WO2022203399A1 - Antagoniste du récepteur a2a de l'adénosine et son utilisation - Google Patents

Antagoniste du récepteur a2a de l'adénosine et son utilisation Download PDF

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WO2022203399A1
WO2022203399A1 PCT/KR2022/004084 KR2022004084W WO2022203399A1 WO 2022203399 A1 WO2022203399 A1 WO 2022203399A1 KR 2022004084 W KR2022004084 W KR 2022004084W WO 2022203399 A1 WO2022203399 A1 WO 2022203399A1
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mmol
compound
alkyl
pyrimidin
furan
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PCT/KR2022/004084
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Korean (ko)
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이효선
김시우
조대현
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주식회사 스탠다임
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Priority to KR1020237025050A priority Critical patent/KR102655210B1/ko
Publication of WO2022203399A1 publication Critical patent/WO2022203399A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel A2A receptor antagonist and uses thereof, and more particularly, to a novel A2A receptor antagonist of Formula 1 and a pharmaceutical composition for treating cancer comprising the same.
  • Adenosine is a purine nucleoside that regulates various physiological functions, and adenosine A1, A2A, A2B and A3 receptors (A1R, A2AR, A2BR) belonging to the G protein-coupled receptor (GPCR) superfamily. and A3R) to exhibit a regulatory function.
  • adenosine A2A receptor (hereinafter, A2AR) is based on the functional interaction between A2AR and dopamine D2 in the basal ganglia, and A2AR antagonists have been studied as drugs for treating Parkinson's disease.
  • A2AR antagonism is known to be associated with therapeutic effects such as cognitive enhancement, neuroprotection and analgesia.
  • A2AR plays an important role in life activities such as regulating vasodilation, supporting the formation of new blood vessels, and protecting body tissues from damage caused by inflammation. Therefore, inhibitors of A2AR may provide potent anticancer effects.
  • adenosine ⁇ 10 ⁇ M versus ⁇ 20 nM at physiological levels.
  • Activation of adenosine signaling leads to persistent suppression of the innate immune response, which leads to uncontrolled growth of malignant tumors through immune tolerance.
  • leukocytes such as lymphocytes, T lymphocytes, natural killer cells, and dendritic cells may suppress the immune function of these leukocytes.
  • binding of adenosine and A2AR increases the expression of CD39, CD73 and CTLA4 (T cell checkpoint), resulting in the generation of Treg cells with more potent immunosuppressive properties. Therefore, blocking the A2AR signaling pathway can lead to a decrease in the inhibitory 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.
  • An object of the present invention is to provide an A2AR antagonist represented by the formula (1).
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to A2AR, comprising the A2AR antagonist represented by Formula 1;
  • Another object of the present invention is to provide a method for preventing or treating A2AR-related diseases by using the A2AR antagonist represented by Formula 1.
  • One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
  • G 1 is -(CH 2 ) l -ring A
  • G 2 may be H or -(CH 2 ) m -pyridinyl.
  • l and m are each independently an integer of 0, 1, 2 or 3.
  • l and m may each independently be an integer of 0, 1 or 2, preferably an integer of 0 or 1.
  • G 1 can be Ring A or -(CH 2 )-Ring A.
  • Ring A is C 6-12 aryl; 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S; and 4 to 6 membered cycloalkyl.
  • 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 to 6 membered cycloalkyl.
  • 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 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.
  • Ring A is 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 may be substituted or unsubstituted with one or two substituents selected from the group consisting of.
  • R A and R B may each independently be H or C 1-4 alkyl.
  • 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.
  • G 1 is tolyl, cyanotolyl, cyanophenyl, phenyl, furanyl, furanylmethyl, thiazolyl, methylthiazolyl, pyrimidinyl, azetidinyl, aminoazetidinyl, cyclobutyl, or It may be, but is not limited to, cyclobutyl substituted with one or more halogens.
  • G 1 is 3-cyano-o-tolyl, furan-2-yl, furan-3-yl, furan-2-ylmethyl, 2-methylthiazol-5-yl, pyrimidin-5- yl, 3-amino-azetidin-1-yl or 3,3-difluorocyclobutyl.
  • G 2 can be H or pyridinyl.
  • G 2 can be, but is not limited to, H or pyridin-4-yl.
  • G 2 may be bonded to the 5th position of the pyrimidine ring to which G 1 and G 2 are bonded, and G 1 may be bonded to the remaining substitutable carbon atoms of the pyrimidine ring.
  • the G 2 may be bonded to the para (p-) position or the 1,4 position based on the amino group bonded to the pyrimidine ring, and the G 1 is the remaining substitutable of the pyrimidine ring. It can be bonded to a carbon atom.
  • G 1 can be —(CH 2 ) 1 -ring A, and G 2 can be H.
  • G 1 can be —(CH 2 ) 1 -ring A
  • G 2 can be —(CH 2 ) m -pyridinyl.
  • l and m may each independently be 0 or 1.
  • the -(CH 2 ) 1 -ring A may be -(CH 2 ) 1 -furanyl.
  • the -(CH 2 ) l -furanyl may be furan-2-yl, furan-3-yl, or furan-2-ylmethyl.
  • the -(CH 2 ) m -pyridinyl may be pyridin-4-yl or pyridin-4-ylmethyl.
  • X 1 and X 2 are each independently C or N
  • X 3 is CR' or N
  • X 4 is CH, N or NH
  • X 1 , X 2 , X 3 and X 4 1 to 3 may be N or NH
  • R' may be H or -(CH 2 ) n -pyridinyl.
  • n is an integer of 0, 1, 2 or 3.
  • n may be an integer of 0, 1 or 2, preferably an integer of 0 or 1.
  • R' can be pyridinyl or -(CH 2 )-pyridinyl.
  • R' can be pyridin-4-yl or pyridin-4-ylmethyl.
  • G 1 is -(CH 2 ) 1 -ring A
  • G 2 is H or -(CH 2 ) m -pyridinyl
  • silver , and l and m may be 0 or 1.
  • G 1 is ring A
  • G 2 is H, silver , , or and R' may be H, pyridinyl or -(CH 2 )-pyridinyl.
  • ring A may be furanyl. This When , 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- It may be CO-R 4 or -CO-R 5 .
