WO2022203399A1 - Adenosine a2a receptor antagonist and use thereof - Google Patents

Adenosine a2a receptor antagonist and use thereof 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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French (fr)
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/en
Publication of WO2022203399A1 publication Critical patent/WO2022203399A1/en

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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.

Abstract

The present invention relates to an antagonist of an adenosine A2A receptor, a pharmaceutical composition containing same for preventing or treating adenosine A2A receptor-related disease (for example cancer), and a method for treating and preventing disease by using same. The compound of chemical formula 1 according to the present invention exhibits excellent antagonistic activity for adenosine A2A receptors and thus, can effectively prevent or treat adenosine A2A receptor-related diseases (for example, cancer).

Description

아데노신 A2A 수용체 길항제 및 이의 용도Adenosine A2A receptor antagonists and uses thereof
본 발명은 신규한 A2A 수용체 길항제 및 이의 용도에 관한 것으로서, 구체적으로 화학식 1의 신규한 A2A 수용체 길항제 및 이를 포함하는 암 치료용 약학 조성물에 관한 것이다.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.
아데노신(adenosine)은 다양한 생리 기능을 조절하는 퓨린 뉴클레오사이드로서, G 단백질-결합 수용체(G protein-coupled receptor; GPCR) 수퍼패밀리에 속하는 아데노신 A1, A2A, A2B 및 A3 수용체(A1R, A2AR, A2BR 및 A3R)와 상호 작용하여 조절기능을 나타낸다. 이 중, 아데노신 A2A 수용체(이하, A2AR)는 기저핵에서 A2AR과 도파민 D2 사이의 기능적 상호 작용에 기초하여 A2AR 길항제는 파킨슨병 치료 약물로서 연구되어 왔다. 그 외에 A2AR 길항작용은 인지 향상, 신경 보호 및 진통 등의 치료 효과와 관련되는 것으로 알려져 있다. 최근에 A2AR은 혈관확장을 조절하고 신생혈관의 형성을 지원하며, 염증으로 인한 손상으로부터 신체조직을 보호하는 등 생명활동에서 중요한 역할을 하는 것으로 보고되었다. 따라서, A2AR의 억제제가 강력한 항암 효과를 제공할 수 있다. 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. Among them, 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. In addition, A2AR antagonism is known to be associated with therapeutic effects such as cognitive enhancement, neuroprotection and analgesia. Recently, it was reported that A2AR plays an important role in life activities such as regulating vasodilation, supporting the formation of new blood vessels, and protecting body tissues from damage caused by inflammation. Therefore, inhibitors of A2AR may provide potent anticancer effects.
종양 조직의 저산소증은 더 높은 농도의 아데노신(생리학적 수준에서~10 μM 대 ~20 nM)의 축적을 유도한다. 아데노신 신호전달(signaling)의 활성화는 선천성 면역반응의 지속적 억제를 유발하고, 이는 면역 관용을 통하여 악성 종양의 제어되지 않은 성장을 초래한다. 림프구, T 림프구, 자연살해세포, 수지상세포 등의 백혈구에서 아데노신 및 A2AR의 결합은 이들 백혈구의 면역기능을 기능을 억제할 수 있다. 또한, 아데노신 및 A2AR의 결합은 CD39, CD73 및 CTLA4(T세포 체크포인트)의 발현을 증가시켜, 더 많은 더 강한 면역억제성을 갖는 Treg 세포를 생성하게 한다. 따라서, A2AR의 신호전달경로를 차단할 경우, 면역체계에 대한 억제 효과의 감소 및 T 세포의 면역기능의 향상을 유도할 수 있으므로, A2AR 차단은 종양 성장을 억제시킬 수 있는 유망한 네거티브 피드백 메카니즘으로 여겨진다.Hypoxia of the tumor tissue leads to the accumulation of higher concentrations of adenosine (~10 μM 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. The binding of adenosine and A2AR to leukocytes such as lymphocytes, T lymphocytes, natural killer cells, and dendritic cells may suppress the immune function of these leukocytes. In addition, binding of adenosine and A2AR increases the expression of CD39, CD73 and CTLA4 (T cell checkpoint), resulting in 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.
따라서, 본 발명의 목적은 아데노신 A2A 수용체에 대해 우수한 길항 활성을 나타내는 신규한 A2AR 길항제를 제공하고, 이를 이용하여 면역 반응을 회복 또는 향상시켜 암 및 기타 유형의 비정상 세포 증식의 치료 및 예방에 높은 효능을 달성하는 것이다.Accordingly, it is an object of the present invention to provide a novel A2AR antagonist that exhibits excellent antagonistic activity against adenosine A2A receptor, and by using the same to restore or enhance immune response, high efficacy in the treatment and prevention of cancer and other types of abnormal cell proliferation is to achieve
본 발명의 목적은 화학식 1로 표시되는 A2AR 길항제를 제공하는 것이다.An object of the present invention is to provide an A2AR antagonist represented by the formula (1).
본 발명의 또다른 목적은 화학식 1로 표시되는 A2AR 길항제를 포함하는, A2AR과 관련된 질병을 예방 또는 치료하기 위한 약학적 조성물을 제공하는 것이다.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;
본 발명의 또다른 목적은 화학식 1로 표시되는 A2AR 길항제를 이용하여 A2AR과 관련된 질병을 예방 또는 치료 방법을 제공하는 것이다.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.
본 출원에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 출원에서 개시된 다양한 요소들의 모든 조합이 본 출원의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 출원의 범주가 제한된다고 볼 수 없다.Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. In addition, it cannot be seen that the scope of the present application is limited by the detailed description described below.
본 발명의 일 양상은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 제공한다: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:
[화학식 1][Formula 1]
Figure PCTKR2022004084-appb-I000001
.
Figure PCTKR2022004084-appb-I000001
.
상기 화학식 1에서, G1는 -(CH2)l-고리 A이고, G2는 H 또는 -(CH2)m-피리딘일일 수 있다. 이 경우, l 및 m은 각각 독립적으로 0, 1, 2 또는 3의 정수이다. 일 실시태양에서, l 및 m은 각각 독립적으로 0, 1 또는 2의 정수, 바람직하게는 0 또는 1의 정수일 수 있다.In Formula 1, G 1 is -(CH 2 ) l -ring A, and G 2 may be H or -(CH 2 ) m -pyridinyl. In this case, l and m are each independently an integer of 0, 1, 2 or 3. In one embodiment, l and m may each independently be an integer of 0, 1 or 2, preferably an integer of 0 or 1.
일 실시태양에서, G1은 고리 A 또는 -(CH2)-고리 A일 수 있다. In one embodiment, G 1 can be Ring A or -(CH 2 )-Ring A.
상기 고리 A는 C6-12 아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택될 수 있다. 일 실시태양에서, 고리 A는 C6-10 아릴; N, O 및 S로부터 선택되는 1~2개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; 1개의 N을 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택될 수 있다. 일 실시태양에서, 고리 A는 페닐, 퓨란일, 티아졸일, 피리미딘일, 아제티딘일 및 사이클로부틸로 이루어진 군으로부터 선택될 수 있다. 일 실시태양에서, 고리 A는 페닐, 퓨란-2-일, 퓨란-3-일, 티아졸-5-일, 피리미딘-5-일, 아제티딘-1-일 및 사이클로부틸로 이루어진 군으로부터 선택될 수 있다.wherein 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. In one embodiment, Ring A is C 6-10 aryl; 5- or 6-membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; 4-6 membered heterocyclyl containing 1 N; and 4 to 6 membered cycloalkyl. In one embodiment, Ring A can be selected from the group consisting of phenyl, furanyl, thiazolyl, pyrimidinyl, azetidinyl and cyclobutyl. In one embodiment, Ring A is selected from the group consisting of phenyl, furan-2-yl, furan-3-yl, thiazol-5-yl, pyrimidin-5-yl, azetidin-1-yl and cyclobutyl can be
상기 고리 A는 할로겐, -CN, -OH, C1-6 알킬, 할로겐으로 치환된 C1-6 알킬, C1-6 알콕시, 할로겐으로 치환된 C1-6 알콕시, 및 NRARB로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환 또는 비치환될 수 있다. 이 경우, RA 및 RB는 각각 독립적으로 H 또는 C1-6 알킬일 수 있다. 일 실시태양에서, 고리 A는 할로겐, -CN, -OH, C1-4 알킬, 할로겐으로 치환된 C1-4 알킬, C1-4 알콕시, 할로겐으로 치환된 C1-4 알콕시, 및 NRARB로 이루어진 군으로부터 선택되는 1개 또는 2개의 치환기로 치환 또는 비치환될 수 있다. 이 경우, RA 및 RB는 각각 독립적으로 H 또는 C1-4 알킬일 수 있다. 일 실시태양에서, 고리 A는 할로겐, -CN, -OH, -NH2 및 C1-4 알킬로 이루어진 군에서 선택되는 1개 또는 2개의 치환기로 치환 또는 비치환될 수 있다.wherein ring A is selected from halogen, -CN, -OH, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, and NR A R B It may be substituted or unsubstituted with one or more substituents selected from the group consisting of. In this case, R A and R B may each independently be H or C 1-6 alkyl. In one embodiment, Ring A is halogen, -CN, -OH, C 1-4 alkyl, 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. In this case, R A and R B may each independently be H or C 1-4 alkyl. In one embodiment, Ring A may be unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, -CN, -OH, -NH 2 and C 1-4 alkyl.
예를 들어, G1은 톨일, 시아노톨일, 시아노페닐, 페닐, 퓨란일, 퓨란일메틸, 티아졸일, 메틸티아졸일, 피리미딘일, 아제티딘일, 아미노아제티딘일, 사이클로부틸, 또는 하나 이상의 할로겐으로 치환된 사이클로부틸일 수 있지만, 이에 제한되지 않는다. 예를 들어, G1은 3-시아노-o-톨일, 퓨란-2-일, 퓨란-3-일, 퓨란-2-일메틸, 2-메틸티아졸-5-일, 피리미딘-5-일, 3-아미노-아제티딘-1-일 또는 3,3-디플루오로사이클로부틸일 수 있지만, 이에 제한되지 않는다. For example, 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. For example, 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.
일 실시태양에서, G2는 H 또는 피리딘일일 수 있다. 예를 들어, G2는 H 또는 피리딘-4-일일 수 있지만, 이에 제한되지 않는다.In one embodiment, G 2 can be H or pyridinyl. For example, G 2 can be, but is not limited to, H or pyridin-4-yl.
일 실시태양에서, 상기 화학식 1에서 G1 및 G2 가 결합된 피리미딘 고리의 5번 위치에 G2가 결합되고, 피리미딘 고리의 나머지 치환가능한 탄소 원자에 G1이 결합될 수 있다. 예를 들면, 상기 G2는 상기 피리미딘 고리에 결합된 아미노기를 기준으로 파라(para: p-) 위치 또는 1,4 위치에 결합될 수 있으며, 상기 G1은 상기 피리미딘 고리의 나머지 치환 가능한 탄소 원자에 결합될 수 있다. In one embodiment, in Formula 1, 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. For example, 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.
일 실시태양에서, G1은 -(CH2)l-고리 A이고, G2는 H일 수 있다. 다른 실시태양에서, G1은 -(CH2)l-고리 A이고, G2는 -(CH2)m-피리딘일일 수 있다. 이 경우, l 및 m은 각각 독립적으로 0 또는 1일 수 있다. 예를 들어, 상기 -(CH2)l-고리 A는 -(CH2)l-퓨란일일 수 있다. 예를 들어, 상기 -(CH2)l-퓨란일은 퓨란-2-일, 퓨란-3-일 또는 퓨란-2-일메틸일 수 있다. 예를 들어, 상기 -(CH2)m-피리딘일은 피리딘-4-일 또는 피리딘-4-일메틸일 수 있다.In one embodiment, G 1 can be —(CH 2 ) 1 -ring A, and G 2 can be H. In another embodiment, G 1 can be —(CH 2 ) 1 -ring A, and G 2 can be —(CH 2 ) m -pyridinyl. In this case, l and m may each independently be 0 or 1. For example, the -(CH 2 ) 1 -ring A may be -(CH 2 ) 1 -furanyl. For example, the -(CH 2 ) l -furanyl may be furan-2-yl, furan-3-yl, or furan-2-ylmethyl. For example, the -(CH 2 ) m -pyridinyl may be pyridin-4-yl or pyridin-4-ylmethyl.
