.03-8.00 (m, 1H), 7.80 (s, 1H), 7.57-7.56 (m, 1H) ), 7.44-7.30 (m, 3H), 6.60 (s, 2H), 3.85 (s, 3H), 2.68 (s, 3H); MS m/z: 417 [M+H] ⁺ .

Step 6: 1-[6-(furan-2-yl)-2-methanesulfonyl-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1,2,3- Synthesis of Benzotriazole

The compound obtained in step 5 (1.20 g, 2.88 mmol) was stirred mixed in MeOH (20.0 mL) and potassium peroxymonosulfate (H ₃ K ₅ O ₁₈ S ₄ ) (5.31 g in H ₂ O (10.0 mL)). , 8.64 mmol) solution was added. The resulting mixture was stirred at 25 °C for 4 hours. The reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 1-[6-(furan-2-yl)-2-methanesulfonyl-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1 ,2,3-benzotriazole (1.00 g, crude) was obtained as a yellow solid. MS m/z: 449 [M+H] ⁺ .

Step 7: 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)-5-(pyridin-4-yl)pyrimidine-2- synthesis of amines

The compound obtained in step 6 (1.00 g, 2.23 mmol) was stirred in THF (5.00 mL) and NH ₃ .H ₂ O (5.00 mL) was added. The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with water (100 mL) and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 4-(furan-2-yl)-6-(5-methoxy-1,2 Obtained 220 mg, 23.0% of ,3-benzotriazol-1-yl)-5-(pyridin-4-yl)pyrimidin-2-amine as an off-white solid. MS m/z: 386 [M+H] ⁺ .

Step 8: 1-[2-amino-6-(furan-2-yl)-5-(pyridin-4-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol Synthesis of (Ex-27)

The compound obtained in step 7 (25.0 mg, 0.065 mmol) and BBr ₃ were stirred in DCM (1M) (2 mL) under a nitrogen atmosphere at 25° C. for 2 h. The reaction was quenched with MeOH (1 mL). The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30x15 0 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (20% PhaseB, up to 40% in 7 min); Detector, UV 254&220 nm. The collected fractions were lyophilized to obtain 1-[2-amino-6-(furan-2-yl)-5-(pyridin-4-yl)pyrimidin-4-yl]-1,2,3-benzotriazole. Obtained -5-ol (Ex-27; 5.00 mg, 20.7%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 9.85 (s, 1H), 8.45 (d, J = 4.5 Hz, 2H), 7.95 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.44(s, 2H), 7.22(d, J = 4.5 Hz, 2H), 7.16-7.11(m, 2H), 6.51-6.49(m, 1H), 6.25-6.24(m, 1H) ); MS m/z: 372 [M+H] ⁺ .

Example 28: 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)-5-(pyridin-4-yl ) Pyrimidine-2-amine (Ex-28)

The compound of Example 27 (35.0 mg, 0.094 mmol) and bromocyclopentane (42.0 mg, 0.280 mmol) were mixed with stirring in DMF (3.00 mL) and Cs ₂ CO ₃ (77.0 mg, 0.230 mmol) was added. The resulting mixture was stirred at 60 °C for 2 h and the reaction was quenched with MeOH (2.00 mL). The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (38% PhaseB, up to 49% in 10 min); Detector, UV 254&220 nm. The collected fractions were freeze-dried to obtain 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)-5-(pyridin- Obtained 4-yl)pyrimidin-2-amine (Ex-28; 17.1 mg, 40.9%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.46 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 1.6 Hz) , 1H), 7.46(s, 2H), 7.40(d, J = 2.1 Hz, 1H), 7.22(d, J = 4.5 Hz, 2H), 7.20-7.17(m, 1H), 6.51-6.50(m, 1H), 6.25-6.24 (m, 1H), 1.97-1.90 (m, 2H), 1.75-1.57 (m, 6H); MS m/z: 440 [M+H] ⁺ .

Example 29: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1H-1,3-benzodiazole-5- All (Ex-29)

Compound (Ex-29) was prepared according to Scheme 12 below.

[Scheme 12]

Step 1: Synthesis of 6-(furan-2-yl)-N-(4-methoxy-2-nitrophenyl)-2-(methylsulfanyl)pyrimidin-4-amine

Compound (I) (4.10 g, 19.8 mmol) obtained in Preparation Example 9 was stirred and mixed in THF (40.0 mL), and NaH (1.58 g, 39.6 mmol, 60% dispersed in mineral oil) was added at 0 ° C. under a nitrogen atmosphere. added in portions. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere and 1-fluoro-4-methoxy-2-nitrobenzene (6.70 g, 39.6 mmol) was added at 0°C. The resulting mixture was stirred at 60° C. for an additional 5 h and the reaction was quenched with water (100 mL). The mixture was extracted with EtOAc (3 x 300 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexanes (3 x 100 mL). The resulting solid was dried under infrared light to obtain 6-(furan-2-yl)-N-(4-methoxy-2-nitrophenyl)-2-(methylsulfanyl)pyrimidin-4-amine (5.50 g, 72.9 %) was obtained as a red solid. MS m/z: 359 [M+H] ⁺ .

Step 2: Synthesis of N1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-4-methoxybenzene-1,2-diamine

A mixture of the compound obtained in step 1 (5.50 g, 15.3 mmol) and Pd/C (800 mg, 10%) was stirred in EtOAc (50.0 mL) under a hydrogen atmosphere at 25° C. for 6 hours. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 300 mL), and the filtrate was concentrated under reduced pressure to obtain N1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine-4. Obtained -yl]-4-methoxybenzene-1,2-diamine (4.00 g, 72.2%) as a purple solid. MS m/z: 329 [M+H] ⁺ .

Step 3: 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3- Synthesis of benzodiazoles

The compound obtained in step 2 (1.50 g, 4.56 mmol) and 4-formyl pyridine (587 mg, 5.48 mmol) were stirred and mixed in DMF (30.0 mL), Na ₂ S ₂ O ₅ (4.30 g, 22.8 mmol) ) was added. The final reaction mixture was microwaved at 140°C for 3 hours. The mixture was then cooled to room temperature and the resulting mixture was poured into water (400 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:5) to give 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5- Obtained 800 mg, 40.5% of methoxy-2-(pyridin-4-yl)-1,3-benzodiazole as a dark yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.68-8.67 (m, 2H), 8.03 (s, 1H), 7.64-7.57 (m, 1H), 7.50-7.49 (m, 2H) ), 7.43-7.42(m, 2H), 7.27-7.26(m, 1H), 7.10-7.07(m, 1H), 6.84-6.78(m, 1H), 3.86(s, 3H), 2.23(s, 3H) ); MS m/z: 416 [M+H] ⁺ .

Step 4: 1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3-benzodia synthesis of sol

The compound obtained in step 3 (800 mg, 1.92 mmol) and potassium peroxymonosulfate (H ₃ K ₅ O ₁₈ S ₄ ) (9.40 g, 15.4 mmol) were mixed with MeOH (30.0 mL) and H ₂ O (15.0 mL). Stir and mix at 25° C. for 3 hours in a bath. The reaction was quenched with sodium thiosulfate solution (200 mL) and the resulting mixture was poured into water (100 mL) and extracted with CH ₂ Cl ₂ (3 x 200 mL). The combined organic layers were washed with sodium bicarbonate solution (2 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-[6-(furan-2-yl)-2-methanesulfonylpyrimidine Obtained -4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3-benzodiazole (900 mg, 93.0%) as an off-white solid. MS m/z: 448 [M+H] ⁺ .

Step 5: 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine synthesis

The compound obtained in step 4 (900 mg, 2.01 mmol) and NH ₃ .H ₂ O (10.0 mL) were stirred in THF (10.0 mL) at 25° C. for 3 hours, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with CH ₂ Cl ₂ /MeOH (10:1) to give 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl) Obtained -1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 60.1%) as a brown solid. MS m/z: 385 [M+H] ⁺ .

Step 6: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzodiazol-5-ol (Ex -29) Synthesis of

The compound obtained in step 5 (100 mg, 0.260 mmol) and BBr ₃ were stirred and mixed in DCM (1 M, 2.00 mL) at 25° C. for 5 hours. The reaction was quenched with MeOH (2.00 mL). The crude product was purified by Prep-HPLC with the following conditions: column, Xselect CSH OBD column 30 x 150 mm 5 μm, n; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (15% PhaseB, up to 45% in 9 min); Detector, UV 254 nm. The collected fractions were lyophilized to obtain 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzodiazole-5 -ol (Ex-29; 5.30 mg, 5.45%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.43 (s, 1H), 8.66-8.64 (m, 2H), 7.90 (s, 1H), 7.59-7.57 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 2H), 6.90–6.87 (m, 1H), 6.86 (s , 1H), 6.70-6.69 (m, 1H); MS m/z: 371 [M+H] ⁺ .

Example 30: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-2-(pyridin-4-yl)-1H-1,3-benzo Diazol-1-yl} pyrimidin-2-amine (Ex-30)

Compound (Ex-30) was prepared according to Scheme 13 below.