  • 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.
  • o and p may each independently be an integer of 0, 1, 2, or 3, and q and r may each independently be an integer of 0 or 1.
  • R may be bonded to a carbon atom that is not adjacent to a 5-membered ring comprising X 1 to X 4 .
  • the compound of Formula 1 may be represented by any one of the following structural formulas:
  • 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 1-2 N; and C 6-12 aryl.
  • 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.
  • R 1 and R 2 may each independently be 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; 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 5-6 membered heterocyclyl containing 1-2 N, O or S optionally substituted with R'''.
  • 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 5-6 membered heterocyclyl containing 1-2 Ns optionally substituted with R''', such as pyrrolidinyl optionally substituted with R'''. have.
  • R'' and R''' are each independently halogen, cyano, OH, amino, nitro, COOH, COO-(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 alkoxy may be selected from the group.
  • R'' and R''' are each independently halogen, cyano, OH, COOH, COO-(C 1-6 alkyl), C 1-6 alkyl and C 1-6 alkoxy. can be selected from
  • the 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 .
  • R a and R b together with the N to which they are attached form a 5-6 membered heterocyclyl optionally further comprising one N, wherein said 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.
  • s is an integer of 0, 1, 2 or 3.
  • 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 attached form piperazinyl or piperidinyl, wherein said piperazinyl or piperidinyl is optionally -(CH 2 ) s -Can be substituted with phenyl or fused with phenyl.
  • s may be an integer of 0 or 1.
  • R 3 can be, but is not limited to, —NH-phenyl, or piperazinyl optionally substituted with phenyl or —(CH 2 )-phenyl.
  • R 4 can be, but is not limited to, —NH-thiophenyl or tetrahydroisoquinolinyl.
  • R 5 can be, but is not limited to -(CH 2 )-phenyl or piperazinyl optionally substituted with phenyl.
  • 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.
  • G 1 is furanyl or —CH 2 -furanyl
  • G 2 is H, pyridinyl or —CH 2 -pyridinyl
  • silver can be
  • R is -OH, -O-(CH 2 ) o -R 1 , -(CH 2 ) p -OR 2 , -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r
  • R 1 to R 5 , o, p, q and r are the same as described above.
  • R may be -OH, -O-(CH 2 ) o -R 1 or -(CH 2 ) p -OR 2 (o and p are 0 or 1 respectively), wherein R 1 and R 2 may each independently be C 4-6 cycloalkyl. wherein 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 optionally substituted with C 1-6 alkyl optionally interrupted by 1-2 Os.
  • G 1 is furanyl or -CH 2 -furanyl
  • G 2 is H
  • 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 It may be -O-CO-R 4 or -CO-R 5 , and R 1 to R 5 , o, p, q and r are the same as described above.
  • R can be -OH, -O-(CH 2 ) o -R 1 or -(CH 2 ) p -OR 2 (o and p are 0 or 1 respectively), R 1 and R 2 are Each independently may be a 5-6 membered heterocyclyl containing 1 N. wherein 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 optionally substituted with C 1-6 alkyl optionally interrupted by 1-2 Os.
  • G 1 is furanyl or -CH 2 -furanyl
  • G 2 is H
  • silver can be
  • 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 the same as described above.
  • R can be -OH, -O-(CH 2 ) o -R 1 or -(CH 2 ) p -OR 2 (o and p are 0 or 1 respectively), R 1 and R 2 are Each may independently be phenyl. wherein 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 optionally substituted with C 1-6 alkyl optionally interrupted by 1-2 Os.
  • G 1 is ring A
  • G 2 is H
  • silver can be
  • R may be OH.
  • ring A is C 6-12 aryl; 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S; and 4 to 6 membered cycloalkyl.
  • the ring A is phenyl; 5- or 6-membered heteroaryl containing 1 to 2 heteroatoms selected from N and S; 4-6 membered heterocyclyl containing 1 N; and 4 to 6 membered cycloalkyl.
  • Ring A can be, but is not limited to, thiazolyl, pyrimidyl, azetidinyl, cyclobutyl, or phenyl. The substituent of the ring A is as described above.
  • R A is -(CH 2 ) o -R 1 or -(CH 2 ) q -CO-R 3 .
  • the compound of Formula 1 may 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 for several tens of minutes to several hours in a suitable solvent (eg, DMSO, DMF, THF, t-BuOK, etc.) within the range of 5°C to 150°C, 20°C to 120°C, or room temperature to 110°C. have.
  • a suitable solvent eg, DMSO, DMF, THF, t-BuOK, etc.
  • any reagent or base eg, CuI, K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , 1,10-phenanthroline, etc.
  • any reagent or base eg, CuI, K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , 1,10-phenanthroline, etc.
  • R A -Br protected with an appropriate protecting group (eg, THP (tetrahydropyranyl), Boc (tert-butoxycarbonyl), etc.) instead of R A -Br or R A -Cl in Scheme A above.
  • R A -Cl may be reacted, and the compound of Formula 1 may be prepared by hydrolysis or removal of a protecting group in an appropriate solvent (MeOH and H 2 O, TFA and DCM, etc.).
  • R is -(CH 2 ) p -OR 2 or -(CH 2 ) r -O-CO-R 4
  • R is -(CH 2 ) It can be prepared by appropriately changing reaction conditions and reagents using a compound of p -OH or -(CH 2 ) r -OH as a starting material.
  • the compound in which R is -CO-R 5 among the compounds of Formula 1 can be prepared by appropriately changing reaction conditions and reaction reagents using a compound in which R is -COOH instead of the compound in which R is OH in Scheme A as a starting material.
  • the compound in which R is -(CH 2 ) p -OH, -(CH 2 ) r -OH or -COOH can be easily prepared based on the technical common knowledge of those skilled in the art with reference to the Preparation Examples and Examples herein. have.
  • the compound represented by Formula 1 may be selected from the following group:
  • furan of “furanyl” refers to a heterocyclic group consisting of a 5-membered aromatic ring composed of 4 carbon atoms and 1 oxygen atom.
  • 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 a C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 alkyl group.
  • 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. have.
  • the alkyl group may include alkyl interrupted by one or two oxygen atoms.