일 실시태양에서, X1 및 X2는 각각 독립적으로 C 또는 N이고, X3는 CR' 또는 N이고, X4는 CH, N 또는 NH이되, X1, X2, X3 및 X4 중 1~3개가 N 또는 NH일 수 있고, R'은 H 또는 -(CH2)n-피리딘일일 수 있다. 이 경우, n은 0, 1, 2 또는 3의 정수이다. 또한, n은 0, 1 또는 2의 정수, 바람직하게는 0 또는 1의 정수일 수 있다. 일 실시태양에서, R'은 피리딘일 또는 -(CH2)-피리딘일일 수 있다. 예를 들어, R'은 피리딘-4-일 또는 피리딘-4-일메틸일 수 있다.In one embodiment, X 1 and X 2 are each independently C or N, X 3 is CR' or N, X 4 is CH, N or NH, wherein X 1 , X 2 , X 3 and X 4 1 to 3 may be N or NH, and R' may be H or -(CH 2 ) n -pyridinyl. In this case, n is an integer of 0, 1, 2 or 3. Also, n may be an integer of 0, 1 or 2, preferably an integer of 0 or 1. In one embodiment, R' can be pyridinyl or -(CH 2 )-pyridinyl. For example, R' can be pyridin-4-yl or pyridin-4-ylmethyl.
일 실시태양에서,
Figure PCTKR2022004084-appb-I000002
은 벤조트리아졸일, [1,2,4]트리아졸로[4,3-a]피리딘일, [1,2,3]트리아졸로[1,5-a]피리딘일, [1,2,4]트리아졸로[1,5-a]피리딘일, 인다졸릴, 벤즈이미다졸릴, 인돌릴 및 이소인돌릴로 이루어진 군으로부터 선택될 수 있다.In one embodiment,
Figure PCTKR2022004084-appb-I000002
Silver benzotriazolyl, [1,2,4] triazolo [4,3-a] pyridinyl, [1,2,3] triazolo [1,5-a] pyridinyl, [1,2,4] triazolo[1,5-a]pyridinyl, indazolyl, benzimidazolyl, indolyl and isoindolyl.
일 실시태양에서,
Figure PCTKR2022004084-appb-I000003
은 하기 군으로부터 선택될 수 있다:
Figure PCTKR2022004084-appb-I000004
,
Figure PCTKR2022004084-appb-I000005
,
Figure PCTKR2022004084-appb-I000006
,
Figure PCTKR2022004084-appb-I000007
및
Figure PCTKR2022004084-appb-I000008
.In one embodiment,
Figure PCTKR2022004084-appb-I000003
can be selected from the group:
Figure PCTKR2022004084-appb-I000004
,
Figure PCTKR2022004084-appb-I000005
,
Figure PCTKR2022004084-appb-I000006
,
Figure PCTKR2022004084-appb-I000007
and
Figure PCTKR2022004084-appb-I000008
.
일 실시태양에서, G1은 -(CH2)l-고리 A이고, G2는 H 또는 -(CH2)m-피리딘일이고,
Figure PCTKR2022004084-appb-I000009
은
Figure PCTKR2022004084-appb-I000010
이고, l 및 m은 0 또는 1일 수 있다.In one embodiment, G 1 is -(CH 2 ) 1 -ring A, G 2 is H or -(CH 2 ) m -pyridinyl,
Figure PCTKR2022004084-appb-I000009
silver
Figure PCTKR2022004084-appb-I000010
, and l and m may be 0 or 1.
일 실시태양에서, G1은 고리 A이고, G2는 H이고,
Figure PCTKR2022004084-appb-I000011
은
Figure PCTKR2022004084-appb-I000012
,
Figure PCTKR2022004084-appb-I000013
,
Figure PCTKR2022004084-appb-I000014
또는
Figure PCTKR2022004084-appb-I000015
이고, R'은 H, 피리딘일 또는 -(CH2)-피리딘일일 수 있다. 이 경우, 고리 A는 퓨란일일 수 있다.
Figure PCTKR2022004084-appb-I000016
이
Figure PCTKR2022004084-appb-I000017
인 경우, R'은 피리딘일 또는 -(CH2)피리딘일일 수 있다.In one embodiment, G 1 is ring A, G 2 is H,
Figure PCTKR2022004084-appb-I000011
silver
Figure PCTKR2022004084-appb-I000012
,
Figure PCTKR2022004084-appb-I000013
,
Figure PCTKR2022004084-appb-I000014
or
Figure PCTKR2022004084-appb-I000015
and R' may be H, pyridinyl or -(CH 2 )-pyridinyl. In this case, ring A may be furanyl.
Figure PCTKR2022004084-appb-I000016
this
Figure PCTKR2022004084-appb-I000017
When , R' may be pyridinyl or -(CH 2 )pyridinyl.
R은 -OH, -O-(CH2)o-R1, -(CH2)p-O-R2, -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5일 수 있다. 이 경우, o 및 p는 각각 독립적으로 0, 1, 2, 3, 4 또는 5의 정수이고, q 및 r은 각각 독립적으로 0, 1, 2 또는 3의 정수이다. 일 실시태양에서, o 및 p는 각각 독립적으로 0, 1, 2 또는 3의 정수이고, q 및 r은 각각 독립적으로 0 또는 1의 정수일 수 있다.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 . In this case, o and p are each independently an integer of 0, 1, 2, 3, 4 or 5, and q and r are each independently an integer of 0, 1, 2 or 3. In one embodiment, o and p may each independently be an integer of 0, 1, 2, or 3, and q and r may each independently be an integer of 0 or 1.
일 실시태양에서, R은 X1 내지 X4를 포함하는 5원환에 인접하지 않은 탄소 원자에 결합할 수 있다. 이 경우, 화학식 1의 화합물은 하기 중 어느 하나의 구조식으로 표시될 수 있다:In one embodiment, R may be bonded to a carbon atom that is not adjacent to a 5-membered ring comprising X 1 to X 4 . In this case, the compound of Formula 1 may be represented by any one of the following structural formulas:
Figure PCTKR2022004084-appb-I000018
Figure PCTKR2022004084-appb-I000019
Figure PCTKR2022004084-appb-I000018
Figure PCTKR2022004084-appb-I000019
상기 R1 및 R2는 각각 독립적으로 C4-6 사이클로알킬; 1~3개의 N 또는 O를 함유하는 5-6원 헤테로아릴; 1~2개의 N을 함유하는 5-6원 헤테로사이클릴; 및 C6-12 아릴로 이루어진 군으로부터 선택될 수 있다. 일 실시태양에서, R1 및 R2는 각각 독립적으로 C4-6 사이클로알킬; 1~2개의 N 및 임의로 1개의 O를 함유하는 5-6원 헤테로아릴; 1개의 N을 포함하는 5-6원 헤테로사이클릴; 및 페닐로 이루어진 군으로부터 선택될 수 있다. 일 실시태양에서, R1 및 R2는 각각 독립적으로 사이클로펜틸, 피리딘일, 피라졸릴, 옥사디아졸릴, 이미다졸릴, 피페리딘일 및 페닐로 이루어진 군으로부터 선택될 수 있다.wherein R 1 and R 2 are each independently C 4-6 cycloalkyl; 5-6 membered heteroaryl containing 1 to 3 N or O; 5-6 membered heterocyclyl containing 1-2 N; and C 6-12 aryl. In one embodiment, R 1 and R 2 are each independently C 4-6 cycloalkyl; 5-6 membered heteroaryl containing 1-2 N and optionally 1 O; 5-6 membered heterocyclyl containing 1 N; and phenyl. In one embodiment, R 1 and R 2 may each independently be selected from the group consisting of cyclopentyl, pyridinyl, pyrazolyl, oxadiazolyl, imidazolyl, piperidinyl, and phenyl.
상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; 아미노; 니트로; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, 아미노, 니트로, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 임의로 1~2개의 O에 의해 중단된 C1-6 알킬; 할로겐, 시아노, OH, 아미노, 니트로, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알콕시; R''으로 임의로 치환된 C6-12 아릴; 및 R'''으로 임의로 치환된 1-2개의 N, O 또는 S를 함유하는 5-6원 헤테로사이클릴로 이루어진 군으로부터 선택되는 치환기에 의해 임의로 치환될 수 있다. 일 실시태양에서, 상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 임의로 1~2개의 O에 의해 중단된 C1-6 알킬; C1-6 알콕시; R''로 임의로 치환된 페닐; 및 R'''로 임의로 치환된 1-2개의 N을 함유하는 5-6원 헤테로사이클릴, 예컨대 R'''로 임의로 치환된 피롤리딘일로 이루어진 군으로부터 선택되는 치환기에 의해 임의로 치환될 수 있다.wherein 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'''. In one embodiment, 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.
상기 R'' 및 R'''은 각각 독립적으로 할로겐, 시아노, OH, 아미노, 니트로, COOH, COO-(C1-6 알킬), C1-6 알킬, 및 C1-6 알콕시로 이루어진 군으로부터 선택될 수 있다. 일 실시태양에서, R'' 및 R'''은 각각 독립적으로 할로겐, 시아노, OH, COOH, COO-(C1-6 알킬), C1-6 알킬 및 C1-6 알콕시로 이루어진 군으로부터 선택될 수 있다.wherein 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. In one embodiment, 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
상기 R3, R4 및 R5는 각각 독립적으로 -NH-C6-12 아릴; -NH-(1~2개의 N, O 또는 S를 포함하는 5-6원 헤테로아릴); 및 -NRaRb로 이루어진 군으로부터 선택될 수 있다. 이 경우, Ra 및 Rb는 이들이 결합한 N과 함께 임의로 1개의 N을 더 포함하는 5-6원 헤테로사이클릴을 형성하되, 상기 5-6원 헤테로사이클릴은 임의로 -(CH2)s-C6-12 아릴로 치환되거나 C6-12 아릴과 융합될 수 있다. 이 경우, s는 0, 1, 2 또는 3의 정수이다. 일 실시태양에서, R3, R4 및 R5는 각각 독립적으로 -NH-페닐; -NH-(1개의 N, O 또는 S를 포함하는 5-6원 헤테로아릴); 및 NRaRb로 이루어진 군으로부터 선택되고, Ra 및 Rb는 이들이 결합한 N과 함께 피페라진일 또는 피페리딘일을 형성하되, 상기 피페라진일 또는 피페리딘일은 임의로 -(CH2)s-페닐로 치환되거나 페닐과 융합될 수 있다. 이 경우, s는 0 또는 1의 정수일 수 있다. 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 . In this case, R a and R b together with the N to which they are attached form a 5-6 membered heterocyclyl optionally further 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. In this case, s is an integer of 0, 1, 2 or 3. In one embodiment, R 3 , R 4 and R 5 are each independently —NH-phenyl; -NH-(5-6 membered heteroaryl containing 1 N, O or S); and NR a R b , wherein R a and R b together with the N to which they are attached form piperazinyl or piperidinyl, wherein said piperazinyl or piperidinyl is optionally -(CH 2 ) s -Can be substituted with phenyl or fused with phenyl. In this case, s may be an integer of 0 or 1.