[Scheme 13]

Step 1: tert-Butyl 4-[([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzo Synthesis of diazol-5-yl]oxy)methyl]piperidine-1-carboxylate

To a stirred mixture of the compound of Example 29 (120 mg, 0.320 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (180 mg, 0.640 mmol) in DMF (3.00 mL) Cs ₂ CO ₃ (263 mg, 0.810 mmol) was added. The resulting mixture was stirred at 60° C. for 1 hour. The resulting mixture was poured into water (100 mL) and extracted with CH ₂ Cl ₂ (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give tert-butyl 4-[([1-[2-amino-6-(furan-2 -yl) pyrimidin-4-yl] -2- (pyridin-4-yl) -1,3-benzodiazol-5-yl] oxy) methyl] piperidine-1-carboxylate (110 mg, 52.6%) as a brown solid. MS m/z: 568 [M+H] ⁺ .

Step 2: 4-(furan-2-yl)-6-{5-(piperidin-4-ylmethoxy)-2-(pyridin-4-yl)-1,3-benzodiazol-1-yl } Synthesis of pyrimidin-2-amine (Ex-30)

The compound obtained in step 1 (100 mg, 0.170 mmol) was stirred in TFA (1.00 mL) and DCM (3.00 mL) for 30 min at 25 °C. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Prep OBD C ₁₈ column, 30 x 150 mm 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (15% PhaseB, up to 45% in 9 min); Detector, UV 254 nm. The collected fractions were lyophilized to obtain 4-(furan-2-yl)-6-[5-(piperidin-4-ylmethoxy)-2-(pyridin-4-yl)-1,3-benzodiazole. -1-yl]pyrimidin-2-amine (Ex-30; 12.6 mg, 15.2%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.67-8.65 (m, 2H), 7.90 (d, J = 2.4 Hz, 1H), 7.64-7.59 (m, 3H), 7.36 ( d, J = 10.2 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.17 (s, 2H), 7.02 (d, J = 11.3 Hz, 1H), 6.87 (s, 1H), 6.70- 6.69(m, 1H), 3.89-3.85(m, 2H), 3.05-2.96(m, 2H), 2.54-2.52(m, 1H), 2.49-2.47(m, 1H), 1.95-1.85(m, 1H) ), 1.83-1.72 (m, 2H), 1.25-1.15 (m, 2H); MS m/z: 468 [M+H] ⁺ .

Example 31: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-[(pyridin-4-yl)methyl]-1H-1,3-benzodiazole -5-ol (Ex-31)

Compound (Ex-31) was prepared according to Scheme 14 below.

[Scheme 14]

Step 1: N-(2-[[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]amino]-5-methoxyphenyl)-2-(pyridin-4 -yl) synthesis of acetamide

HATU (11.1 g, 29.2 mmol) was added to a stirred mixture of the compound obtained in step 2 of Example 29 (8.00 g, 24.4 mmol) and 4-acetylpyridine hydrochloride (5.50 g, 31.7 mmol) in DMF (70.0 mL). and DIEA (9.40 g, 73.1 mmol) were added. The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was poured into water (400 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1), to obtain N-(2-[[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine- Obtained 4-yl]amino]-5-methoxyphenyl)-2-(pyridin-4-yl)acetamide (8.00 g, 67.5%) as a brown oil. MS m/z: 448 [M+H] ⁺ .

Step 2: 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3 -Synthesis of Benzodiazole

The compound obtained in step 1 (8.00 g, 17.9 mmol) was mixed in AcOH (40.0 mL) under a nitrogen atmosphere and the final reaction mixture was microwaved at 120 °C for 1 hour. The mixture was cooled to room temperature. The mixture was then purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (10:1) to give 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine-4- Obtained yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3-benzodiazole (5.20 g, 63.0%) as a brown oil. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.76-8.78 (m, 2H), 8.16 (s, 1H), 7.64-7.52 (m, 3H), 7.28-7.24 (m, 3H) ), 6.99-6.95 (m, 1H), 6.81-6.79 (m, 1H), 4.56 (s, 2H), 3.88 (s, 3H); MS m/z: 430 [M+H] ⁺ .

Step 3: 1-[6-(furan-2-yl)-2-methanesulfinylpyrimidin-4-yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3-benzo synthesis of diazoles

The compound obtained in step 2 (5.20 g, 12.1 mmol) and m-CPBA (1.00 g, 6.05 mmol) were stirred in DCM (50.0 mL) for 25 min at 0 °C. The residue was purified by silica gel column chromatography by eluting with CH ₂ Cl ₂ /MeOH (10:1) to obtain 1-[6-(furan-2-yl)-2-methanesulfinylpyrimidin-4-yl]-5 Obtained -methoxy-2-(pyridin-4-ylmethyl)-1,3-benzodiazole (2.00 g, 34.9%) as a brown oil. MS m/z: 446 [M+H] ⁺ .

Step 4: 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-ylmethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine synthesis of

The compound obtained in step 3 (2.00 g, 4.48 mmol) was stirred in THF (20.0 mL) and NH ₃ .H ₂ O (20.0 mL) for 5 h at 25 °C. The mixture was then purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (10:1) to give 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl) Obtained 700 mg (36.8%) of methyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a brown solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.45-8.43 (m, 2H), 7.95-7.94 (m, 1H), 7.58-7.55 (m, 1H), 7.30-7.21 (m , 6H), 7.17 (s, 1H), 7.00-6.92 (m, 1H), 6.73-6.71 (m, 1H), 4.60 (s, 2H), 3.81 (s, 3H); MS m/z: 399 [M+H] ⁺ .

Step 5: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-ylmethyl)-11H-,3-benzodiazol-5-ol Synthesis of (Ex-31)

The compound obtained in step 4 (50.0 mg, 0.120 mmol) and BBr ₃ were mixed in DCM (1.00 mL) by stirring for 1 h at 25 °C. The reaction was quenched with MeOH (1.00 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (20% PhaseB, up to 50% in 7 min); Detector, UV 254 nm. The collected fractions were lyophilized to obtain 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-ylmethyl)-1,3-benzodiazole- The 5-ol (Ex-31; 5.30 mg, 10.8%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.28 (s, 1H), 8.44-8.42 (m, 2H), 7.93 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.28-7.27(m, 1H), 7.22-7.20(m, 2H), 7.14(s, 2H), 7.00-6.96(m, 2H), 6.79(d, J = 11.2 Hz, 1H), 6.72 -6.70 (m, 1H), 4.57 (s, 2H); MS m/z: 385 [M+H] ⁺ .

Example 32: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-2-[(pyridin-4-yl)methyl]-1H-1, 3-benzodiazol-1-yl} pyrimidin-2-amine (Ex-32)

Compound (Ex-32) was prepared according to Scheme 15 below.

[Scheme 15]

Step 1: tert-Butyl 4-[([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-ylmethyl)-1,3- Synthesis of benzodiazol-5-yl]oxy)methyl]piperidine-1-carboxylate

To a stirred mixture of the compound of Example 31 (200 mg, 0.520 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (434 mg, 1.56 mmol) in acetone (6.00 mL) K ₂ CO ₃ (215 mg, 1.56 mmol) was added. The resulting mixture was stirred at 100 °C for 48 hours. The mixture was cooled to room temperature. The mixture was then purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (10:1) to give tert-butyl 4-[([1-[2-amino-6-(furan-2-yl)pyridine Midin-4-yl]-2-(pyridin-4-ylmethyl)-1,3-benzodiazol-5-yl]oxy)methyl]piperidine-1-carboxylate (110 mg, 27.3%) was obtained as a brown oil. MS m/z: 582 [M+H] ⁺ .

Step 2: 4-(furan-2-yl)-6-[5-(piperidin-4-ylmethoxy)-2-(pyridin-4-ylmethyl)-1,3-benzodiazole-1- Synthesis of yl]pyrimidin-2-amine (Ex-32)

The compound obtained in step 1 (100 mg, 0.170 mmol) was stirred in TFA (2.00 mL) and DCM (2.00 mL) for 30 min at 25 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (30% PhaseB, up to 60% in 7 min); Detector, UV 254 nm. The collected fractions were lyophilized to obtain 4-(furan-2-yl)-6-[5-(piperidin-4-ylmethoxy)-2-(pyridin-4-ylmethyl)-1,3-benzodiazepines. Zol-1-yl]pyrimidin-2-amine (Ex-32; 5.20 mg, 6.27%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43-8.42 (m, 2H), 7.93 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.28-7.14 ( m, 6H), 7.03(s, 1H), 6.98-6.91(m, 1H), 6.72-6.70(m, 1H), 4.57(s, 2H), 3.85-3.83(m, 2H), 2.96-2.93( m, 2H), 2.49-2.46 (m, 2H), 1.88-1.83 (m, 1H), 1.82-1.72 (m, 2H), 1.23-1.11 (m, 2H); MS m/z: 482 [M+H] ⁺ .