  • the alkyl interrupted by 1 or 2 oxygen atoms means that an oxygen atom is inserted between the carbon atom-carbon atom bond of the alkyl (including the case where the terminus of the alkyl is terminated with OH).
  • a C 4 alkyl ie butyl
  • alkoxy refers to an alkyl bound 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.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group.
  • a cycloalkyl group may contain 4 to 10, 4 to 8, 4 to 6, or 5 carbon atoms.
  • the monocycloalkyl group may be, for example, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl, and the like.
  • a bicycloalkyl group is, 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 or the like.
  • the tricycloalkyl group may be, for example, adamantyl.
  • heterocyclyl refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom.
  • a heterocyclyl group may contain 4 to 10, 4 to 8, 4 to 6, or 5 or 6 ring atoms.
  • the heteroatom 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 one or two N.
  • the heteroatom may be one N.
  • the heterocyclyl group may be a single ring group, a two ring group, or a three ring group.
  • the two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group.
  • the heterocyclyl is aziridinyl, azetidinyl tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl, thiazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydroisoquinolinyl, and the like.
  • aryl refers to an aromatic hydrocarbon ring having 6 to 12 carbon atoms, including groups in which the 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 a C 6 to C 8 aryl group.
  • Non-limiting examples of aryl include phenyl, naphthyl, or tetrahydronaphthyl, and the like.
  • heteroaryl refers to a monocyclic or bicyclic aromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S, the remaining ring atoms being carbon.
  • the heteroaryl group may contain, for example, 1 to 5, 1 to 3 or 1 or 2 heteroatoms.
  • the heteroaryl group may contain 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 Ns 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,
  • halogen refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine.
  • cyano refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom as -CN.
  • hydroxy refers to a -OH functional group (hydroxyl group).
  • nitro refers to —NO 2 .
  • amino refers to —NH 2 .
  • substituted refers to introduced 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
  • substituted refers to an introduced atomic group
  • the substituent is, 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 Alkoxy (eg, methoxy, ethoxy), C 2 To C 20 Alkoxyalkyl (eg, methoxyethoxymethyl), hydroxy 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,
  • 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 5-6 membered heterocyclyl.
  • the substituent may be further substituted with a substituent 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 that has the same molecular formula but does not have the same spatial arrangement or connection mode of constituent atoms in the molecule.
  • Isomers include, for example, structural isomers, and stereoisomers.
  • the stereoisomer may be a diastereomer or an enantiomer.
  • Enantiomers refer to isomers that do not overlap their mirror images, such as the relationship between the left and right hands, and are also called optical isomers. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when 4 or more substituents differ from each other at the chiral central carbon.
  • Diastereomers refer to stereoisomers that are not in a mirror image relationship, and are isomers caused by different spatial arrangement of atoms.
  • the diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.
  • solvate refers to a compound solvated in an organic or inorganic solvent.
  • the solvate is, for example, a hydrate.
  • salt refers to inorganic and organic acid addition salts of compounds.
  • 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 properties of the compound.
  • the inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate.
  • the organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate It may be an acid.
  • the metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
  • the compound of Formula 1 may be an antagonist to the adenosine A2A receptor.
  • the adenosine A2A receptor may be a protein belonging to a G-protein-coupled receptor (GPCR) having seven transmembrane alpha helices.
  • GPCR G-protein-coupled receptor
  • the adenosine A2A receptor may also be referred to as ADORA2A, adenosine A 2A 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, comprising the compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to an aspect .
  • the compound of Formula 1, stereoisomer, solvate, pharmaceutically acceptable salt, and adenosine A2A receptor 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 in organs such as liver, lung, breast, and skin.
  • Non-solid cancers are cancers that arise in the blood and are also called blood cancers.
  • the cancer may be a carcinoma, a sarcoma, a hematopoietic cell-derived cancer, a germ cell tumor, or a blastoma.
  • the cancer is, for example, breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colorectal 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 system cancer and sarcoma.
  • MDS myelodysplastic syndromes
  • the pharmaceutical composition may further include other anticancer agents.
  • the anticancer agent may be an immune anticancer agent.
  • the immuno-oncology agent may be an immune checkpoint inhibitor, an immune cell therapeutic 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), may be an antagonist for one selected from the group consisting of 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.
  • the compound of Formula 1 may be a composition for oral administration
  • the anticancer agent may be a composition for parenteral administration.
  • prevention refers to any action of inhibiting the onset of or delaying the onset of a disease associated with adenosine A2A receptors by administration of the pharmaceutical composition.
  • treatment refers to any action in which the symptoms of adenosine A2A receptor-related diseases are improved or beneficially altered by administration of the pharmaceutical composition.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier.
  • the carrier is used in the sense of including excipients, diluents or adjuvants.
  • the carrier may be, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pi It may be selected from the group consisting of rolidone, water, physiological saline, buffers such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil.
  • the composition may include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, or a combination thereof
  • the pharmaceutical composition may be prepared in any formulation according to a conventional method.
  • the composition may be formulated, for example, as an oral dosage form (eg, a powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (eg, an injection).
  • the composition may be prepared as a systemic formulation, or as a topical formulation.
  • the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule.
  • the solid formulation may further include an excipient.
  • the excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin.
  • the solid formulation may further include a lubricant such as magnesium stearate or talc.
  • the oral liquid formulation may be a suspension, an internal solution, an emulsion, or a syrup.
  • the liquid formulation may contain water or liquid paraffin.
  • the liquid formulation may contain excipients, for example, wetting agents, sweetening agents, perfuming agents, or preservatives.
  • the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried or suppository.
  • Non-aqueous solvents or suspending agents 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, or glycerogelatin.
  • the pharmaceutical composition includes the compound according to an aspect, a stereoisomer, a solvate, or a 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, anticancer).
  • the pharmaceutical composition may include the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof in an effective amount.
  • effective amount refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need thereof.
  • the effective amount can be appropriately selected by those skilled in the art depending on the cell or individual to be selected.
  • the preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the subject, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the compound, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof may be, for example, in an amount from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg. It can be administered 1 to 24 times a day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times in 1 month to 12 months dividedly administered.