예를 들어, R3은 -NH-페닐, 또는 페닐 또는 -(CH2)-페닐로 임의로 치환된 피페라진일일 수 있지만, 이에 제한되지 않는다. 예를 들어, R4는 -NH-티오페닐 또는 테트라히드로이소퀴놀리닐일 수 있지만, 이에 제한되지 않는다. 예를 들어, R5는 -(CH2)-페닐 또는 페닐로 임의로 치환된 피페라진일일 수 있지만, 이에 제한되지 않는다.For example, R 3 can be, but is not limited to, —NH-phenyl, or piperazinyl optionally substituted with phenyl or —(CH 2 )-phenyl. For example, R 4 can be, but is not limited to, —NH-thiophenyl or tetrahydroisoquinolinyl. For example, R 5 can be, but is not limited to -(CH 2 )-phenyl or piperazinyl optionally substituted with phenyl.
상기 R3, R4 및 R5는 각각 독립적으로 할로겐, 시아노, OH, 아미노, 니트로, COOH, COO-(C1-6 알킬), C1-6 알킬, 및 C1-6 알콕시로 이루어진 군으로부터 선택된 치환기로 임의로 치환될 수 있다.wherein R 3 , R 4 and R 5 are each independently halogen, cyano, OH, amino, nitro, COOH, COO-(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 alkoxy It may be optionally substituted with a substituent selected from the group.
일 실시태양에서, 상기 화학식 1의 G1은 퓨란일 또는 -CH2-퓨란일이고, G2는 H, 피리딘일 또는 -CH2-피리딘일이고;
Figure PCTKR2022004084-appb-I000020
은
Figure PCTKR2022004084-appb-I000021
일 수 있다. 이 경우, R은 -OH, -O-(CH2)o-R1, -(CH2)p-O-R2, -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5일 수 있고, R1 내지 R5, o, p, q 및 r은 전술한 바와 같다. 예를 들어, R은 -OH, -O-(CH2)o-R1 또는 -(CH2)p-O-R2일 수 있고(o 및 p는 각각 0 또는 1), 상기 R1 및 R2는 각각 독립적으로 C4-6 사이클로알킬일 수 있다. 상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 또는 임의로 1~2개의 O에 의해 중단된 C1-6 알킬로 임의로 치환될 수 있다. In one embodiment, in Formula 1, G 1 is furanyl or —CH 2 -furanyl, G 2 is H, pyridinyl or —CH 2 -pyridinyl;
Figure PCTKR2022004084-appb-I000020
silver
Figure PCTKR2022004084-appb-I000021
can be In this case, R is -OH, -O-(CH 2 ) o -R 1 , -(CH 2 ) p -OR 2 , -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r It may be -O-CO-R 4 or -CO-R 5 , and R 1 to R 5 , o, p, q and r are the same as described above. For example, R may be -OH, -O-(CH 2 ) o -R 1 or -(CH 2 ) p -OR 2 (o and p are 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.
일 실시태양에서, 상기 화학식 1의 G1은 퓨란일 또는 -CH2-퓨란일이고, G2는 H이고,
Figure PCTKR2022004084-appb-I000022
은
Figure PCTKR2022004084-appb-I000023
이고, R'은 피리딘일 또는 -(CH2)-피리딘일일 수 있다. 이 경우, R은 -OH, -O-(CH2)o-R1, -(CH2)p-O-R2, -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5일 수 있고, R1 내지 R5, o, p, q 및 r은 전술한 바와 같다. 예를 들어, R은 -OH, -O-(CH2)o-R1 또는 -(CH2)p-O-R2일 수 있고(o 및 p는 각각 0 또는 1), R1 및 R2는 각각 독립적으로 1개의 N을 포함하는 5-6원 헤테로사이클릴일 수 있다. 상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 또는 임의로 1~2개의 O에 의해 중단된 C1-6 알킬로 임의로 치환될 수 있다. In one embodiment, in Formula 1, G 1 is furanyl or -CH 2 -furanyl, G 2 is H,
Figure PCTKR2022004084-appb-I000022
silver
Figure PCTKR2022004084-appb-I000023
and R' may be pyridinyl or -(CH 2 )-pyridinyl. In this case, R is -OH, -O-(CH 2 ) o -R 1 , -(CH 2 ) p -OR 2 , -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r It may be -O-CO-R 4 or -CO-R 5 , and R 1 to R 5 , o, p, q and r are the same as described above. For example, R can be -OH, -O-(CH 2 ) o -R 1 or -(CH 2 ) p -OR 2 (o and p are 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.
일 실시태양에서, 상기 화학식 1의 G1은 퓨란일 또는 -CH2-퓨란일이고, G2는 H이고,
Figure PCTKR2022004084-appb-I000024
은
Figure PCTKR2022004084-appb-I000025
일 수 있다. 이 경우, R은 -OH, -O-(CH2)o-R1, -(CH2)p-O-R2, -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5일 수 있고, R1 내지 R5, o, p, q 및 r은 전술한 바와 같다. 예를 들어, R은 -OH, -O-(CH2)o-R1 또는 -(CH2)p-O-R2(o 및 p는 각각 0 또는 1)일 수 있고, R1 및 R2는 각각 독립적으로 페닐일 수 있다. 상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 또는 임의로 1~2개의 O에 의해 중단된 C1-6 알킬로 임의로 치환될 수 있다.In one embodiment, in Formula 1, G 1 is furanyl or -CH 2 -furanyl, G 2 is H,
Figure PCTKR2022004084-appb-I000024
silver
Figure PCTKR2022004084-appb-I000025
can be In this case, R is -OH, -O-(CH 2 ) o -R 1 , -(CH 2 ) p -OR 2 , -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r It may be -O-CO-R 4 or -CO-R 5 , and R 1 to R 5 , o, p, q and r are the same as described above. For example, R can be -OH, -O-(CH 2 ) o -R 1 or -(CH 2 ) p -OR 2 (o and p are 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.
일 실시태양에서, 상기 화학식 1의 G1은 고리 A이고, G2는 H이고,
Figure PCTKR2022004084-appb-I000026
은
Figure PCTKR2022004084-appb-I000027
일 수 있다. 이 경우, R은 OH일 수 있다. 이 경우, 상기 고리 A는 C6-12 아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택될 수 있다. 또한, 상기 고리 A는 페닐; N 및 S로부터 선택되는 1~2개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; 1개의 N을 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택될 수 있다. 예를 들어, 상기 고리 A는 티아졸릴, 피리미딜, 아제티딘일, 사이클로부틸, 또는 페닐일 수 있지만, 이에 제한되지 않는다. 상기 고리 A의 치환기는 전술한 바와 같다.In one embodiment, in Formula 1, G 1 is ring A, G 2 is H,
Figure PCTKR2022004084-appb-I000026
silver
Figure PCTKR2022004084-appb-I000027
can be In this case, R may be OH. In this case, 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. In addition, 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. For example, 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.
화학식 1의 화합물 중 R이 OH인 화합물은 본원 제조예 및 실시예를 참조하여 당업자의 기술상식을 기초로 용이하게 제조할 수 있다.Compounds in which R is OH among the compounds of Formula 1 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.
화학식 1의 화합물 중 R이 -O-(CH2)o-R1 또는 -O-(CH2)q-CO-R3인 화합물은 하기 반응식 A에 따라서 제조될 수 있다.Among the compounds of Formula 1, a compound in which R is -O-(CH 2 ) o -R 1 or -O-(CH 2 ) q -CO-R 3 may be prepared according to Scheme A below.
[반응식 A][Scheme A]
Figure PCTKR2022004084-appb-I000028
Figure PCTKR2022004084-appb-I000028
(상기 반응식 A에서, RA는 -(CH2)o-R1 또는 -(CH2)q-CO-R3이다.)(In Scheme A, R A is -(CH 2 ) o -R 1 or -(CH 2 ) q -CO-R 3 .)
상기 반응식 A에 따라서, 화학식 1의 화합물은 R이 OH인 화합물에 RA-Br 또는 RA-Cl을 반응시켜서 제조될 수 있다.According to Scheme A, 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.
상기 반응은 적절한 용매(예컨대, DMSO, DMF, THF, t-BuOK 등) 중에서 5℃ 내지 150℃, 20℃ 내지 120℃, 또는 상온 내지 110℃의 범위 내에서 수십분 내지 수 시간 동안 적절히 수행될 수 있다. 상기 반응 시 필요에 따라서 임의의 시약이나 염기(예컨대, CuI, K3PO4, K2CO3, Cs2CO3, 1,10-페난트롤린 등)를 첨가할 수 있다.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. In the reaction, any reagent or base (eg, CuI, K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , 1,10-phenanthroline, etc.) may be added as needed.
경우에 따라서, 상기 반응식 A에서 RA-Br 또는 RA-Cl 대신에 적절한 보호기(예컨대, THP(테트라하이드로피란일), Boc(tert-부톡시카보닐) 등)로 보호된 RA-Br또는 RA-Cl을 반응시키고, 적절한 용매(MeOH 및 H2O, TFA 및 DCM 등) 중에서 가수분해 또는 보호기 제거 반응을 거쳐서 화학식 1의 화합물을 제조할 수 있다. Optionally, 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. Alternatively, 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.).
또한, 상기 반응식 A에서 RA-Br 또는 RA-Cl 대신에 RA'-Br 또는 RA'-Cl을 반응시키고, RA'을 RA로 변형하기 위한 적절한 화학적 반응, 예컨대 CH3MgBr와 같은 그리냐르 시약을 사용한 에스테르로부터 알콜 형성, 예컨대 LiOH 존재 하의 에스테르의 염기성 가수분해 등을 거쳐서 화학식 1의 화합물을 제조할 수 있다.In addition, in Scheme A above, a suitable chemical reaction for reacting R A '-Br or R A '-Cl instead of R A -Br or R A -Cl and transforming R A ' into R A , such as CH 3 MgBr The compound of formula 1 can be prepared from an ester using a Grignard reagent such as
화학식 1의 화합물 중 R이 -(CH2)p-O-R2 또는 -(CH2)r-O-CO-R4 인 화합물은 반응식 A에서 R이 OH인 화합물 대신에 R이 -(CH2)p-OH 또는 -(CH2)r-OH인 화합물을 출발 물질로 하여 반응조건 및 반응시약을 적절히 변경하여 제조할 수 있다. In the compound of Formula 1, R is -(CH 2 ) p -OR 2 or -(CH 2 ) r -O-CO-R 4 In Scheme A, instead of the compound in which R is OH, 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.
화학식 1의 화합물 중 R이 -CO-R5인 화합물은 반응식 A에서 R이 OH인 화합물 대신에 R이 -COOH인 화합물을 출발 물질로 하여 반응조건 및 반응시약을 적절히 변경하여 제조할 수 있다. 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.
상기 출발 물질로서 R이 -(CH2)p-OH, -(CH2)r-OH 또는 -COOH인 화합물은 본원 제조예 및 실시예를 참조하여 당업자의 기술상식을 기초로 용이하게 제조할 수 있다.As the 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.