Example 33: 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1H-1,2,3-benzotriazol-1-yl]pyrimidine- 2-amine (Ex-33)

Compound (Ex-33) was prepared according to Scheme 16 below.

[Scheme 16]

Steps 1 to 4: Synthesis of 5-bromo-1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazole

Starting from 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (33.0 g, 188 mmol) and 6-bromo 1-fluoro-2-nitrobenzene (50.0 g, 227 mmol) In the same manner as in Steps 1 to 4 of Example 2, 5-bromo-1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3 - Benzotriazole (28.0 g, 78.1%) was obtained as a black solid. MS m/z: 388 [M+H] ⁺ .

Step 5: 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Synthesis of borolan-2-yl)-1,2,3-benzotriazole

To a stirred mixture of the compound obtained in step 4 (16.0 g, 41.2 mmol) and bis(pinacolato)diboron (21.0 g, 82.9 mmol) in dioxane (160 mL) was added CH ₃ COOK (12.0 g, 122 mmol) ) and Pd(PPh ₃ ) ₂ Cl ₂ (2.89 g, 4.11 mmol) were added. The resulting mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hours. The mixture was left to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5 Obtained -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzotriazole (5.00 g, 25.1%) as a yellow solid did MS m/z: 436 [M+H] ⁺ .

Step 6: Synthesis of 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl boronic acid

The compound obtained in step 5 (5.00 g, 11.5 mmol) was stirred in THF (50.0 mL) and HCl (6M, 50.0 mL) for 2 h at 80 °C. The mixture was left to cool to room temperature. The mixture was added to water (150 mL). The precipitated solid was collected by filtration and washed with water (50.0 mL) to obtain 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3 - Benzotriazole-5-ylboronic acid (1.80 g, 44.4%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.65 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.38 (s, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.08 (s, 1H), 7.58-7.57 (m, 1H), 6.82-6.80 (m, 1H), 2.74 (s, 3H); MS m/z: 354 [M+H] ⁺ .

Step 7: tert-Butyl 4-([1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazole-5- Synthesis of yl]oxy)pyrazole-1-carboxylate

The compound obtained in step 6 (1.80 g, 5.09 mmol) and tert-butyl 4-hydroxypyrazole-1-carboxylate (1.80 g, 10.2 mmol) were mixed by stirring in DCM (100 mL) and Cu ( OAc) ₂ (1.80 g, 10.2 mmol) and TEA (1.50 g, 15.3 mmol) were added. The resulting mixture was stirred at room temperature under O ₂ atmosphere for 16 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give tert-butyl 4-([1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine- Obtained 4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (500 mg, 18.4%) as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.09 (s, 2H), 7.94 (s, 1H) , 7.85(s, 1H), 7.67-7.64(m, 1H), 7.59-7.58(m, 1H), 6.82-6.81(m, 1H), 2.72(s, 3H), 1.59(s, 9H); MS m/z: 492 [M+H] ⁺ .

Step 8: tert-butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyra Synthesis of sol-1-carboxylate

To a stirred solution of the compound obtained in step 7 (260 mg, 0.520 mmol) in DCM (10.0 mL) was added m-CPBA (365 mg, 2.11 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ (40.0 mL) at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (80 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzo Triazol-5-yl]oxy)pyrazole-1-carboxylate (230 mg, 74.8%) was obtained as an off-white solid. MS m/z: 524 [M+H] ⁺ .

Step 9: tert-Butyl 4-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy) Synthesis of pyrazole-1-carboxylate

To a stirred mixture of the compound obtained in step 8 (230 mg, 0.430 mmol) in THF (3.00 mL) was added NH ₃ .H ₂ O (3.00 mL). The resulting mixture was stirred at 25° C. for 3 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give tert-butyl 4-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl] Obtained -1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (120 mg, 53.4%) as a white solid. MS m/z: 461 [M+H] ⁺ .

Step 10: 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex- Synthesis of 33)

To a stirred mixture of the compound obtained in step 9 (60.0 mg, 0.130 mmol) in DCM (4.00 mL), TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C18 ExRS, 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (40% PhaseB, up to 60% in 7 min); Detector, UV &254/220 nm. Product fractions were lyophilized to yield 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin- 2-Amine (Ex-33; 9.20 mg, 19.5%) was obtained as a white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.91 (s, 1H), 8.80-8.77 (m, 1H), 7.98 (s, 1H), 7.90 (s, 1H), 7.62 ( s, 1H), 7.54 (s, 2H), 7.52-7.51 (m, 1H), 7.34 (d, J = 2.7 Hz, 3H), 6.75-6.73 (m, 1H); MS m/z: 361 [M+H] ⁺ .

Example 34: 1-{2-amino-6-[(furan-2-yl)methyl]pyrimidin-4-yl}-1H-1,2,3-benzotriazol-5-ol (Ex-34 )

Compound (Ex-34) was prepared according to Scheme 17 below.

[Scheme 17]

Steps 1 to 3: Synthesis of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

Steps 1 to 2 of Example 2, except that 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine was used instead of 2,6-dichloropyrimidin-4-amine in Step 1 of Example 2. In the same manner as in 3, 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole (12.0 g, 44.5%) was obtained in brown color. Obtained as a solid. MS m/z: 308 [M+H] ⁺ .

Step 4: Synthesis of 5-methoxy-1-[2-(methylsulfanyl)-6-(trimethylstannyl)pyrimidin-4-yl]-1,2,3-benzotriazole

To a stirred mixture of the compound obtained in step 3 (12.0 g, 39.0 mmol) and hexamethyldistannane (19.2 g, 58.5 mmol) in toluene (200 mL) was added Pd(PPh ₃ ) ₄ (9.01 g, 7.79 mmol). was added. The resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The mixture was left to cool to room temperature. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 5-methoxy-1-[2-(methylsulfanyl)-6-(trimethylstannyl)pyrimidin-4-yl ]-1,2,3-benzotriazole (3.00 g, 15.0%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.50 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.48 (s, 1H), 7.30 (d, J = 8.0 Hz , 1H), 3.95 (s, 3H), 2.72 (s, 3H), 0.46 (s, 9H); MS m/z: 438 [M+H] ⁺ .

Step 5: Synthesis of 1-[6-(furan-2-carbonyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

To the compound obtained in step 4 (3.00 g, 6.87 mmol) and furoyl chloride (4.19 g, 34.4 mmol) were stirred in toluene (60.0 mL), Pd(PPh ₃ ) ₄ (1.59 g, 1.37 mmol) was added. did The resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The mixture was left to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 1-[6-(furan-2-carbonyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5 -Methoxy-1,2,3-benzotriazole (1.20 g, 42.7%) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.40 (d, J = 8.0 Hz, 1H), 8.28 -8.27 (m, 2H), 8.08-8.06 (m, 1H), 7.84- 7.82 (m, 1H), 7.48-7.47 (m, 1H), 6.89-6.88 (m, 1H), 3.91 (s, 3H), 2.78 (s, 3H); MS m/z: 368 [M+H] ⁺ .

Step 6: Synthesis of furan-2-yl[6-(5-methoxy-1,2,3-benzotriazol-1-yl)-2-(methylsulfanyl)pyrimidin-4-yl]methanol

To a stirred mixture of the compound obtained in step 5 (1.20 g, 3.26 mmol) in MeOH (60.0 mL) was added NaBH ₄ (1.20 g, 31.7 mmol) portionwise at 0 °C. The resulting mixture was stirred at 25° C. for 16 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to furan-2-yl[6-(5-methoxy-1,2,3-benzotriazol-1-yl)-2 Obtained -(methylsulfanyl)pyrimidin-4-yl]methanol (700 mg, 52.2%) as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.41 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.69-7.63 (m, 2H), 7.44-7.41 ( m, 1H), 6.61-6.60 (m, 1H), 6.45-6.40 (m, 2H), 5.76-5.73 (m, 1H), 3.90 (s, 3H), 2.65 (s, 3H); MS m/z: 370 [M+H] ⁺ .

Step 7: Synthesis of 1-[6-(furan-2-ylmethyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

To a stirred solution of the compound obtained in step 6 (700 mg, 1.89 mmol) in triethoxysilane (20.0 mL) was added TFA (20.0 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at 25° C. for 2 hours. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 1-[6-(furan-2-ylmethyl)-2-(methylsulfanyl)pyrimidin-4-yl]- Obtained 5-methoxy-1,2,3-benzotriazole (200 mg, 26.9%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.39 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.68-7.64 (m, 2H), 7.43-7.39 ( m, 1H), 6.47-6.46 (m, 1H), 6.40-6.38 (m, 1H), 4.26 (s, 2H), 3.90 (s, 3H), 2.67 (s, 3H); MS m/z: 354 [M+H] ⁺ .