  • the compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof is included in an amount of from about 0.0001% to about 10% by weight, or from 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 locally, alone or in combination with other pharmaceutically active compounds.
  • Another aspect of the present invention is a method of preventing or treating a disease related to adenosine A2A receptor comprising administering to an individual the compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to an aspect to provide.
  • the compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, and diseases, prevention, and treatment related to adenosine A2A receptors 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 suffering from, or likely to suffer from, symptoms associated with a disease associated with adenosine A2A receptors.
  • the method may further comprise administering to the subject an active ingredient known to have an effect of preventing or treating a disease related to adenosine A2A receptors.
  • the known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to an aspect, a stereoisomer, a solvate, or a 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 locally, alone or in combination with other pharmaceutically active compounds.
  • the preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may 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.
  • the administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year.
  • Another aspect of the present invention provides the use of a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect for use in the prevention or treatment of a disease associated with adenosine A2A receptors.
  • Another aspect of the present invention provides the use of a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect, for the manufacture of a medicament for preventing or treating a disease associated with adenosine A2A receptors. do.
  • adenosine A2A receptor-related diseases, prevention, and treatment the compound 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.
  • a pharmaceutical composition for preventing or treating adenosine A2A receptor-related diseases including the same, and a method for treating and preventing diseases using the same, adenosine A2A receptor-related diseases , for example, can effectively prevent or treat cancer.
  • adenosine A2A receptor-related diseases eg, cancer
  • a method for treating and preventing diseases using the same, adenosine A2A receptor-related diseases for example, can effectively prevent or treat cancer.
  • 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. under a nitrogen atmosphere for 3 hours.
  • the mixture was cooled to room temperature, and the solution was concentrated under reduced pressure.
  • Step 1 Synthesis of methyl 2-(3-bromo-4-fluorophenyl)acetate
  • step 1 above 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. MeI (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 at 0° C. with water/ice.
  • Phenylpiperazine (1.00 g, 6.16 mmol) and TEA (1.87 g, 18.5 mmol) were stirred and mixed in DCM (15.0 mL), and chloroacetyl chloride (1.04 g, 9.24 mmol) was added dropwise at 0°C under a nitrogen atmosphere. did.
  • the resulting mixture was stirred under a nitrogen atmosphere at 25° C. for 1 h, and the reaction was quenched with water (50.0 mL).
  • the resulting mixture was extracted with CH 2 Cl 2 (2 ⁇ 50.0 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 .
  • 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.
  • the mixture was cooled to room temperature, and the solution was partially concentrated under reduced pressure.
  • step 1 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), NH 4 Cl (30 g, 572.84 mmol, 3.00 equiv) was added. The mixture was stirred at 80° C. for 16 h and cooled to room temperature.
  • step 2 The compound obtained in step 2 (90.0 g, 179.91 mmol, 1.00 equiv, 57%) was stirred and mixed in AcOH (1.2 L) and H 2 O (400 mL) at 0° C., NaNO 2 (13.6 g, 197.91 mmol, 1.10 eq) were added in portions. The resulting mixture was stirred at 25° C. for 30 min.
  • 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 mixed with CH 3 CN (400 mL) and H Stir mixed in 2 O (400 mL) and (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 h.
  • step 1 The compound obtained in step 1 (7.9 g, 33.04 mmol, 1.00 equiv) and NH 3 (g) were stirred and mixed in MeOH (7 M, 20 mL) and EtOH (20 mL) under nitrogen atmosphere at 80° C. for 5 hours. .
  • the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (2:1), to 2-chloro-6-(3,3-difluorocyclobutyl)pyri.
  • Midin-4-amine (compound K; 2.3 g, 30.55%) was obtained as a white solid.
  • Example 1 1- [2-amino-6- (furan-2-yl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-5-ol (Ex-01)
  • Step 4 Synthesis of 1-(2-chloro-6-(furan-2-yl)pyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole
  • step 3 The compound obtained in step 3 (144 mg, 742 ⁇ mol) and 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, To a solution of 675 ⁇ mol) in dioxane (10.0 mL) and H 2 O (2.00 mL) was added K 2 CO 3 (186 mg, 1.35 mmol) and Pd(dppf)Cl 2 (24.7 mg, 33.7 ⁇ mol), The mixture was stirred at 80° C. for 2 h.
  • Step 5 Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyrimidin-2-amine
  • step 4 To a solution of the compound obtained in step 4 (140 mg, 427 ⁇ mol) in EtOH (200 ⁇ L) 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 h. The mixture was concentrated to give a residue. Without purification 4-(furan-2-yl)-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyrimidin-2-amine (130 mg, 421 ⁇ mol, 98.7% yield) was obtained as a white solid. MS m/z: 309.2 [M+H] + .
  • step 1 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 stirred at 80° C. for 2 h. The mixture was cooled to room temperature. After filtration of the resulting mixture, the filter cake was washed with EtOAc (3 x 300 mL), and the filtrate was concentrated under reduced pressure.
  • step 2 The compound obtained in step 2 (16.0 g, 50.5 mmol) was stirred and 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 addition of water (200 mL) at room temperature, the precipitated solid was collected by filtration and washed with ethanol (3 x 30.0 mL), 1-(2,6-dichloropyrimidin-4-yl) 5-Methoxy-1,2,3-benzotriazole (8 g, 48%) was obtained as a red solid.
  • step 3 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. under a nitrogen atmosphere for 16 hours. Water (300 mL) was added to quench the reaction, and the resulting mixture was extracted with CH 2 Cl 2 (3 ⁇ 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.
  • step 4 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 to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (1:2) to 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazole-1 -yl)pyrimidin-2-amine (940 mg, 42.5%) was obtained as a pink solid. MS m/z: 309 [M+H] + .
  • step 5 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 h. The mixture was cooled to room temperature and MeOH (20.0 mL) was added at 0°C. The resulting mixture was concentrated under reduced pressure, and then poured into a saturated aqueous solution of NaHCO 3 .
  • 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)
  • step 6 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 under a nitrogen atmosphere at 110° C. for 1 hour 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 ⁇ 20.0 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • Step 7 of Example 2 Same as 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 1 The compound obtained in step 1 above (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 under the following conditions: column, Xselect CSH OBD column 30x150 mm 5 ⁇ m, 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.