일 실시태양에서, 상기 화학식 1로 표시되는 화합물은 하기 군으로부터 선택될 수 있다:In one embodiment, the compound represented by Formula 1 may be selected from the following group:
Figure PCTKR2022004084-appb-I000029
;
Figure PCTKR2022004084-appb-I000030
;
Figure PCTKR2022004084-appb-I000029
;
Figure PCTKR2022004084-appb-I000030
;
Figure PCTKR2022004084-appb-I000031
;
Figure PCTKR2022004084-appb-I000032
;
Figure PCTKR2022004084-appb-I000031
;
Figure PCTKR2022004084-appb-I000032
;
Figure PCTKR2022004084-appb-I000033
;
Figure PCTKR2022004084-appb-I000034
;
Figure PCTKR2022004084-appb-I000033
;
Figure PCTKR2022004084-appb-I000034
;
Figure PCTKR2022004084-appb-I000035
;
Figure PCTKR2022004084-appb-I000036
;
Figure PCTKR2022004084-appb-I000035
;
Figure PCTKR2022004084-appb-I000036
;
Figure PCTKR2022004084-appb-I000037
;
Figure PCTKR2022004084-appb-I000038
;
Figure PCTKR2022004084-appb-I000037
;
Figure PCTKR2022004084-appb-I000038
;
Figure PCTKR2022004084-appb-I000039
;
Figure PCTKR2022004084-appb-I000040
;
Figure PCTKR2022004084-appb-I000039
;
Figure PCTKR2022004084-appb-I000040
;
Figure PCTKR2022004084-appb-I000041
;
Figure PCTKR2022004084-appb-I000042
;
Figure PCTKR2022004084-appb-I000041
;
Figure PCTKR2022004084-appb-I000042
;
Figure PCTKR2022004084-appb-I000043
;
Figure PCTKR2022004084-appb-I000044
;
Figure PCTKR2022004084-appb-I000043
;
Figure PCTKR2022004084-appb-I000044
;
Figure PCTKR2022004084-appb-I000045
;
Figure PCTKR2022004084-appb-I000046
;
Figure PCTKR2022004084-appb-I000045
;
Figure PCTKR2022004084-appb-I000046
;
Figure PCTKR2022004084-appb-I000047
;
Figure PCTKR2022004084-appb-I000048
;
Figure PCTKR2022004084-appb-I000047
;
Figure PCTKR2022004084-appb-I000048
;
Figure PCTKR2022004084-appb-I000049
;
Figure PCTKR2022004084-appb-I000050
;
Figure PCTKR2022004084-appb-I000049
;
Figure PCTKR2022004084-appb-I000050
;
Figure PCTKR2022004084-appb-I000051
;
Figure PCTKR2022004084-appb-I000052
;
Figure PCTKR2022004084-appb-I000051
;
Figure PCTKR2022004084-appb-I000052
;
Figure PCTKR2022004084-appb-I000053
;
Figure PCTKR2022004084-appb-I000054
;
Figure PCTKR2022004084-appb-I000053
;
Figure PCTKR2022004084-appb-I000054
;
Figure PCTKR2022004084-appb-I000055
;
Figure PCTKR2022004084-appb-I000056
;
Figure PCTKR2022004084-appb-I000055
;
Figure PCTKR2022004084-appb-I000056
;
Figure PCTKR2022004084-appb-I000057
;
Figure PCTKR2022004084-appb-I000058
;
Figure PCTKR2022004084-appb-I000057
;
Figure PCTKR2022004084-appb-I000058
;
Figure PCTKR2022004084-appb-I000059
;
Figure PCTKR2022004084-appb-I000060
;
Figure PCTKR2022004084-appb-I000059
;
Figure PCTKR2022004084-appb-I000060
;
Figure PCTKR2022004084-appb-I000061
;
Figure PCTKR2022004084-appb-I000062
;
Figure PCTKR2022004084-appb-I000061
;
Figure PCTKR2022004084-appb-I000062
;
Figure PCTKR2022004084-appb-I000063
;
Figure PCTKR2022004084-appb-I000064
;
Figure PCTKR2022004084-appb-I000063
;
Figure PCTKR2022004084-appb-I000064
;
Figure PCTKR2022004084-appb-I000065
;
Figure PCTKR2022004084-appb-I000066
;
Figure PCTKR2022004084-appb-I000065
;
Figure PCTKR2022004084-appb-I000066
;
Figure PCTKR2022004084-appb-I000067
;
Figure PCTKR2022004084-appb-I000068
;
Figure PCTKR2022004084-appb-I000067
;
Figure PCTKR2022004084-appb-I000068
;
Figure PCTKR2022004084-appb-I000069
;
Figure PCTKR2022004084-appb-I000070
;
Figure PCTKR2022004084-appb-I000069
;
Figure PCTKR2022004084-appb-I000070
;
Figure PCTKR2022004084-appb-I000071
; 및
Figure PCTKR2022004084-appb-I000072
.
Figure PCTKR2022004084-appb-I000071
; and
Figure PCTKR2022004084-appb-I000072
.
본원에서, "퓨란일"의 용어 "퓨란"은 4개의 탄소 원자와 1개의 산소 원자로 구성된 5원자 방향족 고리로 이루어진 헤테로고리기를 말한다.As used herein, the term “furan” of “furanyl” refers to a heterocyclic group consisting of a 5-membered aromatic ring composed of 4 carbon atoms and 1 oxygen atom.
용어 "알킬"은 완전 포화된 분지형 또는 비분지형 (또는, 직쇄 또는 선형) 탄화수소를 말한다. 상기 알킬은 치환 또는 비치환된 알킬기일 수 있다. 상기 C1-6 알킬은 C1 내지 C5, C1 내지 C4, C1 내지 C3, 또는 C1 내지 C2인 알킬기일 수 있다. 상기 알킬의 비제한적인 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸, n-펜틸, 이소펜틸, 네오펜틸, iso-아밀, 또는 n-헥실일 수 있다.The term “alkyl” refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon. The alkyl may be a substituted or unsubstituted alkyl group. The C 1-6 alkyl may be 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.
상기 알킬기는 1~2개의 산소 원자에 의해 중단된 알킬을 포함할 수 있다. 상기 1~2개의 산소 원자에 의해 중단된 알킬은 알킬의 탄소 원자-탄소 원자 결합 사이에 산소 원자가 삽입됨(알킬의 말단이 OH로 종결되는 경우를 포함함)을 의미한다. 예컨대, C4 알킬(즉 부틸)은 2개의 산소에 의해 중단되는 경우, 예컨대 메톡시에톡시메틸(CH3O(CH2)2OCH3-)기를 형성할 수 있다.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). For example, a C 4 alkyl (ie butyl) can form, for example, a methoxyethoxymethyl (CH 3 O(CH 2 ) 2 OCH 3 —) group when it is interrupted by two oxygens.
용어 "알콕시"는 산소 원자에 결합된 알킬을 말한다. 상기 C1 내지 C6의 알콕시기는 C1 내지 C5, C1 내지 C4, C1 내지 C3, 또는 C1 내지 C2인 알콕시일 수 있다.The term “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.
용어 "사이클로알킬"은 포화 또는 부분 불포화된 비방향족(non-aromatic) 모노사이클릭, 비사이클릭 또는 트리사이클릭 탄화수소기를 말한다. 사이클로알킬기는 4 내지 10개, 4 내지 8개, 4 내지 6개, 또는 5개의 탄소 원자를 함유할 수 있다. 모노사이클로알킬기는 예를 들어, 사이클로부틸, 사이클로펜틸, 사이클로펜테닐, 사이클로헥실, 또는 사이클로헥세닐 등일 수 있다. 비사이클로알킬기는 예를 들어, 보르닐, 데카히드로나프틸, 비사이클로[2.1.1]헥실, 비사이클로[2.2.1]헵틸, 비사이클로[2.2.1]헵테닐, 또는 비사이클로[2.2.2]옥틸일 등일 수 있다. 트리사이클로알킬기는 예를 들어, 아다만틸(adamantyl)일 수 있다.The term “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.
용어 "헤테로사이클릴"은 적어도 하나의 헤테로원자를 포함하는 포화 또는 부분 불포화 사이클릭 탄화수소를 말한다. 헤테로사이클릴기는 4 내지 10개, 4 내지 8개, 4 내지 6개, 또는 5 또는 6개의 고리 원자를 함유할 수 있다. 상기 헤테로원자는 N, O 및 S로 이루어진 군으로부터 선택된 어느 하나 이상, 바람직하게는 1개 내지 3개일 수 있다. 상기 헤테로사이클릴은 N, O 또는 S로부터 선택된 하나 이상의 헤테로원자를 1개 또는 2개 포함할 수 있다. 상기 헤테로원자는 1개 또는 2개의 N일 수 있다. 상기 헤테로원자는 1개의 N일 수 있다.The term “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.
상기 헤테로사이클릴기는 하나의 고리기, 두개의 고리기, 또는 세개의 고리기일 수 있다. 상기 두개의 고리기는 스피로 고리기(spiro-ring), 브릿지 고리기(briged-ring), 및 융합 고리기(fused-ring)일 수 있다. 일례로서, 상기 헤테로사이클릴은 아지리딘일, 아제티딘일 테트라하이드로퓨란일, 테트라하이드로티오페닐, 피롤리딘일, 옥사졸리딘일, 이소옥사졸리딘일, 이소티아졸리딘일, 티아졸리딘일, 모르폴린일, 피페라진일, 피페리딘일, 테트라히드로이소퀴놀린일 등을 포함하지만, 이에 제한되는 것은 아니다.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. As an example, the heterocyclyl is aziridinyl, azetidinyl tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl, thiazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydroisoquinolinyl, and the like.
용어 "아릴"은 탄소수 6 내지 12의 방향족 탄화수소 고리를 지칭하며, 방향족 고리가 하나 이상의 탄소 고리에 융합된 그룹도 포함한다. 상기 C6 내지 C12의 아릴기는 예를 들면, C6 내지 C10, 또는 C6 내지 C8인 아릴기일 수 있다. 아릴의 비제한적인 예로는, 페닐, 나프틸, 또는 테트라히드로나프틸 등을 들 수 있다.The term "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.
용어 "헤테로아릴"은 N, O, 및 S로 이루어진 군으로부터 선택된 하나 이상의 헤테로원자를 포함하고, 나머지 고리원자가 탄소인 모노시클릭(monocyclic) 또는 바이시클릭(bicyclic) 방향족 화합물을 의미한다. 상기 헤테로아릴기는 예를 들어 1 내지 5개, 1 내지 3개 또는 1 또는 2개의 헤테로원자를 포함할 수 있다. 상기 헤테로아릴기는 5 내지 10개, 5 내지 7개, 또는 5 또는 6개의 고리 원소를 포함할 수 있다. 상기 헤테로아릴은 1개 또는 2개의 N, O 또는 S를 함유하는 5-6원 헤테로아릴일 수 있다. 상기 헤테로아릴은 1개 또는 2개의 N 및 임의로 1개의 O를 함유하는 5-6원 헤테로아릴일 수 있다. The term "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.
상기 헤테로아릴기는 하나의 고리기, 두개의 고리기, 또는 세개의 고리기일 수 있다. 상기 두개의 고리기는 스피로 고리기(spiro-ring), 브릿지 고리기(briged-ring), 및 융합 고리기(fused-ring)일 수 있다. "헤테로아릴"의 비제한적인 예로는, 피리딘일, 티에닐, 티오펜일, 피리미딘일, 푸릴, 피롤릴, 이미다졸릴, 피라졸릴, 티아졸릴, 이소티아졸릴, 1,2,3-옥사디아졸릴, 1,2,4-옥사디아졸릴, 1,2,5-옥사디아졸릴, 1,3,4-옥사디아졸릴기, 1,2,3-티아디아졸릴, 1,2,4-티아디아졸릴, 1,2,5-티아디아졸릴, 1,3,4-티아디아졸릴, 이소티아졸-3-일, 이소티아졸-4-일, 이소티아졸-5-일, 옥사졸-2-일, 옥사졸-4-일, 옥사졸-5-일, 이소옥사졸-3-일, 이소옥사졸-4-일, 이소옥사졸-5-일, 1,2,4-트리아졸-3-일, 1,2,4-트리아졸-5-일, 1,2,3-트리아졸-4-일, 1,2,3-트리아졸-5-일, 테트라졸릴, 피리드-2-일, 피리드-3-일, 2-피라진-2일, 피라진-4-일, 피라진-5-일, 2-피리미딘-2-일, 4- 피리미딘-2-일, 5-피리미딘-2-일, 이소퀴놀린일 등을 들 수 있다. The heteroaryl group may be a single ring group, two ring groups, or three ring groups. The two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group. Non-limiting examples of "heteroaryl" include pyridinyl, thienyl, thiophenyl, pyrimidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl group, 1,2,3-thiadiazolyl, 1,2,4 -Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxa Zol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4- Triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazolyl, p lead-2-yl, pyrid-3-yl, 2-pyrazin-2yl, pyrazin-4-yl, pyrazin-5-yl, 2-pyrimidin-2-yl, 4-pyrimidin-2-yl, 5-pyrimidin-2-yl, isoquinolinyl, etc. are mentioned.