Step 8: Synthesis of 1-[6-(furan-2-ylmethyl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

To a stirred mixture of the compound obtained in step 7 (200 mg, 0.560 mmol) in DCM (20.0 mL) was added m-CPBA (390 mg, 2.26 mmol). The resulting mixture was stirred at 25° C. for 3 hours. The reaction was quenched with a saturated aqueous solution of Na ₂ S ₂ O ₃ . The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 20.0 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 1-[6-(furan-2-ylmethyl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole. (150 mg, 48.1%) as an off-white solid. MS m/z: 386 [M+H] ⁺ .

Step 9: Synthesis of 4-(furan-2-ylmethyl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine

To a stirred mixture of the compound from step 8 (150 mg, 0.270 mmol) in THF (3.00 mL) was added NH ₃ .H ₂ O (3.00 mL). The resulting mixture was stirred at 25 °C for 2 hours. The resulting mixture was diluted with water (20.0 mL). The resulting mixture was extracted with EtOAc (3 x 20.0 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (1:1) to give 4-(furan-2-ylmethyl)-6-(5-methoxy-1,2,3-benzotriazole-1 Obtained -yl)pyrimidin-2-amine (50.0 mg, 51.2%) as an off-white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.66 (d, J = 8.0 Hz, 1H), 7.64-7.61 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H) , 7.26 (s, 2H), 7.17 (s, 1H), 6.44-6.43 (m, 1H), 6.34-6.33 (m, 1H), 4.05 (s, 2H), 3.90 (s, 3H); MS m/z: 323 [M+H] ⁺ .

Step 10: Synthesis of 1-[2-amino-6-(furan-2-ylmethyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-34)

The compound obtained in step 9 (50.0 mg, 0.150 mmol) and BBr ₃ were mixed in DCM (1M) (3.00 mL) by stirring for 1 hour at 25° C. under a nitrogen atmosphere. The reaction was quenched by the addition of MeOH (1 mL) at 0 °C. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (25% PhaseB, 7 min to 45%); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 1-[2-amino-6-(furan-2-ylmethyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-34; 7.30 mg, 14.9%) as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ (ppm): 8.60 (d, J = 9.0 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.14 (s, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.33 (d, J = 3.3 Hz, 1H), 4.03 (s, 2H); MS m/z: 309 [M+H] ⁺ .

Example 35: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indol-5-ol (Ex-35)

Compound (Ex-35) was prepared according to Scheme 18 below.

[Scheme 18]

Step 1: Synthesis of 4-chloro-6-(furan-2-yl)pyrimidin-2-amine

A stirred solution of 4,6-dichloropyridin-2-amine (1.00 g, 6.09 mmol) in DMF (10 mL) was degassed with argon for 5 min. Dikis (0.210 g, 0.300 mmol) was added at room temperature and stirred for 5 minutes. Tributyl(furan-2-yl)stannane (2.17 g, 6.09 mmol) was added and stirred at 80°C for 16 hours. After 16 hours, the reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product eluted with 15-20% EtOAc in hexanes to obtain 4-chloro-6-(furan-2-yl)pyrimidin-2-amine (0.500 g, 41.0%). MS m/z: 196.2 [M+H] ⁺ .

Step 2: Synthesis of 4-(furan-2-yl)-6-iodopyrimidin-2-amine

HI (37.0 mL) was added to a stirred solution of the compound (1.00 g, 5.11 mmol) obtained in step 1, and the reaction mixture was stirred at 50°C for 16 hours. After 16 hours, the reaction was poured into ice water (50.0 mL) and the solid filtered and dried under vacuum to give 4-(furan-2-yl)-6-iodopyrimidin-2-amine (1.00 g, 68.0%). . ¹ H NMR (400 MHz, DMSO-d) δ 7.95 (s, 1H), 7.31 (d, J = 2.8 Hz, 2H), 6.71 (q, 1H); MS m/z: 288.17 [MH] ⁺ .

Step 3: Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1H-indol-1-yl)pyrimidin-2-amine

CuI (0.013 g, 0.06 mmol), K ₂ CO ₃ (0.36 g, 2.61 mmol) and 5-methoxy-1H-indole were added to a DMF (5 mL) solution of the compound obtained in step 2 (0.5 g, 1.74 mmol). (0.120 g, 0.870 mmol) was added. The reaction was stirred at 125 °C for 16 hours. After 16 hours, the reaction was diluted with water and extracted with ethyl acetate (2 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product eluted with 15% EtOAc in hexanes to obtain 4-(furan-2-yl)-6-(5-methoxy-1H-indole-1- 1) Pyrimidine-2-amine (0.150 g, 28.0%) was obtained. ¹ H NMR (400 MHz, DMSO-d) δ 8.76 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 3.6 Hz, 1H), 7.92 (s, 1H), 7.31 (t, 2H), 8.76 (d, J = 2.4 Hz, 1H) 6.95 (s, 1H) 6.89 (d, J = 2.4 Hz, J = 2.8 Hz 1H) 6.72 (d, J = 2 Hz, 2H) 3.34 (s, 3H).

Step 4: Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indol-5-ol (Ex-35)

To a cooled and stirred solution of the compound obtained in step 3 (0.125 g, 0.400 mmol) in DCM (1.25 mL) at -78 °C, BBr ₃ (1M in DCM, 5.00 mL) was added dropwise and the reaction was stirred at room temperature for 4 hours. Stir. The reaction was diluted with NaHCO ₃ and extracted with ethyl acetate (2 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by prep HPLC to give 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indol-5-ol (Ex-35; 18.0 mg, 15.0%) was obtained. ^1H NMR (400 MHz, DMSO-d) δ 8.65 (d, J = 8.8 Hz, 1H), 8.36 (s, 1H), 8.10 (d, J = 3.6 Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 3.2 Hz, 1H) 7.18 (s, 1H) 6.93 (m, 3H) 6.77 (m, 2H) 6.63 (d, J = 3.2 Hz, 1H); MS m/z: 293.19 [M+H] ⁺ .

Example 36: 4-[7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-6-(furan-2-yl)pyrimidine-2 -Amine (Ex-36)

Compound (Ex-36) was prepared according to Scheme 19 below.

[Scheme 19]

Step 1: Synthesis of 4-(benzyloxy)-2-chloropyridine

To a stirred solution of 2-chloro-4-fluoropyridine (2.00 g, 15.4 mmol) in DMF (20.0 mL) cooled at 0 °C was added NaH (0.670 g, 16.9 mmol, 60% dispersion in mineral oil) and stirred for 20 Stir for a minute. Benzyl alcohol (1.82 g, 16.9 mmol) was added and further stirred at room temperature for 6 hours. After 6 hours, the reaction was diluted with water and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted in 4% EtOAc in hexanes to give 4-(benzyloxy)-2-chloropyridine (1.80 g, 53.0%). ¹ H NMR (400 MHz, DMSO-d) δ 8.24 (d, J = 5.6 1H), 7.48 (m, 4H), 7.33 (m, 1H), 7.24 (m, 1H), 7.09 (t, 1H) 5.25 (s, 2H).

Step 2: Synthesis of 4-(benzyloxy)-2-hydrazinylpyridine

Hydrazine hydrate (0.820 g, 16.4 mmol) was added to a stirred solution of the compound (1.80 g, 8.21 mmol) obtained in step 1 in pyridine (54.0 mL), and the mixture was stirred at 120° C. for 32 hours. After 32 hours, the reaction was poured into ice water (50 mL) and the solid was filtered and dried under vacuum to give 4-(benzyloxy)-2-hydrazinylpyridine (1.50 g, 85.0%). MS m/z: 216.2 [M+H] ⁺ .

Step 3: Synthesis of 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine

A solution of 4-(benzyloxy)-2-hydrazinylpyridine (1.00 g, 4.65 mmol) in trimethyl orthoformate (0.500 g, 46.5 mmol) was stirred at 130° C. for 2 h. After 2 h, the reaction was diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine (0.500 g, 47.0%). MS m/z: 226.24 [M+H] ⁺ .

Step 4: 4-[7-(Benzyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-6-(furan-2-yl)pyrimidin-2- Synthesis of amine (Ex-36)

To a stirred solution of the compound obtained in step 3 (0.420 g, 1.86 mmol) in DMSO (4.20 mL), 4-(furan-2-yl)-6-iodopyrimidin-2-amine (0.80 g, 2.79 mmol), PPh ₃ (97.0 mg, 0.370 mmol), K ₂ CO ₃ (510 mg, 3.73 mmol), and CuI (70.0 mg, 0.37 mmol) were added and the reaction was degassed for 15 min. The reaction was stirred in the microwave at 140 °C for 1 hour. After completion of the reaction, the reaction was diluted with water and extracted with ethyl acetate (2 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted with 1% MeOH in DCM to give 4-[7-(benzyloxy)-[1,2,4]triazolo[4,3- a]pyridin-3-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-36; 200 mg, 28.0%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (d, J = 7.6 1H), 7.96 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 6.8 2H), 7.45 (m , 4H), 7.28 (d, J = 2.8 1H), 7.10 (s, 2H) 6.94 (d, J = 6, 1H), 6.73 (s, 1H), 5.29 (s, 2H); MS m/z: 385.34 [M+H] ⁺ .