  • 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
  • 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)
  • step 1 The compound obtained in step 1 (40.0 mg, 0.087 mmol) was stirred and mixed in THF (5.00 mL), and CH 3 MgBr (80 ⁇ L, 0.694 mmol, 1M THF solution) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 16 hours. The reaction was quenched with water (25.0 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 ⁇ 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 under the following conditions: column, Xselect CSH OBD column 30x150 mm 5 ⁇ m, n; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (45% PhaseB, to 65% in 7 min); Detector, UV 254 & 220 nm.
  • Example 8 4-[5-(benzyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-08 )
  • Example 8 4-(furan-2-yl)- in the same manner as in Example 8 except that 3-bromo-1-methylpiperidine hydrobromide (528 mg, 2.04 mmol) was used instead of benzyl bromide in Example 8 6-[5-[(1-methylpiperidin-3-yl)oxy]-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex-09; 9.00 mg, 3.36 %) as a white solid.
  • the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Prep OBD C 18 column, 19 ⁇ 250 mm, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (41% PhaseB, to 52% in 10 min); Detector, UV 254&220 nm.
  • the collected fractions were freeze-dried to methyl 2-[3-( ⁇ 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5 -yl ⁇ oxy)pyridin-2-yl]acetate (Ex-10; 5.00 mg, 1.10%) was obtained as an off-white solid.
  • 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
  • step 1 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 under the following conditions: column, SunFire Prep C18 OBD column, 19 ⁇ 150 mm 5 ⁇ m 10 nm; mobile phase, water (0.05% TFA) and ACN (45% PhaseB, up to 65% in 7 min); Detector, UV 254/220 nm.
  • 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
  • step 1 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 under the following conditions: column, XSelect CSH fluoro phenyl, 30 mm X 150 mm, 5 ⁇ m; mobile phase, water (50 mmol/L NH 4 HCO 3 ) and ACN (40% PhaseB, up to 60% in 7 min); Detector, UV.
  • 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)
  • 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)
  • Example 16 4-(furan-2-yl)-6- ⁇ 5-[3-(1H-imidazol-1-yl)propoxy]-1H-1,2,3-benzotriazole-1- mono ⁇ pyrimidin-2-amine (Ex-16)
  • Example 8 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, 4-(furan-2-yl)-6- ⁇ 5- [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.
  • Example 17 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 17)
  • Step 1 tert-Butyl 4-[([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy Synthesis of )methyl]piperidine-1-carboxylate
  • 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)
  • step 1 The compound obtained in step 1 (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 under the following conditions: Column: XBridge Prep OBD C 18 column, 30 ⁇ 150 mm 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; Gradient: 25B to 45B at 7 min, RT1: 5.52.
  • Example 20 1- [2-amino-6- (furan-2-yl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-6-ol (Ex-20)
  • Steps 1 to 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
  • 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.
  • Example 20 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) were added in portions. The resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 1.5 h, and the mixture was cooled to room temperature. The desired product could be identified by LCMS.
  • the crude product was purified by Prep-HPLC under the following conditions (column: Kinetex EVO C 18 column, 30x150, 5 ⁇ m; 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 4-(furan-2-yl)-6- ⁇ 6-[3-(imidazol-1-yl)propoxy]-1,2,3-benzotriazol-1-yl ⁇ Pyrimidin-2-amine (Ex-21; 10.7 mg, 7.00%) was obtained as an off-white solid.
  • Example 23 4-(furan-2-yl)-6- ⁇ 6-[2-(piperidin-4-yl)ethoxy]-1H-1,2,3-benzotriazol-1-yl ⁇ pyrimidin-2-amine (Ex-23)
  • 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
  • Example 20 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) Mix and add K 2 CO 3 (140 mg, 1.02 mmol) in portions at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 80° C. for 1 hour, and the mixture was cooled to room temperature. The desired product could be identified by LCMS.
  • 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)
  • step 1 The compound obtained in step 1 above (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 identified by LCMS.
  • the crude product was purified under the following conditions (column: Kinetex EVO C 18 column, 30x150, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min).
  • Example 24 4-[5-(4-benzylpiperazine-1-carbonyl)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidine -2-amine (Ex-24)
  • 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.
  • Step 6 Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylic acid
  • step 5 The compound obtained in step 5 above (2.00 g, 5.94 mmol) was stirred and 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 ⁇ m, 60A; 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).
  • Step 7 4-[5-(4-Benzylpiperazine-1-carbonyl)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidine- Synthesis of 2-amine (Ex-24)
  • step 6 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 under the following conditions: column, YMC-Actus Triart C18, 30 mm X 150 mm, 5 ⁇ m; 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.
  • the product fractions were freeze-dried to 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.
  • step 1 The compound obtained in step 1 (50.0 mg, 0.160 mmol) and 3-isocyanatothiophene (44.0 mg, 0.350 mmol) were mixed by stirring in DMF (2.00 mL), and DIEA (68.0 mg, 0.520 mmol) was added added. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was poured into water (80.0 mL), extracted with EtOAc (80.0 mL), and the combined organic layers were washed with brine (80.0 mL) and dried over anhydrous Na 2 SO 4 .
  • Steps 1 to 3 Synthesis of 1-[5-bromo-6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
  • Step 4 1-[6-chloro-2-(methylsulfanyl)-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole synthesis
  • step 3 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 under a nitrogen atmosphere at 80° C. for 2 h, and the mixture was cooled to room temperature.
  • the mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 600 mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 5 1-[6-(furan-2-yl)-2-(methylsulfanyl)-5-(pyridin-4-yl))pyrimidin-4-yl]-5-methoxy-1,2 Synthesis of ,3-benzotriazole
  • step 4 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), 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. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, diluted with water (60.0 mL) and extracted with EtOAc (3 ⁇ 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 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.
  • step 5 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) (5.31 g) , 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 aqueous solution, and the resulting mixture was extracted with EtOAc (3 ⁇ 100 mL). The organic layers were collected, washed with a saturated aqueous solution of NaHCO 3 , and dried over anhydrous Na 2 SO 4 .
  • Step 7 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)-5-(pyridin-4-yl)pyrimidin-2- Synthesis of amines
  • step 6 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 ⁇ 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na 2 SO 4 .