용어 "할로겐" 원자는 주기율표의 17족에 속하는 원자를 말한다. 할로겐 원자는 불소, 염소, 브롬, 및 요오드 등을 포함한다.The term "halogen" atom refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine.
용어 "시아노(cyano)"는 -CN으로서, 탄소 원자와 질소 원자 사이에 삼중결합으로 이루어진 작용기를 말한다.The term "cyano" refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom as -CN.
용어 "히드록시(hydroxy)"는 -OH 기능기(수산기)를 말한다.The term "hydroxy" refers to a -OH functional group (hydroxyl group).
용어 "니트로(nitro)"는 -NO2를 말한다.The term “nitro” refers to —NO 2 .
용어 "아미노(amino)"는 -NH2를 말한다.The term “amino” refers to —NH 2 .
상기 "치환된"의 용어 "치환"은 유기 화합물 중의 하나 이상의 수소 원자를 다른 원자단으로 치환하여 유도체를 형성한 경우 수소 원자 대신에 도입되는 것을 말하고, "치환기"는 도입된 원자단을 말한다. 치환기는 예를 들면, 히드록시기(예, 프로판올, 에탄올), 할로겐 원자, 할로겐 원자로 치환된 C1 내지 C20의 알킬기(예, CCF3, CHCF2, CH2F, CCl3 등), C1 내지 C20의 알콕시(예, 메톡시, 에톡시), C2 내지 C20의 알콕시알킬(예, 메톡시에톡시메틸), 히드록시기, 니트로기, 시아노기, 아미드기(예, 아세트아미드), 아미노기, 아미디노기, 히드라진, 히드라존, 카르보닐기, 카르복실기나 그의 염(예, 아세테이트, 프로판산, 카르밤산염), 술포닐기, 술파모일(sulfamoyl)기, 술폰산기나 그의 염, 인산이나 그의 염, 또는 C1 내지 C20 알킬기(예, 메틸), C2 내지 C20 알케닐기, C2 내지 C20 알키닐기, C1 내지 C20 헤테로알킬기(예, 피롤리딘, 피페리딘), C6 내지 C20 아릴기(예, 페닐, 벤질, 벤조산), C6 내지 C20 아릴알킬기, C6 내지 C20 헤테로아릴기(예, 피리딘일), C7 내지 C20헤테로아릴알킬기, C6 내지 C20 헤테로아릴옥시기, 및 C6 내지 C20 헤테로아릴옥시알킬기, C6 내지 C20 헤테로아릴알킬기, 또는 이들의 조합일 수 있다.The term “substituted” of “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, and “substituent” 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, methyl), C 2 to C 20 alkenyl group, C 2 to C 20 alkynyl group, C 1 to C 20 heteroalkyl group (eg, pyrrolidine, piperidine), C 6 to C 20 aryl group (eg, phenyl, benzyl, benzoic acid), C 6 to C 20 arylalkyl group, C 6 to C 20 heteroaryl group (eg, pyridinyl), C 7 to C 20 heteroarylalkyl group, C 6 to C 20 heteroaryloxy group, and C 6 to C 20 heteroaryloxyalkyl group, C 6 to C 20 heteroarylalkyl group, or a combination thereof.
또한, 치환기는 할로겐; 시아노; OH; 아미노; 니트로; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, 아미노, 니트로, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 임의로 1~2개의 O에 의해 중단된 C1-6 알킬; 할로겐, 시아노, OH, 아미노, 니트로, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알콕시; C6-12 아릴; 또는 5-6원 헤테로사이클릴일 수 있다. 또한, 상기 치환기는 할로겐, 시아노, OH, 아미노, 니트로, COOH, COO-(C1-6 알킬), C1-6 알킬, C1-6 알콕시 등의 치환기로 추가로 치환될 수 있다.In addition, the substituent is halogen; cyano; OH; amino; nitro; COOH; COO-(C 1-6 alkyl); C 1-6 alkyl optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO—(C 1-6 alkyl); C 1-6 alkyl optionally interrupted by 1-2 O; C 1-6 alkoxy optionally substituted with halogen, cyano, OH, amino, nitro, COOH or COO—(C 1-6 alkyl); C 6-12 aryl; or 5-6 membered heterocyclyl. In addition, 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.
용어 "입체이성질체"의 "이성질체(isomer)"는 분자식은 같지만 분자 내에 있는 구성 원자의 연결 방식이나 공간 배열이 동일하지 않은 화합물을 말한다. 이성질체는 예를 들면, 구조 이성질체(structural isomers), 및 입체이성질체(stereoisomer)를 포함한다. 상기 입체이성질체는 부분입체 이성질체(diastereomer) 또는 거울상 이성질체(enantiomer)일 수 있다. 거울상이성질체는 왼손과 오른손의 관계처럼 그 거울상과 겹쳐지지 않는 이성질체를 말하고, 광학 이성질체(optical isomer)라고도 한다. 거울상 이성질체는 키랄 중심 탄소에 4개 이상의 치환기가 서로 다른 경우 R(Rectus: 시계방향) 및 S(Sinister: 반시계 방향)로 구분한다. 부분입체이성질체는 거울상 관계가 아닌 입체 이성질체를 말하고, 원자의 공간 배열이 달라 생기는 이성질체이다. 상기 부분입체이성질체는 시스(cis)-트랜스(trans) 이성질체 및 형태이성질체(conformational isomer 또는 conformer) 로 나뉠 수 있다.The term "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.
용어 "용매화물(solvate)"은 유기 또는 무기 용매에 용매화된 화합물을 말한다. 상기 용매화물은 예를 들어 수화물이다.The term “solvate” refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.
용어 "염(salt)"은 화합물의 무기 및 유기산 부가염을 말한다. 상기 약학적으로 허용가능한 염은 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 염일 수 있다. 상기 무기산염은 염산염, 브롬산염, 인산염, 황산염, 또는 이황산염일 수 있다. 상기 유기산염은 포름산염, 아세트산염, 프로피온산염, 젖산염, 옥살산염, 주석산염, 말산염, 말레인산염, 구연산염, 푸마르산염, 베실산염, 캠실산염, 에디실염, 트리클로로아세트산, 트리플루오로아세트산염, 벤조산염, 글루콘산염, 메탄술폰산염, 글리콜산염, 숙신산염, 4-톨루엔술폰산염, 갈룩투론산염, 엠본산염, 글루탐산염, 에탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 또는 아스파르트산염일 수 있다. 상기 금속염은 칼슘염, 나트륨염, 마그네슘염, 스트론튬염, 또는 칼륨염일 수 있다.The term "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.
상기 화학식 1의 화합물은 아데노신 A2A 수용체에 대해 길항제일 수 있다. 상기 아데노신 A2A 수용체는 7개의 막관통 알파 나선을 갖는 G-단백질-결합 수용체(G protein-coupled receptor: GPCR)에 속하는 단백질일 수 있다. 상기 아데노신 A2A 수용체는 ADORA2A, 아데노신 A2A 수용체, A2AR, ADORA2, 또는 RDC8로도 불릴 수 있다. 상기 아데노신 A2A 수용체는 Uniprot No. P29274의 아미노산 서열을 포함하는 단백질일 수 있다.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. 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.
본 발명의 다른 양상은 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 포함하는, 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하기 위한 약학적 조성물을 제공한다.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 .
상기 화학식 1의 화합물, 입체이성질체, 용매화물, 약학적으로 허용가능한 염, 및 아데노신 A2A 수용체는 전술한 바와 같다.The compound of Formula 1, stereoisomer, solvate, pharmaceutically acceptable salt, and adenosine A2A receptor are as described above.
아데노신 A2A 수용체와 관련된 질병은 암, 염증, 겸상적혈구증 패혈증, 패혈성 쇼크, 뇌수막염, 복막염, 관절염, 용혈성 요도증후군, 녹내장, 고안압증, 및 파킨슨병으로 이루어진 군으로부터 선택된 것일 수 있다.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.
상기 암은 고형암 또는 비고형암일 수 있다. 고형암은 예를 들어 간, 폐, 유방, 피부 등 장기에 암 종양이 발생한 것을 말한다. 비고형암은 혈액 내에서 발생한 암이고, 혈액암으로도 불린다. 상기 암은 암종(carcinoma), 육종(sarcoma), 조혈세포 유래의 암, 배세포 종양(germ cell tumor), 또는 모세포종(blastoma)일 수 있다. 상기 암은 예를 들어 유방암, 피부암, 두경부암, 췌장암, 폐암, 대장암, 결장직장암, 위암, 난소암, 전립선암, 방광암, 요도암, 간암, 신장암, 투명세포 육종, 흑색종, 뇌척수종양, 뇌암, 흉선종, 중피종, 식도암, 담도암, 고환암, 생식세포종, 갑상선암, 부갑상선암, 자궁 경부암, 자궁 내막암, 림프종, 골수형성이상 증후군(myelodysplastic syndromes: MDS), 골수섬유증(myelofibrosis), 급성 백혈병, 만성 백혈병, 다발성 골수종, 호치킨병(Hodgkin's Disease), 내분비계암 및 육종으로 이루어진 군으로부터 선택된다.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.
상기 약학적 조성물은 다른 항암제를 더 포함할 수 있다. 상기 항암제는 면역항암제일 수 있다. 상기 면역항암제는 면역 체크포인트 저해제, 면역세포 치료제, 치료용 항체, 항암 백신, 또는 이들의 조합일 수 있다. 상기 면역 체크포인트 저해제는 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), 아르기나제(arginase), B7 패밀리 저해성 리간드 B7-H3, B7 패밀리 저해성 리간드 B7-H4, LAG3(lymphocyte activation gene 3), 2B4, BTLA(B and T lymphocyte attenuator), TIM3(T cell membrane protein 3), CD39 및 CD73으로 이루어진 군으로부터 선택된 하나에 대한 길항제일 수 있다. 상기 면역 체크포인트 저해제는 이필리무맙(ipilimumab), 트레멜리무맙(tremelimumab), 니보루맙(nivolumab), 펨브롤리주맙(pembrolizumab), 피딜리주맙(pidilizumab), MEDI-0680, REGN2810, AMP-224, BMS-936559/MDX-1105, MPDL3280A/RG7446/아테졸리무맙(atezolizumab), MSB0010718C/아베루맙(avelumab), 또는 MEDI4736/둘바루맙(durvalumab)일 수 있다. 상기 약학적 조성물은 단일 조성물 또는 개별적인 조성물일 수 있다. 예를 들어, 상기 화학식 1의 화합물은 경구 투여 제형의 조성물이고, 상기 항암제는 비경구 투여 제형의 조성물일 수 있다.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. For example, the compound of Formula 1 may be a composition for oral administration, and the anticancer agent may be a composition for parenteral administration.
용어 "예방"은 상기 약학적 조성물의 투여에 의해 아데노신 A2A 수용체와 관련된 질병의 발생을 억제하거나 그의 발병을 지연시키는 모든 행위를 말한다. 용어 "치료"는 상기 약학적 조성물의 투여에 의해 아데노신 A2A 수용체와 관련된 질병의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다.The term "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. The term "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.
상기 약학적 조성물은 약학적으로 허용가능한 담체를 포함할 수 있다. 상기 담체는 부형제, 희석제 또는 보조제를 포함하는 의미로 사용된다. 상기 담체는 예를 들면, 락토스, 덱스트로스, 수크로스, 소르비톨, 만니톨, 자일리톨, 에리트리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 생리식염수, PBS와 같은 완충액, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 및 미네랄 오일로 이루어진 군으로부터 선택된 것일 수 있다. 상기 조성물은 충진제, 항응집제, 윤활제, 습윤제, 풍미제, 유화제, 보존제, 또는 이들의 조합을 포함할 수 있다.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.