Example 37: 3-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-[1,2,4]triazolo[4,3-a]pyridin-7-ol ( Ex-37)

To a stirred solution of the compound of Example 36 (150 mg, 0.390 mmol) in methanol (1.50 mL), 10% Pd/C (50% moisture, 150 mg) was added and stirred at room temperature for 2 hours under H ₂ atmosphere. . After 2 h, the reaction was filtered through a Celite bed and washed with methanol. The organic layer was concentrated in vacuo to give crude product which was purified by prep HPLC to give 3-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-[1,2,4]triazolo[4 ,3-a]pyridin-7-ol (Ex-37; 18.0 mg, 15.0%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (d, J = 7.6 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.26 (d, J = 3.2 1H), 7.03(s, 2H), 6.90(s, 1H) 6.79(m, 2H); MS m/z: 295.26 [M+H] ⁺ .

Example 38: 3-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indazol-6-ol (Ex-38)

Compound (Ex-38) was prepared according to Scheme 20 below.

[Scheme 20]

Step 1: Synthesis of 6-((tert-butyldimethylsilyl)oxy)-1H-indazole

To a stirred solution of 1H-indazol-6-ol (2.00 g, 14.9 mmol) in DMF (20.0 mL) cooled at 0 ° C., imidazole (2.00 g, 29.8 mmol) was added and stirred at the same temperature for 5 minutes. did TBDMS-Cl (3.37 g, 22.4 mmol) was added and the reaction was stirred at room temperature for 16 hours. After 16 hours, the reaction was diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 6-((tert-butyldimethylsilyl)oxy)-1H-indazole (3.50 g, 94.0%). MS m/z: 249.27 [M+H] ⁺ .

Step 2: Synthesis of 6-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole

t-BuOK (2.50 g, 22.6 mmol) and I ₂ (5.73 g, 22.6 mmol) were added to a stirred solution of the compound (3.50 g, 14.1 mmol) obtained in step 1, and the reaction was stirred at room temperature for 16 hours. After 16 hours, the reaction was diluted with saturated sodium thiosulfate solution and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 6-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole (3.50 g, 66.0%). MS m/z: 375.11 [M+H] ⁺ .

Step 3: Synthesis of 6-((tert-butyldimethylsilyl)oxy)-3-(tributylstannyl)-1H-indazole

To a solution of the compound obtained in step 2 (4.00 g, 10.7 mmol) in THF (40 mL) cooled at 0 °C was added NaH (850 mg, 12.8 mmol, 60% dispersion in mineral oil) and the reaction was stirred for 15 min. and further cooled to -10 °C. i-PrMgCl (2M solution in THF, 6.41 mL) was added dropwise to this solution and stirred at the same temperature for 30 minutes. After 30 minutes, Bu ₃ SnCl (4.50 g, 13.9 mmol) was added at -10 °C and stirred at the same temperature for 20 minutes and then at room temperature for 30 minutes. After 30 min, the reaction was diluted with water and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product eluted with 5% EtOAc in hexanes to obtain 6-((tert-butyldimethylsilyl)oxy)-3-(tributylstannyl)-1H- Indazole (1.00 g, 17.0%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H) 7.52 (d, J = 12 1H) 6.89 (s, 1H) 6.67 (d, J = 8.8 1H), 1.60 (m, 6H) , 1.35(m, 7H), 1.17(m, 6H), 0.98(s, 9H) 0.86(t, 8H) 0.22(s, 6H).

Step 4: Synthesis of 4-(6-((tert-butyldimethylsilyl)oxy)-1H-indazol-3-yl)-6-(furan-2-yl)pyrimidin-2-amine

To a stirred solution of the compound obtained in step 3 (600 mg, 1.11 mmol) in DMF (6.00 mL) was added palladium(II)bis(triphenylphosphine) dichloride (0.078 g, 110 μmol) and TEA (0.44 mL). was added and the reaction was degassed under argon for 15 minutes. 4-(furan-2-yl)-6-iodopyrimidin-2-amine (320 mg, 1.11 mmol) was added to the reaction and the reaction was stirred at 90° C. for 6 hours. After 6 hours, the reaction was diluted with water and extracted with ethyl acetate (2 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product eluted with 20% EtOAc in hexanes to obtain 4-(6-((tert-butyldimethylsilyl)oxy)-1H-indazol-3-yl )-6-(furan-2-yl)pyrimidin-2-amine (120 mg, 26.0%) was obtained. MS m/z: 408.35 [M+H] ⁺ .

Step 5: Synthesis of 3-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-indazol-6-ol (Ex-38)

A stirred solution of the compound obtained in step 4 (100 mg, 0.280 mmol) in THF (1.25 mL) was cooled to 0 °C and TBAF (1M THF solution) (300 μL) was added dropwise. The reaction was stirred at 0 °C for 30 min. After 30 min, the reaction was diluted with water and extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by prep HPLC to obtain 3-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-indazol-6-ol (Ex-38; 15.0 mg, 20.0%). was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (s, 1H) 9.72 (s, 1H) 8.48 (d, J = 8.8 1H) 8.14 (s, 1H) 7.91 (s, 1H) 7.57 (s, 1H) 7.20 (d, J = 3.2 1H), 6.83 (d, J = 1.2 1H), 6.77 (m, 2H), 6.70 (q, 1H); MS m/z: 294.34 [M+H] ⁺ .

Example 39: 4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1H-1,2,3-benzotriazol-1-yl]pyrimidine- 2-amine (Ex-39)

Compound (Ex-39) was prepared according to Scheme 21 below.

[Scheme 21]

Step 1: Synthesis of tert-butyl 4-hydroxypyrazole-1-carboxylate

tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (20.0 g, 68.0 mmol) and NaOH ( To a stirred mixture of 5.44 g, 136 mmol) in THF (150 mL) was added H ₂ O ₂ (15.4 g, 136 mmol, 30%) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 25° C. under a nitrogen atmosphere. The resulting mixture was diluted with DCM (250 mL). The mixture was acidified to pH 2 with aqueous HCl solution. The organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-hydroxypyrazole-1-carboxylate (8.00 g, 57.5%) as an off-white solid. MS m/z: 185 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(3-amino-4-nitrophenoxy)pyrazole-1-carboxylate

To a stirred mixture of the compound obtained in step 1 (8.00 g, 43.4 mmol) and 5-fluoro-2-nitroaniline (6.78 g, 43.4 mmol) in DMF (100 mL) was added K ₂ CO ₃ (15.0 g, 109 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere at 80° C. for 16 hours. The mixture was left to cool to room temperature. The reaction was quenched with water (300 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give tert-butyl 4-(3-amino-4-nitrophenoxy)pyrazole-1-carboxylate (2.10 g, 13.6 %) was obtained as a yellow solid. MS m/z: 321 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(3,4-diaminophenoxy)pyrazole-1-carboxylate

To a stirred mixture of the compound obtained in step 2 (2.10 g, 6.56 mmol) in methanol (50.0 mL) was added Pd/C (500 mg, 10%) portionwise. The resulting mixture was stirred under a hydrogen atmosphere at 25° C. for 2 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give tert-butyl 4-(3,4-diaminophenoxy)pyrazole-1-carboxylate (1.50 g, 70.9% ) was obtained as a pale yellow solid. MS m/z: 291 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-(1H-1,2,3-benzotriazol-5-yloxy)pyrazole-1-carboxylate

To a stirred mixture of the compound obtained in step 3 (1.50 g, 5.16 mmol) in AcOH (25.0 mL) was added a solution of NaNO ₂ (534 mg, 7.75 mmol) in H ₂ O (5.00 mL) at 0 °C under a nitrogen atmosphere. it was added The resulting mixture was stirred under a nitrogen atmosphere at 25° C. for 1 hour. The reaction was quenched with water at 0 °C. The precipitated solid was collected by filtration and washed with water to obtain tert-butyl 4-(1H-1,2,3-benzotriazol-5-yloxy)pyrazole-1-carboxylate (700 mg, 40.5%) was obtained as a dark yellow solid. MS m/z: 302 [M+H] ⁺ .

Step 5: tert-Butyl 4-([1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazol-1- Carboxylate and tert-butyl 4-([3-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyra Synthesis of a mixture of sol-1-carboxylates

To a stirred mixture of the compound obtained in step 4 (700 mg, 2.32 mmol) in DMF (20.0 mL) was added NaH (102 mg, 2.55 mmol, 60% dispersion in mineral oil) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0° C. under a nitrogen atmosphere. To the mixture was added 4,6-dichloro-2-(methylsulfanyl)pyrimidine (498 mg, 2.55 mmol). The resulting mixture was stirred at 25 °C for an additional 2 h. The reaction was quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give tert-butyl 4-([1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-1 ,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[6-chloro-2-(methylsulfanyl)pyrimidine-4- A mixture of yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (500 mg, 42.2%) was obtained as an off-white solid. MS m/z: 460 [M+H] ⁺ .