  • 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)
  • step 7 The compound obtained in step 7 (25.0 mg, 0.065 mmol) and BBr 3 were stirred in DCM (1M) (2 mL) under nitrogen atmosphere at 25° C. for 2 hours. The reaction was quenched with MeOH (1 mL).
  • the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 ⁇ m; 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.
  • Example 28 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)-5-(pyridin-4-yl ) pyrimidin-2-amine (Ex-28)
  • Example 27 The compound of Example 27 (35.0 mg, 0.094 mmol) and bromocyclopentane (42.0 mg, 0.280 mmol) were stirred and mixed 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 under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 ⁇ m; 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 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)-5-(pyridin- 4-yl)pyrimidin-2-amine (Ex-28; 17.1 mg, 40.9%) was obtained as a white solid.
  • Step 1 Synthesis of 6-(furan-2-yl)-N-(4-methoxy-2-nitrophenyl)-2-(methylsulfanyl)pyrimidin-4-amine
  • step 1 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 h. 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 N1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine-4 -yl]-4-methoxybenzene-1,2-diamine (4.00 g, 72.2%) was obtained 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
  • step 2 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), and Na 2 S 2 O 5 (4.30 g, 22.8 mmol) ) was added. The final reaction mixture was irradiated with microwaves 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.
  • Step 4 1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3-benzodia synthesis of sol
  • Step 5 of 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine synthesis
  • step 4 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 eluting with CH 2 Cl 2 /MeOH (10:1) to 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl) -1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 60.1%) was obtained as a brown solid.
  • Step 6 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzodiazol-5-ol (Ex -29) synthesis
  • step 5 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 under the following conditions: column, Xselect CSH OBD column 30 ⁇ 150 mm 5 ⁇ m, 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.
  • 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
  • Example 29 The compound of Example 29 (120 mg, 0.320 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (180 mg, 0.640 mmol) were added to a stirred mixture 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 h. The resulting mixture was poured into water (100 mL) and extracted with CH 2 Cl 2 (3 ⁇ 100 mL).
  • 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)
  • step 1 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 under the following conditions: column, XBridge Prep OBD C 18 column, 30 ⁇ 150 mm 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (15% PhaseB, to 45% in 9 min); Detector, UV 254 nm.
  • Example 31 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-[(pyridin-4-yl)methyl]-1H-1,3-benzodiazole -5-all (Ex-31)
  • Step 2 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3 -Synthesis of benzodiazole
  • step 1 The compound obtained in step 1 (8.00 g, 17.9 mmol) was mixed in AcOH (40.0 mL) under nitrogen atmosphere, and the final reaction mixture was irradiated with microwaves at 120° C. for 1 hour. The mixture was cooled to room temperature. Then, the mixture was purified by silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (10:1) to 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine-4- yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3-benzodiazole (5.20 g, 63.0%) was obtained as a brown oil.
  • step 2 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 eluted with CH 2 Cl 2 /MeOH (10:1) and purified by silica gel column chromatography to 1-[6-(furan-2-yl)-2-methanesulfinylpyrimidin-4-yl]-5 -Methoxy-2-(pyridin-4-ylmethyl)-1,3-benzodiazole (2.00 g, 34.9%) was obtained 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
  • step 3 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 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl) Obtained methyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine (700 mg, 36.8%) as a brown solid.
  • step 4 The compound obtained in step 4 (50.0 mg, 0.120 mmol) and BBr 3 were mixed in DCM (1.00 mL) by stirring at 25° C. for 1 hour. 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 under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (20% PhaseB, to 50% in 7 min); Detector, UV 254 nm.
  • 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
  • Example 31 The compound of Example 31 (200 mg, 0.520 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (434 mg, 1.56 mmol) were added to a stirred mixture 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 h. The mixture was cooled to room temperature.
  • 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)
  • step 1 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 under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (30% PhaseB, to 60% in 7 min); Detector, UV 254 nm.
  • Steps 1 to 4 Synthesis of 5-bromo-1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazole
  • 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (33.0 g, 188 mmol) and 6-bromo 1-fluoro-2-nitrobenzene (50.0 g, 227 mmol) were used as starting materials 5-bromo-1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3 in the same manner as in steps 1 to 4 of Example 2 -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
  • Step 6 Synthesis of 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl boronic acid
  • step 5 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 allowed 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), 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3 -Benzotriazol-5-ylboronic acid (1.80 g, 44.4%) was obtained as an off-white solid.
  • 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
  • step 6 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), 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 h. The resulting mixture was concentrated under vacuum.
  • 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
  • step 7 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 .
  • 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
  • step 8 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 h. The resulting mixture was concentrated under vacuum. The residue was eluted with PE/EtOAc (1:1), purified by silica gel column chromatography, and tert-butyl 4-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl] -1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (120 mg, 53.4%) was obtained as a white solid. MS m/z: 461 [M+H] + .
  • Example 34 1- ⁇ 2-amino-6-[(furan-2-yl)methyl]pyrimidin-4-yl ⁇ -1H-1,2,3-benzotriazol-5-ol (Ex-34 )
  • 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
  • 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine was used instead of 2,6-dichloropyrimidin-4-amine in Step 1 of Example 2
  • 1- [6-chloro-2- (methylsulfanyl) pyrimidin-4-yl] -5-methoxy-1,2,3-benzotriazole (12.0 g, 44.5%) was browned obtained as a solid.
  • Step 4 Synthesis of 5-methoxy-1-[2-(methylsulfanyl)-6-(trimethylstannyl)pyrimidin-4-yl]-1,2,3-benzotriazole
  • step 3 To a stirred mixture of the compound obtained in step 3 (12.0 g, 39.0 mmol) and hexamethyldistannan (19.2 g, 58.5 mmol) in toluene (200 mL) Pd(PPh 3 ) 4 (9.01 g, 7.79 mmol) was added. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature.
  • the crude product was purified by silica gel column chromatography, eluting with PE/EtOAc (2:1), to 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.