상기 약학적 조성물은 통상의 방법에 따라 임의의 제형으로 준비될 수 있다. 상기 조성물은 예를 들면, 경구 투여 제형(예를 들면, 분말, 정제, 캡슐, 시럽, 알약, 또는 과립), 또는 비경구 제형(예를 들면, 주사제)으로 제형화될 수 있다. 또한, 상기 조성물은 전신 제형, 또는 국부 제형으로 제조될 수 있다.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). In addition, the composition may be prepared as a systemic formulation, or as a topical formulation.
상기 약학적 조성물에 있어서, 경구 투여를 위한 고형 제제는 정제, 환제, 산제, 과립제, 또는 캡슐제일 수 있다. 상기 고형 제제는 부형제를 더 포함할 수 있다. 부형제는 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 또는 젤라틴일 수 있다. 또한, 상기 고형 제제는 마그네슘 스테아레이트, 또는 탈크와 같은 윤활제를 더 포함할 수 있다. 상기 약학적 조성물에 있어서, 경구를 위한 액상 제제는 현탁제, 내용액제, 유제, 또는 시럽제일 수 있다. 상기 액상 제제는 물, 또는 리퀴드 파라핀을 포함할 수 있다. 상기 액상 제제는 부형제, 예를 들면 습윤제, 감미제, 방향제, 또는 보존제를 포함할 수 있다. 상기 약학적 조성물에 있어서, 비경구 투여를 위한 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 또는 및 좌제일 수 있다. 비수성용제 또는 현탁제는 식물성 기름 또는 에스테르를 포함할 수 있다. 식물성 기름은 예를 들면, 프로필렌글리콜, 폴리에틸렌 글리콜, 또는 올리브 오일일 수 있다. 에스테르는 예를 들면 에틸올레이트일 수 있다. 좌제의 기제는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 또는 글리세로젤라틴일 수 있다.In the pharmaceutical composition, 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. In addition, the solid formulation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, 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. In the pharmaceutical composition, 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.
상기 약학적 조성물은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 상기 약학적 조성물의 유효 성분으로 포함한다. "유효 성분"은 약리학적 활성(예를 들면, 항암)을 달성하기 위해 사용되는 생리활성 물질을 말한다.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).
상기 약학적 조성물은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 유효한 양으로 포함할 수 있다. 용어 "유효한 양"은 예방 또는 치료를 필요로 하는 개체에게 투여되는 경우 질병의 예방 또는 치료의 효과를 나타내기에 충분한 양을 말한다. 상기 유효한 양은 당업자가 선택되는 세포 또는 개체에 따라 적절하게 선택할 수 있다. 상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 상기 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염은 예를 들면, 약 0.0001 ㎎/㎏ 내지 약 100 ㎎/㎏, 또는 약 0.001 ㎎/㎏ 내지 약 100 ㎎/㎏의 양을 1일 1회 내지 24회, 2일 내지 1주에 1 내지 7회, 또는 1개월 내지 12개월에 1 내지 24회로 나누어 투여할 수 있다. 상기 약학적 조성물에서 상기 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염은 전체 조성물 총 중량에 대하여 약 0.0001 중량% 내지 약 10 중량%, 또는 약 0.001 중량% 내지 약 1 중량%로 포함될 수 있다.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. The term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need 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. However, 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. In the pharmaceutical composition, 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
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.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.
본 발명의 다른 양상은 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 개체에게 투여하는 단계를 포함하는 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하는 방법을 제공한다.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.
상기 화학식 1의 화합물, 입체이성질체, 용매화물, 약학적으로 허용가능한 염, 아데노신 A2A 수용체와 관련된 질병, 예방, 및 치료는 전술한 바와 같다.The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, and diseases, prevention, and treatment related to adenosine A2A receptors are as described above.
상기 개체는 포유동물, 예를 들면, 인간, 마우스, 래트, 소, 말, 돼지, 개, 원숭이, 양, 염소, 유인원, 또는 고양이일 수 있다. 상기 개체는 아데노신 A2A 수용체와 관련된 질병과 연관된 증상을 앓고 있거나, 앓을 가능성이 큰 개체일 수 있다.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.
상기 방법은 상기 개체에 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하는 효과의 공지의 유효 성분을 투여하는 단계를 더 포함할 수 있다. 상기 공지의 유효 성분은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염과 동시, 개별, 또는 순차로 상기 개체에 투여될 수 있다.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.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 약학적 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.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.
상기 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 투여량은 예를 들어, 성인 기준으로 약 0.001 ㎎/kg 내지 약 100 ㎎/kg, 약 0.01 ㎎/kg 내지 약 10 ㎎/kg, 또는 약 0.1 ㎎/kg 내지 약 1 ㎎/kg의 범위 내 일 수 있다. 상기 투여는 1일 1회, 1일 다회, 또는 1주일에 1회, 2주일에 1회, 3주일에 1회, 또는 4주일에 1회 내지 1년에 1회 투여될 수 있다.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. can be 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.
본 발명의 다른 양상은 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료에 사용하기 위한, 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.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.
본 발명의 다른 양상은 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하기 위한 의약을 제조하기 위한, 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.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.
상기 아데노신 A2A 수용체와 관련된 질병, 예방, 치료, 화학식 1의 화합물, 입체이성질체, 용매화물, 및 약학적으로 허용가능한 염은 전술한 바와 같다.The adenosine A2A receptor-related diseases, prevention, and treatment, the compound of Formula 1, stereoisomers, solvates, and pharmaceutically acceptable salts are as described above.
본 발명의 화학식 1의 화합물은 아데노신 A2A 수용체에 대하여 우수한 길항 활성을 나타낸다.The compound of Formula 1 of the present invention exhibits excellent antagonistic activity against adenosine A2A receptors.
본 발명의 아데노신 A2A 수용체의 길항제, 이를 포함하는 아데노신 A2A 수용체와 관련된 질병(예컨대, 암)의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법에 의하면, 아데노신 A2A 수용체와 관련된 질병, 예를 들어 암을 효과적으로 예방 또는 치료할 수 있다.According to the adenosine A2A receptor antagonist of the present invention, a pharmaceutical composition for preventing or treating adenosine A2A receptor-related diseases (eg, cancer) 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.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, it will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
제조예 1: 메틸 3-(6-브로모피리딘-2-일)벤조에이트(화합물 A)Preparation Example 1: Methyl 3-(6-bromopyridin-2-yl)benzoate (Compound A)
Figure PCTKR2022004084-appb-I000073
Figure PCTKR2022004084-appb-I000073
3-(메톡시카르보닐)페닐보론산(3.00 g, 16.7 mmol) 및 2,6-디브로모피리딘(3.90 g, 16.7 mmol)을 H2O:1,4-디옥산(1:5, 120 mL) 중에서 교반 혼합하고, Pd(dppf)Cl2CH2Cl2(2.00 g, 2.50 mmol) 및 K2CO3(6.90 g, 50.0 mmol)를 첨가하였다. 생성된 혼합물을 질소 대기 하에 85℃에서 3시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 용액을 감압 농축시켰다. 혼합물을 PE/EtOAc(1:1)로 용출시켜 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(6-브로모피리딘-2-일)벤조에이트(화합물 A; 1.7 g, 32.1%)를 황백색(off-white) 고체로서 수득하였다. MS m/z: 292 [M+H]+.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. The mixture was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give methyl 3-(6-bromopyridin-2-yl)benzoate (Compound A; 1.7 g, 32.1%) off-white (off). -white) as a solid. MS m/z: 292 [M+H] + .
제조예 2: 2-브로모-6-[(2-메톡시에톡시)메틸]피리딘(화합물 B)Preparation 2: 2-Bromo-6-[(2-methoxyethoxy)methyl]pyridine (Compound B)
Figure PCTKR2022004084-appb-I000074
Figure PCTKR2022004084-appb-I000074
DMF(8.00 mL) 중에 교반된 2-메톡시에탄올(303 mg, 3.98 mmol) 용액에 NaH(159 mg, 3.98 mmol, 미네랄 오일 중 60% 분산)를 질소 대기하에 0℃에서 나누어 첨가하였다. 생성된 혼합물을 질소 대기하에 0℃에서 30분 동안 교반하였다. 상기 혼합물에 2-브로모-6-(브로모메틸)피리딘(500 mg, 1.99 mmol)을 0℃에서 첨가하였다. 생성된 혼합물을 25℃에서 추가로 1시간 동안 교반하였다. 반응을 물(25.0 mL)로 퀀칭시켰다. 생성된 혼합물을 EtOAc(3 x 25.0 mL)로 추출하였다. 유기층을 모아서 염수(3 x 25.0 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하였다. 잔사를 PE/EtOAc(1:1)로 용출시켜 실리카겔 컬럼 크로마토그래피로 정제하여 2-브로모-6-[(2-메톡시에톡시)메틸]피리딘(화합물 B; 300 mg, 58.1%)을 황백색 오일로 수득하였다. MS m/z: 246/248 [M+H]+.To a stirred solution of 2-methoxyethanol (303 mg, 3.98 mmol) in DMF (8.00 mL) was added NaH (159 mg, 3.98 mmol, 60% dispersion in mineral oil) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 min under a nitrogen atmosphere. To the mixture was added 2-bromo-6-(bromomethyl)pyridine (500 mg, 1.99 mmol) at 0°C. The resulting mixture was stirred at 25° C. for an additional 1 h. The reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL). The combined organic layers were washed with brine (3 x 25.0 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 2-bromo-6-[(2-methoxyethoxy)methyl]pyridine (Compound B; 300 mg, 58.1%). It was obtained as an off-white oil. MS m/z: 246/248 [M+H] + .
제조예 3: 1-(6-브로모피리딘-2-일)피롤리딘-3-올(화합물 C)Preparation 3: 1- (6-bromopyridin-2-yl) pyrrolidin-3-ol (Compound C)
Figure PCTKR2022004084-appb-I000075
Figure PCTKR2022004084-appb-I000075
2,6-디브로모피리딘(2.00 g, 8.44 mmol) 및 피롤리딘-3-올 하이드로클로라이드(1.10 g, 9.28 mmol)를 THF(30.0mL) 중에 교반 혼합하고, DBU(3.80 g, 25.3 mmol)를 첨가하였다. 생성된 혼합물을 70℃에서 2시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 혼합물을 감압 농축시키고, PE/EtOAc(2:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-(6-브로모피리딘-2-일)피롤리딘-3-올(화합물 C; 1.00 g, 48.3%)을 황색 고체로 수득하였다. 1H-NMR(CDCl3, 400 MHz) δ(ppm): 7.29-7.27(m, 1H), 6.68(d, J = 8.0 Hz, 1H), 6.28(d, J = 8.0 Hz, 1H), 4.64-4.60(m, 1H), 3.65-3.52(m, 4H), 2.18-2.08(m, 2H); MS m/z: 243/245 [M+H]+.2,6-dibromopyridine (2.00 g, 8.44 mmol) and pyrrolidin-3-ol hydrochloride (1.10 g, 9.28 mmol) were stirred mixed in THF (30.0 mL) and DBU (3.80 g, 25.3 mmol) ) was added. The resulting mixture was stirred at 70° C. for 2 h, and the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure, eluted with PE/EtOAc (2:1), and purified by silica gel column chromatography to obtain 1-(6-bromopyridin-2-yl)pyrrolidin-3-ol (Compound C; 1.00 g). , 48.3%) as a yellow solid. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 7.29-7.27 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.64 -4.60 (m, 1H), 3.65-3.52 (m, 4H), 2.18-2.08 (m, 2H); MS m/z: 243/245 [M+H] + .