Step 6: tert-Butyl 4-([1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazole-5- yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1, Synthesis of a mixture of 2,3-benzotriazol-5-yl] oxy) pyrazole-1-carboxylates

The mixture obtained in step 5 (500 mg, 1.08 mmol) was added to a stirred mixture of tributyl(furan-2-yl)stannane (582 mg, 1.63 mmol) and Pd(PPh ₃ ) ₂ Cl in DMF (20.0 mL). ₂ (915 mg, 1.30 mmol) was added. The resulting mixture was stirred for 2 hours at 25° C. under a nitrogen atmosphere. The reaction was quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give tert-butyl 4-([1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine -4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[6-(furan-2-yl) A mixture of -2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (300 mg, 50.5%) Obtained as an off-white solid. MS m/z: 492 [M+H] ⁺ .

Step 7: tert-butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyra sol-1-carboxylate and tert-butyl 4-([3-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzotriazole Synthesis of mixtures of -5-yl]oxy)pyrazole-1-carboxylates

To the mixture obtained in step 6 (300 mg, 0.610 mmol) was stirred in DCM (15.0 mL) was added m-CPBA (316 mg, 1.83 mmol) dropwise. The resulting mixture was stirred at 25° C. for 12 hours. The reaction was quenched with a saturated aqueous solution of Na ₂ S ₂ O ₃ . The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic layers were washed with saturated aqueous saturated NaHCO ₃ and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzo triazol-5-yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl] A mixture of -1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (300 mg, crude) was obtained as a pale yellow solid. MS m/z: 524 [M+H] ⁺ .

Step 8: tert-Butyl 4-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazol- 1-carboxylate and tert-butyl 4-([3-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl Synthesis of a mixture of ]oxy)pyrazole-1-carboxylates

To the mixture obtained in step 7 (300 mg, 0.570 mmol) was stirred in THF (5.00 mL), NH ₃ .H ₂ O (5.00 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 4 hours. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give tert-butyl 4-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl] -1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[2-amino-6-(furan-2-yl)pyridine A mixture of midin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (120 mg, 40.9%) was obtained as an off-white solid. MS m/z: 461 [M+H] ⁺ .

Step 9: 4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex- 39) Synthesis of

The mixture from step 8 (120 mg, 0.26 mmol) was stirred mixed in DCM (4.00 mL) and TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C18 ExRS, 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (38% PhaseB, up to 53% in 9 min); Detector, UV 254&220 nm. The collected fractions were lyophilized to obtain 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidine. -2-amine (9.20 mg, 9.76%) and 4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazole-1 Obtained -yl]pyrimidin-2-amine (Ex-39; 10.5 mg, 22.1%) as a white solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.89 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.34-7.20 (m, H), 6.75-6.74 (m, 1H); MS m/z: 361 [M+H] ⁺ .

Example 40: 1-[2-amino-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5 -All (Ex-40)

Compound (Ex-40) was synthesized according to Reaction Scheme 22 using Compound J of Preparation Example 10 as a starting material.

[Scheme 22]

Step 1: 1-[2-chloro-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole synthesis of

Compound J prepared in Preparation Example 10 (3.0 g, 7.09 mmol, 1.00 equivalent, 70%) and 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1,3-thiazole (798 mg, 3.54 mmol, 0.50 equiv) was stirred and mixed in dioxane (15 mL) and H ₂ O (3 mL), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (1.1 g, 1.41 mmol, 0.2 equiv) and K ₂ CO ₃ (3.9 g, 28.36 mmol, 4 equiv) were added. The resulting mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by reverse flash chromatography under the following conditions: column, C ₁₈ silica gel, 80 g, 20-35 μm; Mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient in 30 minutes); Detector, UV 254/220 nm. The solution was concentrated under reduced pressure to obtain 1-[2-chloro-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzo Triazole (600 mg, 15.33%) was obtained as an off white solid. ¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.96 (s, 1H), 8.79 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 2.77 (s, 3H); MS m/z: 359 [M+H] ⁺ .

Step 2: 4-(5-methoxy-1,2,3-benzotriazol-1-yl)-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-2-amine synthesis of

The compound obtained in step 1 (600 mg, 1.67 mmol, 1.00 equiv) and NH ₃ .H ₂ O were stirred in MeOH (7 M, 5 mL) and EtOH (5 mL) at 80° C. for 16 h under a nitrogen atmosphere. . After cooling the mixture to room temperature, it was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography under the following conditions: column, C ₁₈ silica gel, 80 g, 20-35 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (0% to 100% gradient in 30 min); Detector, UV 254/220 nm. The mixture was concentrated under reduced pressure to obtain 4-(5-methoxy-1,2,3-benzotriazol-1-yl)-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-2 -Amine (100 mg, 14.10%) was obtained as an off-white solid. MS m/z: 340 [M+H] ⁺

Step 3: 1-[2-amino-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- Synthesis of All (Ex-40)

The compound obtained in step 2 (100 mg, 0.236 mmol, 1.00 eq, 80%) and BBr ₃ were stirred in DCM (1M, 3.00 mL) at 25° C. for 1 h. The reaction was quenched with MeOH (50 mL) and the resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C ₁₈ , 30 mm X 150 mm, 5 μm; Mobile Phase A: Water (50 MMOL/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25 B to 45 B in 9 min, 254 nm; RT1: 7.93. The collected fractions were lyophilized to obtain 1-[2-amino-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-1H-1,2,3-benzotria. Zol-5-ol (Ex-40; 5.4 mg, 6.92%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.01 (s, 1H), 8.64 (s, 1H), 8.62 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H) , 7.37 (s, 1H), 7.32 (s, 2H), 7.22 (d, J = 11.2 Hz, 1H), 2.72 (s, 3H); MS m/z: 326 [M+H] ⁺ .

Example 41: 1-{2-amino-[4,5′-bipyrimidin]-6-yl}-1H-1,2,3-benzotriazol-5-ol (Ex-41)

Pyri instead of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole in step 1 of Example 40 1-{2-amino-[4,5'-bipyrimidin]-6-yl}-1H-1,2,3 in the same manner as in Example 40, except that midin-4-yl boronic acid was used. - Benzotriazol-5-ol (Ex-41; 14.06%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.04 (s, 1H), 9.52 (s, 2H), 9.34 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H) , 8.02 (s, 1H), 7.47 (s, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.26–7.23 (m, 1H); MS m/z: 307 [M+H] ⁺ .

Example 42: 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex- 42)

Compound (Ex-42) was synthesized according to Reaction Scheme 23 using Compound J of Preparation Example 10 as a starting material.

[Scheme 23]

Step 1: tert-Butyl N-[1-[2-chloro-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]azetidin-3- Synthesis of general] carbamate

Compound J of Preparation 10 (1.5g, 5.06 mmol, 1.00 equivalent) and tert-butyl N-(azetidin-3)-yl)carbamate hydrochloride (1.0g, 5.06 mmol, 1 equivalent) were mixed with DMF (15 mL). ) and DIEA (2.6 g, 20.26 mmol, 4 eq) was added. The resulting mixture was stirred at 25° C. for 5 min, and the crude product was purified by reverse flash chromatography under the following conditions: column, C ₁₈ silica gel, 330 g, 20-35 μm; Mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient in 30 minutes); Detector, UV 254/220 nm. The mixture was then concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: Column: YMC-Actus Triart C ₁₈ , 30 mm X 150 mm, 5 μm; Mobile Phase A: Water (50 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18 B to 35 B in 12 min, 254 nm; RT1: 10.47. The mixture was concentrated under reduced pressure to obtain tert-butyl N-[1-[2-chloro-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]azetidine- 3-yl]carbamate (first isomer eluting) (150 mg, 6.31%) was obtained as a white solid. ¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.27 (d, J = 8.8 Hz, 1H), 7.72-7.70 (m, 1H), 7.63-7.62 (m, 1H), 7.38-7.35 (m, 1H), 6.94 (m, 1H), 4.56-4.47 (m, 1H), 4.45-4.30 (m, 2H), 4.05-4.00 (m, 2H), 3.88 (s, 3H), 1.41 (s) , 9H); MS m/z: 432 [M+H] ⁺ .

Step 2: tert-Butyl N-[1-[2-amino-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]azetidin-3- Synthesis of general] carbamate

The compound obtained in step 1 (150 mg, 0.34 mmol, 1.00 equiv) and NH ₃ (g) were stirred in MeOH (7M, 3 mL) and EtOH (2 mL) under a nitrogen atmosphere at 100° C. for 5 days. After the mixture was cooled to room temperature and concentrated under reduced pressure, the crude product was purified by reverse flash chromatography under the following conditions: column, C ₁₈ silica gel, 40 g, 20-35 μm; Mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient in 30 minutes); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain tert-butyl N-[1-[2-amino-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]ase Thidin-3-yl]carbamate (95 mg, 64.26%) was obtained as a pink solid. ¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.61 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.58 (s, 1H), 7.27-7.25 (m , 1H), 6.85 (brs, 2H), 6.31 (s, 1H), 4.47-4.44 (m, 1H), 4.31-4.27 (m, 2H), 3.90-3.87 (m, 2H); MS m/z: 413 [M+H] ⁺ .