  • Step 5 Synthesis of 1-[6-(furan-2-carbonyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
  • step 4 To a stirred compound of the compound obtained in step 4 (3.00 g, 6.87 mmol) and furoyl chloride (4.19 g, 34.4 mmol) in toluene (60.0 mL) was added Pd(PPh 3 ) 4 (1.59 g, 1.37 mmol) did. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum.
  • Step 6 Synthesis of furan-2-yl[6-(5-methoxy-1,2,3-benzotriazol-1-yl)-2-(methylsulfanyl)pyrimidin-4-yl]methanol
  • step 5 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) in portions at 0°C. The resulting mixture was stirred at 25° C. for 16 h. The resulting mixture was concentrated under vacuum. The residue was eluted with PE/EtOAc (1:1), purified by silica gel column chromatography, and furan-2-yl[6-(5-methoxy-1,2,3-benzotriazol-1-yl)-2 -(methylsulfanyl)pyrimidin-4-yl]methanol (700 mg, 52.2%) was obtained as a pale yellow solid.
  • Step 7 Synthesis of 1-[6-(furan-2-ylmethyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
  • Step 8 Synthesis of 1-[6-(furan-2-ylmethyl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
  • step 7 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 ⁇ 20.0 mL). The combined organic layers were washed with a saturated aqueous NaHCO 3 solution, and dried over anhydrous Na 2 SO 4 .
  • m-CPBA 390 mg, 2.26 mmol
  • step 8 To a stirred mixture of the compound obtained in 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 h. 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.
  • Step 10 Synthesis of 1-[2-amino-6-(furan-2-ylmethyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-34)
  • step 9 The compound obtained in step 9 (50.0 mg, 0.150 mmol) and BBr 3 were mixed in DCM (1M) (3.00 mL) for 1 hour at 25° C. under nitrogen atmosphere by stirring. The reaction was quenched by adding MeOH (1 mL) at 0 °C.
  • the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 ⁇ m; 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.
  • step 3 To a cooled 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. stirred. The reaction was diluted with NaHCO 3 and extracted with ethyl acetate (2 ⁇ 50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product.
  • Example 36 4-[7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-6-(furan-2-yl)pyrimidine-2 -Amine (Ex-36)
  • step 2 To a stirred solution of the compound obtained in step 1 (1.80 g, 8.21 mmol) in pyridine (54.0 mL), hydrazine hydrate (0.820 g, 16.4 mmol) was added and stirred at 120°C for 32 hours. After 32 h, 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 4 4-[7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-6-(furan-2-yl)pyrimidin-2- Synthesis of amines (Ex-36)
  • step 3 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 h. After completion of the reaction, the reaction was diluted with water and extracted with ethyl acetate (2 x 50.0 mL).
  • Example 36 To a stirred solution of the compound of Example 36 (150 mg, 0.390 mmol) in methanol (1.50 mL), 10% Pd/C (50% water, 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 the crude product which was purified by prep HPLC to 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.
  • step 1 To a stirred solution of the compound obtained in step 1 (3.50 g, 14.1 mmol), t-BuOK (2.50 g, 22.6 mmol) and I 2 (5.73 g, 22.6 mmol) were added, and the reaction was stirred at room temperature for 16 hours. After 16 h, 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 under vacuum to give 6-((tert-butyldimethylsilyl)oxy)-3-iod-1H-indazole (3.50 g, 66.0%). MS m/z: 375.11 [M+H] + .
  • step 2 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 stirred for 15 min. and further cooled to -10 °C.
  • NaH 850 mg, 12.8 mmol, 60% dispersion in mineral oil
  • i-PrMgCl (2M solution in THF, 6.41 mL) was added dropwise and stirred at the same temperature for 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, followed by stirring at room temperature for 30 minutes.
  • Step 4 Synthesis of 4-(6-((tert-butyldimethylsilyl)oxy)-1H-indazol-3-yl)-6-(furan-2-yl)pyrimidin-2-amine
  • step 3 To a stirred solution of the compound obtained in step 3 (600 mg, 1.11 mmol) in DMF (6.00 mL) palladium(II)bis(triphenylphosphine) dichloride (0.078 g, 110 ⁇ mol) and TEA (0.44 mL) was added and the reaction was degassed under argon for 15 minutes. To the reaction mixture, 4-(furan-2-yl)-6-iodopyrimidin-2-amine (320 mg, 1.11 mmol) was added, and the reaction mixture was stirred at 90° C. for 6 hours. After 6 h, the reaction was diluted with water and extracted with ethyl acetate (2 x 50.0 mL).
  • 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
  • H 2 O 2 (15.4 g, 136 mmol, 30%) dropwise at 0° C. under nitrogen atmosphere.
  • the resulting mixture was stirred for 2 h 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.
  • Step 2 Synthesis of tert-butyl 4-(3-amino-4-nitrophenoxy)pyrazole-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3,4-diaminophenoxy)pyrazole-1-carboxylate
  • step 2 To a 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%) little by little. The resulting mixture was stirred for 2 h at 25° C. under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography, followed by tert-butyl 4-(3,4-diaminophenoxy)pyrazole-1-carboxylate (1.50 g, 70.9%). ) 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
  • step 3 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 nitrogen atmosphere. was added dropwise. The resulting mixture was stirred at 25° C. under nitrogen atmosphere for 1 hour. The reaction was quenched with water at 0°C. The precipitated solid was collected by filtration and washed with water, 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)pyrazole-1- Carboxylate and tert-butyl 4-([3-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyra Synthesis of mixtures of sol-1-carboxylates
  • step 4 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 at 0° C. under nitrogen atmosphere for 30 min. 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).
  • 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 mixtures of 2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate
  • 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
  • Step 8 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)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl Synthesis of mixtures of ]oxy)pyrazole-1-carboxylates
  • Step 9 4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex- 39) synthesis
  • step 8 The mixture obtained in step 8 (120 mg, 0.26 mmol) was stirred and mixed in DCM (4.00 mL), and TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 1 h. The resulting mixture was concentrated under vacuum.
  • the crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C18 ExRS, 30 mm X 150 mm, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (38% PhaseB, to 53% in 9 min); Detector, UV 254&220 nm.
  • 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)
  • Step 1 1-[2-Chloro-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole synthesis of
  • 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 ⁇ m; mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient in 30 min); Detector, UV 254/220 nm.