제조예 4: 메틸 2-(3-브로모-4-플루오로페닐)-2-메틸프로파노에이트(화합물 D)Preparation 4: Methyl 2- (3-bromo-4-fluorophenyl) -2-methylpropanoate (Compound D)
Figure PCTKR2022004084-appb-I000076
Figure PCTKR2022004084-appb-I000076
단계 1: 메틸 2-(3-브로모-4-플루오로페닐)아세테이트의 합성Step 1: Synthesis of methyl 2-(3-bromo-4-fluorophenyl)acetate
MeOH(50 mL) 중에 교반된 (3-브로모-4-플루오로페닐)아세트산(5.00 g, 21.5 mmol)의 혼합물에 SOCl2(4.00 g, 33.6 mmol)를 0℃에서 첨가하였다. 생성된 혼합물을 질소 대기하에 85℃에서 3시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 반응을 NaHCO3 수용액으로 퀀칭시켰다. 혼합물을 물(500 mL)에 붓고 에틸 아세테이트(500 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 2-(3-브로모-4-플루오로페닐)아세테이트(4.00 g, 68.7%)를 황색 고체로서 수득하였다.To a mixture of (3-bromo-4-fluorophenyl)acetic acid (5.00 g, 21.5 mmol) stirred in MeOH (50 mL) was added SOCl 2 (4.00 g, 33.6 mmol) at 0 °C. The resulting mixture was stirred at 85[deg.] C. under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and the reaction was quenched with aqueous NaHCO 3 solution. The mixture was poured into water (500 mL), extracted with ethyl acetate (500 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography, followed by methyl 2-(3-bromo-4-fluorophenyl)acetate (4.00 g, 68.7%). ) as a yellow solid.
단계 2: 메틸 2-(3-브로모-4-플루오로페닐)-2-메틸프로파노에이트(화합물 D)의 합성Step 2: Synthesis of methyl 2-(3-bromo-4-fluorophenyl)-2-methylpropanoate (compound D)
상기 단계 1에서 수득된 화합물(4.00 g, 16.2 mmol)을 DMF(30.0 mL) 중에 교반하여 혼합하고 NaH(777 mg, 32.4 mmol, 미네랄 오일 중 60% 분산)를 0℃에서 첨가하였다. 생성된 혼합물을 0℃에서 30분 동안 교반하고, 0℃에서 MeI(4.60 g, 32.4 mmol)를 첨가하였다. 생성된 혼합물을 질소 대기하에 25℃에서 3시간 동안 교반하고, 0℃에서 물/얼음으로 반응을 퀀칭시켰다. 혼합물을 물(500 mL)에 첨가하고 에틸 아세테이트(500 mL)로 추출하고, 유기층을 모아서 염수(2 x 500 mL)로 세척한 후 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 2-(3-브로모-4-플루오로페닐)-2-메틸프로파노에이트(화합물 D; 3.00 g, 57.3%)를 무색 오일로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm):7.59-7.52(m, 1H), 7.36-7.29(m, 2H), 3.58(s, 3H), 1.48(s, 6H).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. The mixture was added to water (500 mL) and extracted with ethyl acetate (500 mL), and the combined organic layers were washed with brine (2×500 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (10:1) and purified by silica gel column chromatography, followed by methyl 2-(3-bromo-4-fluorophenyl)-2-methylpropanoate. (Compound D; 3.00 g, 57.3%) was obtained as a colorless oil. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 7.59-7.52 (m, 1H), 7.36-7.29 (m, 2H), 3.58 (s, 3H), 1.48 (s, 6H).
제조예 5: 2-[2-[(3-브로모-5-메틸페닐)메톡시]에톡시]옥산(화합물 E)Preparation 5: 2- [2- [(3-bromo-5-methylphenyl) methoxy] ethoxy] oxane (Compound E)
Figure PCTKR2022004084-appb-I000077
Figure PCTKR2022004084-appb-I000077
DMF(10.0 mL) 중에 교반된 (3-브로모-5-메틸페닐)메탄올(1.00 g, 4.97 mmol)의 혼합물에 NaH(300 mg, 7.50 mmol, 미네랄 오일 중 60% 분산)를 0℃에서 첨가하였다. 생성된 혼합물을 질소 대기하에 0℃에서 30분 동안 교반하였다. 상기 혼합물에 2-(2-브로모에톡시)옥산(1.00 g, 4.78 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기하에 실온에서 3시간 동안 교반하였다. 반응을 물/얼음(90.0 mL)으로 퀀칭시켰다. 생성된 혼합물을 EtOAc(90.0 mL)로 추출하고, 유기층을 모아서 염수(2 x 80.0 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(5:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-[2-[(3-브로모-5-메틸페닐)메톡시]에톡시]옥산(화합물 E; 660 mg, 37.5%)을 무색 고체로 수득하였다.To a mixture of (3-bromo-5-methylphenyl)methanol (1.00 g, 4.97 mmol) stirred in DMF (10.0 mL) was added NaH (300 mg, 7.50 mmol, 60% dispersion in mineral oil) at 0 °C. . The resulting mixture was stirred at 0° C. for 30 min under a nitrogen atmosphere. To the mixture was added 2-(2-bromoethoxy)oxane (1.00 g, 4.78 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction was quenched with water/ice (90.0 mL). The resulting mixture was extracted with EtOAc (90.0 mL), and the combined organic layers were washed with brine (2×80.0 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (5:1) and purified by silica gel column chromatography to 2-[2-[(3-bromo-5-methylphenyl)methoxy]ethoxy] Oxane (compound E; 660 mg, 37.5%) was obtained as a colorless solid.
제조예 6: 2-클로로-N-페닐아세트아미드(화합물 F)Preparation 6: 2-Chloro-N-phenylacetamide (Compound F)
Figure PCTKR2022004084-appb-I000078
Figure PCTKR2022004084-appb-I000078
아닐린(1.00 g, 10.7 mmol) 및 TEA(3.26 g, 32.2 mmol)를 DCM(10.0 mL) 중에 교반하여 혼합하고, 클로로아세틸 클로라이드(2.43 g, 21.5 mmol)를 질소 대기하에 0℃에서 첨가하였다. 생성된 혼합물을 질소 대기하에 25℃에서 1시간 동안 교반하고, 반응을 물(50 mL)로 퀀칭하였다. 생성된 혼합물을 CH2Cl2(3 x 50.0 mL)로 추출하고 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-N-페닐아세트아미드(화합물 F; 700 mg, 36.5%)를 황색 고체로 수득하였다. MS m/z: 170 [M+H]+.Aniline (1.00 g, 10.7 mmol) and TEA (3.26 g, 32.2 mmol) were stirred and mixed in DCM (10.0 mL) and chloroacetyl chloride (2.43 g, 21.5 mmol) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under nitrogen atmosphere at 25° C. for 1 h, and the reaction was quenched with water (50 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 50.0 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 2-chloro-N-phenylacetamide (Compound F; 700 mg, 36.5%) as a yellow solid. was obtained with MS m/z: 170 [M+H] + .
제조예 7: 2-클로로-1-(4-페닐피페라진-1-일)에탄온(화합물 G)Preparation 7: 2-Chloro-1- (4-phenylpiperazin-1-yl) ethanone (Compound G)
Figure PCTKR2022004084-appb-I000079
Figure PCTKR2022004084-appb-I000079
페닐피페라진(1.00 g, 6.16 mmol) 및 TEA(1.87 g, 18.5 mmol)을 DCM(15.0 mL)에 교반하여 혼합한 후, 클로로아세틸 클로라이드(1.04 g, 9.24 mmol)를 질소 대기하에 0℃에서 적가하였다. 생성된 혼합물을 질소 대기하에 25℃에서 1시간 동안 교반하고, 반응을 물(50.0 mL)로 퀀칭하였다. 생성된 혼합물을 CH2Cl2(2 x 50.0 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-1-(4-페닐피페라진-1-일)에탄온(화합물 G; 700 mg, 45.2%)을 담황색 고체로 수득하였다. MS m/z: 239 [M+H]+.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 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography, followed by 2-chloro-1-(4-phenylpiperazin-1-yl)ethanone (Compound G). ; 700 mg, 45.2%) as a pale yellow solid. MS m/z: 239 [M+H] + .
제조예 8: 5-브로모-6-클로로-2-(메틸설파닐)피리미딘-4-아민(화합물 H) Preparation 8: 5-bromo-6-chloro-2- (methylsulfanyl) pyrimidin-4-amine (Compound H)
Figure PCTKR2022004084-appb-I000080
Figure PCTKR2022004084-appb-I000080
DCM(500 mL) 중에 교반된 6-클로로-2-(메틸설파닐)피리미딘-4-아민(35.0 g, 199 mmol) 혼합물에 NBS(53.0 g, 299 mmol)를 첨가하였다. 생성된 혼합물을 25℃에서 2시간 동안 교반하였다. 생성된 혼합물을 여과하고, 필터 케이크를 수집하고, DCM(3 x 800 mL)으로 세척하여 5-브로모-6-클로로-2-(메틸설파닐)피리미딘-4-아민(화합물 H; 28.0g, 52.0%)을 백색 고체로 수득하였다. MS m/z: 254 [M+H]+.To a mixture of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (35.0 g, 199 mmol) stirred in DCM (500 mL) was added NBS (53.0 g, 299 mmol). The resulting mixture was stirred at 25° C. for 2 h. The resulting mixture was filtered, the filter cake was collected and washed with DCM (3 x 800 mL) to 5-bromo-6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (Compound H; 28.0). g, 52.0%) as a white solid. MS m/z: 254 [M+H] + .
제조예 9: 6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-아민(화합물 I)Preparation 9: 6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-amine (Compound I)
Figure PCTKR2022004084-appb-I000081
Figure PCTKR2022004084-appb-I000081
디옥산(300 mL) 및 H2O(60.0 mL) 중에 6-클로로-2-(메틸설파닐)피리미딘-4-아민(10.0 g, 56.9 mmol) 및 퓨란-2-일 보론산(12.7 g, 114 mmol)을 교반하여 혼합하고, Pd(dppf)Cl2(4.10 g, 5.69 mmol) 및 Cs2CO3(55.6 g, 171 mmol)을 첨가하였다. 질소 대기하에 85℃에서 3시간 동안 교반한 후, 혼합물을 실온으로 냉각시키고, 용액을 부분적으로 감압 농축시켰다. 혼합물을 EtOAc(3 x 500 mL)로 추출하고, 무수 Na2SO4로 건조하고, 감압 농축하였다. 혼합물을 PE/EtOAc(5:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-아민(화합물 I; 4.10 g, 33.4%)을 황백색 고체로서 수득하였다. 1H-NMR(300 MHz, DMSO-d6) δ(ppm): 7.86-7.85(m, 1H), 7.09-7.08(m, 1H), 7.04(s, 2H), 6.66-6.61(m, 1H), 6.45(s, 1H), 2.45(s, 3H); MS m/z: 208 [M+H]+.6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (10.0 g, 56.9 mmol) and furan-2-yl boronic acid (12.7 g) in dioxane (300 mL) and H 2 O (60.0 mL) , 114 mmol) were stirred to mix, and Pd(dppf)Cl 2 (4.10 g, 5.69 mmol) and Cs 2 CO 3 (55.6 g, 171 mmol) were added. After stirring under a nitrogen atmosphere at 85° C. for 3 hours, the mixture was cooled to room temperature, and the solution was partially concentrated under reduced pressure. The mixture was extracted with EtOAc (3 x 500 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1), to obtain 6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-amine (compound I; 4.10 g, 33.4%) as an off-white solid. 1 H-NMR (300 MHz, DMSO-d 6 ) δ (ppm): 7.86-7.85 (m, 1H), 7.09-7.08 (m, 1H), 7.04 (s, 2H), 6.66-6.61 (m, 1H) ), 6.45(s, 1H), 2.45(s, 3H); MS m/z: 208 [M+H] + .