Step 3: 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-42 ) synthesis of

The compound obtained in step 2 (95 mg, 0.23 mmol, 1.00 equiv) and BBr ₃ were stirred in DCM (1M, 3.00 mL) at 25° C. for 1 h. The reaction was quenched with MeOH (50 mL) and the resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (10% PhaseB, up to 30% in 7 min); detector, 254 nm. The collected fractions were lyophilized to obtain 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol. (Ex-42; 6 mg, 9.64%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.57 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.15 (d, J = 11.2 Hz, 1H), 6.68 (s, 2H), 6.28 (s, 1H), 4.29-4.19 (m, 2H), 3.89-3.81 (m, 1H), 3.66-3.66 (m, 2H); MS, m/z: 299 [M+H] ⁺

Example 43: 1-[2-amino-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex- 43)

Compound (Ex-43) was synthesized according to Scheme 24 below.

[Scheme 24]

Step 1: Synthesis of 2-chloro-6-(3,3-difluorocyclobutyl)-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine

NaH (837 mg, 20.94 mmol, 2.00 equiv, 60%) was added in portions at 0° C. did The resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. To this mixture was added 1-fluoro-4-methoxy-2-nitrobenzene (3.5 g, 20.94 mmol, 2.00 equiv) at 0 °C. The resulting mixture was stirred at 60° C. for an additional 3 h and the reaction was quenched with water (300 mL). The mixture was extracted with ethyl acetate (3 x 300 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1) to give 2-chloro-6-(3,3-difluorocyclobutyl)-N-(4-methoxy-2-nitrophenyl ) Pyrimidine-4-amine (1.5 g, 37.17%) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.99 (s, 1H), 7.55-7.49 (m, 2H), 7.36-7.32 (m, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.43-3.38 (m, 1H), 2.91-2.75 (m, 4H); MS m/z: 371 [M+H] ⁺ .

Step 2: Synthesis of N1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-4-methoxybenzene-1,2-diamine

To a stirred mixture of the compound obtained in step 1 (1.5 g, 4.04 mmol, 1.00 equiv) in EtOH (15 mL) and H ₂ O (3 mL) was added Fe (1.1 g, 20.23 mmol, 5 equiv) and NH ₄ Cl (649 mg, 12.13 mmol, 3 eq) was added. The resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, filtered and the filter cake was washed with ethyl acetate (3 x 700 mL). The filtrate was concentrated under reduced pressure to obtain N1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-4-methoxybenzene-1,2-diamine (1.5 g, 93.57% ) was obtained as an off-white solid. MS m/z: 341 [M+H] ⁺ .

Step 3: Synthesis of 1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole

NaNO ₂ (334 mg, 4.84 mmol, 1.1 equiv) was added to a stirred mixture of the compound obtained in Step 2 (1.5 g, 4.40 mmol, 1.00 equiv) in AcOH (15 mL) and H ₂ O (5 mL) at 0 °C. were added separately. The resulting mixture was stirred at 25° C. for 30 min and the reaction was quenched at room temperature by the addition of water (800 mL). The precipitated solid was collected by filtration and washed with H ₂ O (100 mL) to obtain 1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-5-methyl Toxy-1,2,3-benzotriazole (900 mg, 56.96%) was obtained as an off-white solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.49 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.49 (s, 1H), 7.37-7.34 (m, 1H) , 3.96 (s, 3H), 3.61-3.54 (m, 1H), 3.11-3.02 (m, 4H); MS m/z: 352 [M+H] ⁺ .

Step 4: Synthesis of 4-(3,3-difluorocyclobutyl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine

The compound obtained in step 3 (900 mg, 2.55 mmol, 1.00 equiv) and NH ₃ (g) were stirred in MeOH (7 M, 5 mL) and EtOH (5 mL) under a nitrogen atmosphere at 80° C. for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 4-(3,3-difluorocyclobutyl)-6-(5-methoxy-1,2,3-benzotria Obtained zol-1-yl)pyrimidin-2-amine (360 mg, 37.60%) as an off-white solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.49-8.46 (m, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.30-7.26 (m, 1H), 5.31 ( s, 2H), 3.95 (s, 3H), 3.42-3.38 (m, 1H), 3.07-2.92 (m, 4H); MS m/z: 333 [M+H] ⁺ .

Step 5: 1-[2-amino-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-43) synthesis

The compound obtained in step 4 (150 mg, 0.45 mmol, 1.00 equiv) and BBr ₃ were stirred in DCM (1M, 5 mL) at 25° C. for 10 min. The reaction was quenched with MeOH (5 mL) and the crude product was purified by reverse flash chromatography under the following conditions: column, C ₁₈ silica gel, 80 g, 20-35 μm; Mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (0% to 100% gradient in 30 min). The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C ₁₈ ExRS, 30 x 250, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (42% PhaseB, up to 65% in 7 min); Detector, UV 254 nm. The collected fractions were freeze-dried to obtain 1-[2-amino-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex -43; 9.3 mg, 6.45%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.99 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.30 (s, 1H) , 7.24-7.19 (m, 3H), 3.52-3.46 (m, 1H), 2.97-2.88 (m, 4H); MS m/z: 319 [M+H] ⁺ .

Example 44: 3-[2-amino-6-(5-hydroxy-1H-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]-2-methylbenzonitrile (Ex -44)

3 instead of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole in step 1 of Example 40 3-[2-amino-6-(5-hydroxy-1H-1,2,3-benzotriazole-1- in the same manner as in Example 40, except that amino-2-methylphenyl boronic acid was used. 1) pyrimidin-4-yl] -2-methylbenzonitrile (Ex-44; 18.5 mg, 30.26%) was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.03 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 7.93-7.91 (m, 1H), 7.82-7.80 ( m, 1H), 7.55-7.52 (m, 1H), 7.40-7.37 (m, 4H), 7.26-7.23 (m, 1H), 2.59 (s, 3H); MS m/z: 344 [M+H] ⁺ .

Experimental Example 1: A2AR cAMP functional assay

In order to evaluate the A2A receptor antagonistic activity of the present compound, an A2AR cAMP functional assay was performed.

A 10 mM stock solution was prepared by dissolving the compounds of the above Examples in DMSO. Compounds were evaluated at 10 concentrations (top concentration: 100 μM, 10-fold serial dilution) to determine the IC ₅₀ .

25,000 HEK293 cells (Life technologies, R705-07) per well in 96-well white plates were seeded with 2×10 ⁶ adenosine receptor (A2AR) expressing baculovirus particles and incubated overnight. A dose response evaluation was performed to determine the EC ₈₀ of 5-N-ethylcarboxamidoadenosine (NECA) (Tocris, 1691), an adenosine receptor agonist used in the cAMP function assay. The next day, the medium was removed and replaced with 30 μL of PBS. 7.5 μL of compound was added and incubated at 37° C./5% CO ₂ for 30 min. 7.5 μL of NECA was then added to a final concentration corresponding to EC ₈₀ and incubated at 37° C./5% CO ₂ for 60 min before evaluation in the Hithunter cAMP assay for biologics (DiscoveRx; 90-0075 series). . Changes in the luminescence signal were monitored on a Perkin Elmer Envision. The IC ₅₀ values of the compounds were evaluated according to the criteria shown in Table 1 below and are listed in Table 2 below.

A2AR antagonistic activity (IC ₅₀ ) <100nM 100nM to 1uM >1uM display value +++ ++ +

A2AR antagonistic activity (IC ₅₀ , nM) Example 1 (Ex-01) +++ Example 2 (Ex-02) +++ Example 3 (Ex-03) +++ Example 4 (Ex-04) ++ Example 5 (Ex-05) +++ Example 6 (Ex-06) ++ Example 7 (Ex-07) ++ Example 8 (Ex-08) + Example 9 (Ex-09) + Example 10 (Ex-10) ++ Example 11 (Ex-11) +++ Example 12 (Ex-12) +++ Example 13 (Ex-13) + Example 14 (Ex-14) ++ Example 15 (Ex-15) + Example 16 (Ex-16) + Example 17 (Ex-17) + Example 18 (Ex-18) + Example 19 (Ex-19) ++ Example 20 (Ex-20) + Example 21 (Ex-21) ++ Example 22 (Ex-22) + Example 23 (Ex-23) + Example 24 (Ex-24) ++ Example 25 (Ex-25) ++ Example 26 (Ex-26) ++ Example 27 (Ex-27) ++ Example 28 (Ex-28) +++ Example 29 (Ex-29) + Example 30 (Ex-30) + Example 31 (Ex-31) ++ Example 32 (Ex-32) + Example 33 (Ex-33) + Example 34 (Ex-34) + Example 35 (Ex-35) ++ Example 36 (Ex-36) ++ Example 37 (Ex-37) ++ Example 38 (Ex-38) ++ Example 39 (Ex-39) + Example 40 (Ex-40) + Example 41 (Ex-41) + Example 42 (Ex-42) + Example 43 (Ex-43) + Example 44 (Ex-44) +++

As can be seen from Table 2, the compounds of the Examples herein exhibit excellent antagonistic activity against the A2AR receptor, and in particular, the compounds of Examples 1, 2, 3, 5, 11, 12, 28 and 44 have an IC ₅₀ of 100 nM or less. By having a value, it was confirmed that the antagonistic activity for the A2AR receptor was particularly excellent.