  • the solution was concentrated under reduced pressure to 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.
  • Step 2 4-(5-Methoxy-1,2,3-benzotriazol-1-yl)-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-2-amine synthesis of
  • step 1 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) under nitrogen atmosphere at 80° C. for 16 h. . 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 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 ) and ACN (0% to 100% gradient in 30 min); Detector, UV 254/220 nm.
  • step 2 The compound obtained in step 2 (100 mg, 0.236 mmol, 1.00 equiv, 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 under the following conditions: Column: YMC-Actus Triart C 18 , 30 mm X 150 mm, 5 ⁇ m; mobile phase A: water (50MMOL/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; Gradient: 25B to 45B, 254nm at 9 min; RT1: 7.93.
  • step 1 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 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 ⁇ m; mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient at 30 min); Detector, UV 254/220 nm.
  • Step 3 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-42 ) synthesis
  • step 2 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 under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (10% PhaseB, to 30% in 7 min); Detector, 254 nm.
  • Example 43 1- [2-amino-6- (3,3-difluorocyclobutyl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-5-ol (Ex- 43)
  • Step 1 Synthesis of 2-chloro-6-(3,3-difluorocyclobutyl)-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine
  • step 1 The compound obtained in step 1 (1.5 g, 4.04 mmol, 1.00 equiv) was added to a stirred mixture in EtOH (15 mL) and H 2 O (3 mL) with 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 h. The mixture was cooled to room temperature, filtered and the filter cake was washed with ethyl acetate (3 ⁇ 700 mL).
  • Step 3 Synthesis of 1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
  • step 2 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) was added NaNO 2 (334 mg, 4.84 mmol, 1.1 equiv) at 0 °C was added in portions. The resulting mixture was stirred at 25° C. for 30 min, and the reaction was quenched at room temperature by addition of water (800 mL).
  • Step 4 Synthesis of 4-(3,3-difluorocyclobutyl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine
  • step 3 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 nitrogen atmosphere at 80° C. for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was eluted with PE/EtOAc (2:1) and purified by silica gel column chromatography, followed by 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.
  • Step 5 of 1-[2-amino-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-43) synthesis
  • step 4 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 ⁇ m; 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 under the following conditions: column, YMC-Actus Triart C 18 ExRS, 30 ⁇ 250, 5 ⁇ m; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (42% PhaseB, to 65% in 7 min); Detector, UV 254 nm.
  • the collected fractions were freeze-dried to 1-[2-amino-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex -43; 9.3 mg, 6.45%) was obtained as a white solid.
  • Example 44 3-[2-amino-6-(5-hydroxy-1H-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]-2-methylbenzonitrile (Ex -44)
  • 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 yl)pyrimidin-4-yl]-2-methylbenzonitrile (Ex-44; 18.5 mg, 30.26%) was obtained.
  • a 10 mM stock solution was prepared by dissolving the compounds of the above examples in DMSO. Compounds were evaluated at 10 concentrations (highest concentration: 100 ⁇ M, 10-fold serial dilutions) to determine IC 50 .
  • 25,000 HEK293 cells (Life technologies, R705-07) per well in 96-well white plates were inoculated with baculovirus particles expressing 2 x 10 6 adenosine receptor (A2AR) and incubated overnight.
  • a dose-response evaluation was performed to measure the EC 80 of 5-N-ethylcarboxamidoadenosine (NECA) (Tocris, 1691), an adenosine receptor agonist used in cAMP function analysis.
  • NECA 5-N-ethylcarboxamidoadenosine
  • Tocris, 1691 an adenosine receptor agonist used in cAMP function analysis.
  • A2AR antagonist activity (IC 50 ) ⁇ 100nM 100nM to 1uM >1uM display value +++ ++ +
  • 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
  • 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 against the A2AR receptor was particularly excellent.

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Abstract

La présente invention concerne un antagoniste d'un récepteur A2A de l'adénosine, une composition pharmaceutique le contenant pour prévenir ou traiter une maladie liée au récepteur A2A de l'adénosine (par exemple, le cancer), et une méthode de traitement et de prévention d'une maladie l'utilisant. Le composé de formule chimique 1 selon la présente invention a une excellente activité antagoniste pour les récepteurs A2A de l'adénosine et, par conséquent, peut prévenir ou traiter de manière efficace des maladies associées au récepteur A2A de l'adénosine (par exemple, le cancer).
PCT/KR2022/004084 2021-03-26 2022-03-23 Antagoniste du récepteur a2a de l'adénosine et son utilisation WO2022203399A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110009405A1 (en) * 2009-07-07 2011-01-13 Pathway Therapeutics Limited Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
US20130231519A1 (en) * 2010-11-05 2013-09-05 Merck Patent Gmbh 1H-Pyrrolo[2,3 b]pyridine derivatives
KR20150138383A (ko) * 2013-04-04 2015-12-09 오리온 코포레이션 단백질 키나제 억제제
WO2020079457A1 (fr) * 2018-10-19 2020-04-23 Heptares Therapeutics Limited Dérivés de pyrazole en tant que composés antagonistes de h4

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110009405A1 (en) * 2009-07-07 2011-01-13 Pathway Therapeutics Limited Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
US20130231519A1 (en) * 2010-11-05 2013-09-05 Merck Patent Gmbh 1H-Pyrrolo[2,3 b]pyridine derivatives
KR20150138383A (ko) * 2013-04-04 2015-12-09 오리온 코포레이션 단백질 키나제 억제제
WO2020079457A1 (fr) * 2018-10-19 2020-04-23 Heptares Therapeutics Limited Dérivés de pyrazole en tant que composés antagonistes de h4

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Title
GIRAUD FRANCIS, ALVES GEORGES, DEBITON ERIC, NAUTON LIONEL, THÉRY VINCENT, DURIEU EMILIE, FERANDIN YOAN, LOZACH OLIVIER, MEIJER LA: "Synthesis, Protein Kinase Inhibitory Potencies, and in Vitro Antiproliferative Activities of Meridianin Derivatives", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 54, no. 13, 14 July 2011 (2011-07-14), US , pages 4474 - 4489, XP055971031, ISSN: 0022-2623, DOI: 10.1021/jm200464w *

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