Claims (21)

A compound represented by Formula 1 below, a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
G ¹ is -(CH ₂ ) _l -Ring A, G ² is H or -(CH ₂ ) _m -pyridinyl;
The ring A is C _6-12 aryl; 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; 4-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S; and 4-6 membered cycloalkyl;
Ring A is selected from halogen, -CN, -OH, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkoxy, and NR ^A R ^B may be substituted or unsubstituted with one or more substituents selected from the group consisting of;
R ^A and R ^B are each independently H or C _1-6 alkyl;
X ¹ and X ² are each independently C or N, X ³ is CR' or N, X ⁴ is CH, N or NH, but 1 to 3 of X ¹ , X ² , X ³ and X ⁴ are N or NH;
R' is H or -(CH ₂ ) _n -pyridinyl;
R is -OH, -O-(CH ₂ ) _o -R ¹ , -(CH ₂ ) _p -OR ² , -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r -O- CO-R ⁴ or -CO-R ⁵ ;
R ¹ and R ² are each independently C _4-6 cycloalkyl; 5-6 membered heteroaryl containing 1 to 3 N or O; 5-6 membered heterocyclyl containing 1 to 2 N; And selected from the group consisting of C _6-12 aryl;
The R ¹ and R ² are each independently halogen; cyano; OH; amino; nitro; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO-(C _1-6 alkyl); C _1-6 alkyl optionally interrupted by 1-2 O; C _1-6 alkoxy optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO-(C _1-6 alkyl); C _6-12 aryl optionally substituted with R″; and a 5-6 membered heterocyclyl containing 1-2 N, O or S optionally substituted with R''';
R″ and R″″ are each independently selected from the group consisting of halogen, cyano, OH, amino, nitro, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl, and C _1-6 alkoxy is selected from;
R ³ , R ⁴ and R ⁵ are each independently -NH-C _6-12 aryl; -NH-(5-6 membered heteroaryl containing 1-2 N, O or S); And -NR ^a R ^b is selected from the group consisting of,
R ^a and R ^b together with the N to which they are attached form a 5-6 membered heterocyclyl optionally further containing 1 N, wherein said 5-6 membered heterocyclyl is optionally -(CH ₂ ) _s -C _{6- 12} aryl or fused with C _6-12 aryl;
Wherein R ³ , R ⁴ and R ⁵ are each independently halogen, cyano, OH, amino, nitro, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl, and C _1-6 alkoxy; optionally substituted with a substituent selected from the group;
l, m and n are integers from 0 to 3, o and p are integers from 0 to 5, and q, r and s are each an integer from 0 to 3. According to claim 1,

is benzotriazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,4] A compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof, selected from the group consisting of triazolo[1,5-a]pyridinyl, indazolyl, benzimidazolyl, indolyl and isoindolyl. According to claim 1,

is a compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

,

,

,

and

. According to claim 1,
A compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein R binds to a carbon atom not adjacent to a 5-membered ring containing X ¹ to X ⁴ . According to any one of claims 1 to 4,
R is -OH, -O-(CH ₂ ) _o -R ¹ , -(CH ₂ ) _p -OR ² , -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r -O- CO-R ⁴ or -CO-R ⁵ ;
R ¹ and R ² are each independently C _4-6 cycloalkyl; 5-6 membered heteroaryl containing 1-2 N and optionally 1 O; 5-6 membered heterocyclyl containing 1 N; and phenyl;
The R ¹ and R ² are each independently halogen; cyano; OH; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO-(C _1-6 alkyl); C _1-6 alkyl optionally interrupted by 1-2 O; C _1-6 alkoxy; phenyl optionally substituted with R″; and a 5-6 membered heterocyclyl containing 1-2 Ns optionally substituted with R''';
R″ and R″″ are each independently selected from the group consisting of halogen, cyano, OH, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl and C _1-6 alkoxy;
R ³ , R ⁴ and R ⁵ are each independently -NH-phenyl; -NH-(5-6 membered heteroaryl containing 1 N, O or S); and NR ^a R ^b , wherein R ^a and R ^b together with the N to which they are bonded form piperazinyl or piperidinyl, wherein the piperazinyl or piperidinyl is optionally -(CH ₂ ) _s -may be substituted with or fused with phenyl;
o and p are each an integer from 0 to 3, and q, r and s are each 0 or 1, a compound, stereoisomer, solvate or pharmaceutically acceptable salt thereof. According to claim 5,
R is -OH, -O-(CH ₂ ) _o -R ¹ or -(CH ₂ ) _p -OR ² ;
R ¹ and R ² are each independently selected from the group consisting of cyclopentyl, pyridinyl, pyrazolyl, oxadiazolyl, imidazolyl, piperidinyl and phenyl;
R ¹ and R ² are each independently halogen; cyano; OH; COOH; COO-(C _1-6 alkyl); C _1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO-(C _1-6 alkyl); C _1-6 alkyl optionally interrupted by 1-2 O; C _1-6 alkoxy; phenyl optionally substituted with R″; and pyrrolidinyl optionally substituted with R''';
R″ and R″″ are each independently selected from the group consisting of halogen, cyano, OH, COOH, COO-(C _1-6 alkyl), C _1-6 alkyl and C _1-6 alkoxy;
A compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein o and p are each an integer from 0 to 3. According to claim 5,
R is -O-(CH ₂ ) _q -CO-R ³ , -(CH ₂ ) _r -O-CO-R ⁴ or -CO-R ⁵ ;
R ³ is -NH-phenyl or piperazinyl optionally substituted with phenyl or -(CH ₂ )-phenyl;
R ⁴ is -NH-thiophenyl or tetrahydroisoquinolinyl;
R ⁵ is -(CH ₂ )-phenyl or piperazinyl optionally substituted with phenyl;
q and r are 0 or 1, a compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. According to any one of claims 1 to 7,
G ¹ is -(CH ₂ ) _l -Ring A, G ² is H or -(CH ₂ ) _m -pyridinyl;
Ring A is C _6-10 aryl; 5- or 6-membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; 4-6 membered heterocyclyl containing 1 N; And it is selected from the group consisting of 4-6 membered cycloalkyl;
Ring A is selected from halogen, -CN, -OH, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy and -NR ^A R ^B It is unsubstituted or substituted with one or two substituents selected from the group consisting of
R ^A and R ^B are each independently H or C _1-4 alkyl;
A compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein l and m are each an integer of 0 or 1. According to claim 8,
Ring A is selected from the group consisting of phenyl, furanyl, thiazolyl, pyrimidinyl, azetidinyl and cyclobutyl;
The ring A is a compound, a stereoisomer or a solvate thereof, which is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, -CN, -OH, -NH ₂ and C _1-4 alkyl. or a pharmaceutically acceptable salt. According to any one of claims 1 to 8,
Wherein G ² is bonded to position 5 of the pyrimidine ring, and G ¹ is bonded to the remaining substitutable carbon atoms of the pyrimidine ring, a compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof. According to claim 1,
G ¹ is -(CH ₂ ) _l -Ring A, G ² is H or -(CH ₂ ) _m -pyridinyl;

silver

wherein l and m are 0 or 1, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. According to claim 1,
G ¹ is ring A, G ² is H;

silver

,

,

or

and R' is H, pyridinyl or -(CH ₂ )-pyridinyl, a compound, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof. According to claim 12,
G ¹ is ring A, G ² is H;

silver

and R' is pyridinyl or -(CH ₂ )pyridinyl, a compound, a stereoisomer, a solvate thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
A compound selected from the group below, a stereoisomer, solvate or pharmaceutically acceptable salt thereof:

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

; and

. A pharmaceutical composition for preventing or treating diseases associated with adenosine A2A receptors, comprising the compound of any one of claims 1 to 14, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 15, wherein the disease associated with the adenosine A2A receptor is cancer. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition further comprises an anticancer agent. The pharmaceutical composition according to claim 17, wherein the anti-cancer agent is an immuno-anticancer agent. A method for preventing or treating a disease associated with adenosine A2A receptors, comprising administering to a subject the compound of any one of claims 1 to 14, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. Use of a compound according to any one of claims 1 to 14, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, for use in preventing or treating a disease associated with the adenosine A2A receptor. Use of a compound according to any one of claims 1 to 14, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating a disease associated with the adenosine A2A receptor.