제조예 10: 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1,2,3-벤조트리아졸(화합물 J)Preparation 10: 1- (2,6-dichloropyrimidin-4-yl) -5-methoxy-1,2,3-benzotriazole (Compound J)
Figure PCTKR2022004084-appb-I000082
Figure PCTKR2022004084-appb-I000082
단계 1: 2,6-디클로로-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민의 합성Step 1: Synthesis of 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine
질소 분위기 하에 0℃에서 THF (3L) 중에 교반 혼합된 2,6-디클로로피리미딘-4-아민 (90g, 548.81 mmol, 1.00당량)에 NaH (15.8g, 658.57 mmol, 1.2당량, 60%)을 나누어 첨가하였다. 질소 분위기 하에 0℃에서 1시간 동안 생성된 혼합물을 교반하였다. 0℃에서 상기 혼합물에 1-플루오로-4-메톡시-2-니트로벤젠 (84.5g, 493.93 mmol, 0.9당량)을 첨가하였다. 추가로 16시간 동안 25℃에서 생성된 혼합물을 교반하였다. 실온에서 물 (500 mL)를 첨가하여 반응을 퀀칭(quench)시키고, 생성된 혼합물을 EtOAc (3 x 2 L)로 추출하고 무수 Na2SO4 상에서 건조시킨 후, 감압 농축하였다. 침전된 고체를 여과 수집하고 헥산 (3 x 1.5 L)로 세척하였다. 생성된 고체를 적외선 하에 건조하여, 2,6-디클로로-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민 (110g, 34.79%)을 적색 고체로서 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm):10.27 (s, 1H), 7.56-7.50 (m, 2H), 7.36-7.33 (m, 1H), 6.77 (s, 1H), 3.85 (s, 3H); MS m/z: 315 [M+H]+.NaH (15.8 g, 658.57 mmol, 1.2 equiv, 60%) to 2,6-dichloropyrimidin-4-amine (90 g, 548.81 mmol, 1.00 equiv) stirred and mixed in THF (3 L) at 0 °C under nitrogen atmosphere were added in portions. The resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. To the mixture at 0° C. was added 1-fluoro-4-methoxy-2-nitrobenzene (84.5 g, 493.93 mmol, 0.9 equiv). The resulting mixture was stirred at 25° C. for an additional 16 h. The reaction was quenched by addition of water (500 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 x 2 L), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexanes (3 x 1.5 L). The resulting solid was dried under infrared to give 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (110 g, 34.79%) as a red solid. 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 10.27 (s, 1H), 7.56-7.50 (m, 2H), 7.36-7.33 (m, 1H), 6.77 (s, 1H), 3.85 (s, 3H); MS m/z: 315 [M+H] + .
단계 2: N1-(2,6-디클로로피리미딘-4-일)-4-메톡시벤젠-1,2-디아민의 합성Step 2: Synthesis of N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine
단계 1에서 수득된 화합물 (110g, 190.94 mmol, 1.00당량, 54.7%) 및 Fe (53g, 954.74 mmol, 5.00당량)을 EtOH (1.5 L) 및 H2O (300 mL) 중에서 교반 혼합하고, NH4Cl (30g, 572.84 mmol, 3.00당량)을 첨가하였다. 혼합물을 16시간 동안 80℃에서 교반하고, 실온으로 냉각시켰다. 생성된 혼합물을 여과한 후, 필터 케이크를 EtOAc (3 x 700 mL)로 세척하고, 여액을 감압 농축시켜서 N1-(2,6-디클로로피리미딘-4-일)-4-메톡시벤젠-1,2-디아민(90g, 94.22%)를 적색 고체로서 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 6.14 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 5.12 (s, 2H), 3.66 (s, 3H); MS m/z: 285 [M+H]+.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. After filtration of the resulting mixture, the filter cake was washed with EtOAc (3 x 700 mL), and the filtrate was concentrated under reduced pressure to N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1 ,2-diamine (90 g, 94.22%) was obtained as a red solid. 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 6.14 (d, J = 8.0) Hz, 1H), 5.87 (s, 1H), 5.12 (s, 2H), 3.66 (s, 3H); MS m/z: 285 [M+H] + .
단계 3: 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1,2,3-벤조트리아졸(화합물 J)의 합성Step 3: Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1,2,3-benzotriazole (Compound J)
단계 2에서 수득된 화합물 (90.0g, 179.91 mmol, 1.00당량, 57%)를 0℃에서 AcOH (1.2 L) 및 H2O (400 mL) 중에서 교반 혼합하고, NaNO2 (13.6g, 197.91 mmol, 1.10당량)을 나누어 첨가하였다. 생성된 혼합물을 25℃에서 30분 동안 교반하였다. 실온에서 물 (800 mL)를 첨가하여 반응을 퀀칭시키고, 침전된 고체를 여과하여 수집한 후 HCL (4 M, 3 x 1.0 L)로 세척하여, 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1,2,3-벤조트리아졸 (화합물 J; 40g, 44.22%)을 갈색 고체로서 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.39 (s, 1H), 8.27-8.25 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); MS m/z: 296 [M+H]+ . 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. The reaction was quenched by addition of water (800 mL) at room temperature, the precipitated solid was collected by filtration and washed with HCL (4 M, 3 x 1.0 L), 1-(2,6-dichloropyrimidine-4) -yl)-5-methoxy-1,2,3-benzotriazole (Compound J; 40 g, 44.22%) was obtained as a brown solid. 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.39 (s, 1H), 8.27-8.25 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J) = 8.8 Hz, 1H), 3.88 (s, 3H); MS m/z: 296 [M+H] + .
제조예 11: 2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-아민(화합물 K)Preparation 11: 2-Chloro-6- (3,3-difluorocyclobutyl) pyrimidin-4-amine (Compound K)
Figure PCTKR2022004084-appb-I000083
Figure PCTKR2022004084-appb-I000083
단계 1: 2,4-디클로로-6-(3,3-디플루오로사이클로부틸)피리미딘의 합성Step 1: Synthesis of 2,4-dichloro-6-(3,3-difluorocyclobutyl)pyrimidine
2,4-디클로로피리미딘 (50g, 335.63 mmol, 1.00당량) 및 3,3-디플루오로사이클로부탄-1-카복실산 (36.5g, 268.51 mmol, 0.8당량)을 CH3CN (400 mL) 및 H2O (400 mL) 중에 교반 혼합하고, (NH4)2S2O8 (61.2g, 268.51 mmol, 0.8당량) 및 AgNO3 (9.1g, 53.70 mmol, 0.16당량)을 첨가하였다. 생성된 혼합물을 80℃에서 16시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 여과하여 필터 케이크를 DCM (3 x 300 mL)으로 세척하였다. 여액을 부분적으로 감압 농축시켰다. 혼합물을 CH2Cl2 (3 x 400 mL)로 추출하고, 무수 Na2SO4로 건조하고 감압 농축했다. 잔사를 PE/EtOAc (5:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2,4-디클로로-6-(3,3-디플루오로사이클로부틸)피리미딘 (7.9g, 9.55%)을 연녹색 오일로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.78 (s, 1H), 3.61-3.50 (m, 1H), 3.00-2.82 (m, 4H).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. The mixture was cooled to room temperature, filtered and the filter cake was washed with DCM (3×300 mL). The filtrate was partially concentrated under reduced pressure. The mixture was extracted with CH 2 Cl 2 (3×400 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 2,4-dichloro-6-(3,3-difluorocyclobutyl)pyrimidine (7.9 g, 9.55%) light green obtained as an oil. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.78 (s, 1H), 3.61-3.50 (m, 1H), 3.00-2.82 (m, 4H).
단계 2: 2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-아민(화합물 K)의 합성Step 2: Synthesis of 2-chloro-6- (3,3-difluorocyclobutyl) pyrimidin-4-amine (compound K)
단계 1에서 수득된 화합물 (7.9g, 33.04 mmol, 1.00당량) 및 NH3 (g)을 MeOH (7 M, 20 mL) 및 EtOH (20 mL) 중에서 질소 대기하에 80℃에서 5시간 동안 교반 혼합하였다. 혼합물을 실온으로 냉각시킨 후, 감압 농축시키고, 잔사를 PE/EtOAc (2:1)로 용출시켜 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-아민 (화합물 K; 2.3g, 30.55%)을 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.37 (s, 2H), 6.28 (s, 1H), 3.28-3.25 (m, 1H), 2.85-2.69 (m, 4H); MS m/z: 220 [M+H]+ . 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. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.37 (s, 2H), 6.28 (s, 1H), 3.28-3.25 (m, 1H), 2.85-2.69 (m, 4H); MS m/z: 220 [M+H] + .
실시예 1: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-01)Example 1: 1- [2-amino-6- (furan-2-yl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-5-ol (Ex-01)
Figure PCTKR2022004084-appb-I000084
Figure PCTKR2022004084-appb-I000084
화합물(Ex-01)을 하기 반응식 1에 따라서 합성하였다.Compound (Ex-01) was synthesized according to Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2022004084-appb-I000085
Figure PCTKR2022004084-appb-I000085
Figure PCTKR2022004084-appb-I000086
Figure PCTKR2022004084-appb-I000086
Figure PCTKR2022004084-appb-I000087
Figure PCTKR2022004084-appb-I000087
단계 1: 2,6-디클로로-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민의 합성Step 1: Synthesis of 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine
DMF(10.0 mL) 중의 2,6-디클로로피리미딘-4-아민(1.00 g, 6.10 mmol) 및 1-플루오로-4-메톡시-2-니트로벤젠(869 mg, 5.08 mmol) 용액에 0℃에서 NaH(406 mg, 10.2 mmol, 미네랄 오일 중 60% 분산)를 첨가하였다. 혼합물을 25℃에서 3 시간 동안 교반하였다. 혼합물을 물(50.0 mL) 및 에틸 아세테이트(70.0 mL)에 첨가하고, 유기층을 분리하여 포화 염수(60.0 mL)로 세척하고, Na2SO4로 건조하고, 여과하고, 농축하여 조 생성물을 수득하였다. 생성물을 실리카겔 컬럼 크로마토그래피로 정제하였다(석유 에테르:EtOAc = 100:1 - 5:1). 2,6-디클로로-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민(800 mg, 2.54 mmol, 50.0% 수율)을 적색 고체로 수득하였다. 1H NMR(400 MHz, DMSO-d6) δ 11.15 - 9.17(m, 1H), 7.58(d, J = 2.9 Hz, 1H), 7.53(d, J = 8.9 Hz, 1H), 7.37(dd, J = 2.9, 8.9 Hz, 1H), 6.78(s, 1H), 3.96 - 3.82(m, 3H); MS m/z: 315.0 [M+H]+.To a solution of 2,6-dichloropyrimidin-4-amine (1.00 g, 6.10 mmol) and 1-fluoro-4-methoxy-2-nitrobenzene (869 mg, 5.08 mmol) in DMF (10.0 mL) at 0 °C NaH (406 mg, 10.2 mmol, 60% dispersion in mineral oil) was added. The mixture was stirred at 25° C. for 3 hours. The mixture was added to water (50.0 mL) and ethyl acetate (70.0 mL), and the organic layer was separated, washed with saturated brine (60.0 mL), dried over Na 2 SO 4 , filtered and concentrated to give the crude product. . The product was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 - 5:1). 2,6-Dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (800 mg, 2.54 mmol, 50.0% yield) was obtained as a red solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.15 - 9.17 (m, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.37 (dd, J = 2.9, 8.9 Hz, 1H), 6.78 (s, 1H), 3.96 - 3.82 (m, 3H); MS m/z: 315.0 [M+H] + .
단계 2: N1-(2,6-디클로로피리미딘-4-일)-4-메톡시벤젠-1,2-디아민의 합성Step 2: Synthesis of N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine
단계 1에서 수득된 화합물(400 mg, 1.27 mmol)의 EtOH(20.0 mL) 용액에 Fe(708 mg, 12.7 mmol) 및 NH4Cl(203 mg, 3.81 mmol)을 첨가하였다. 혼합물을 70℃에서 2시간 동안 교반하였다. 혼합물을 여과하고, 케이크를 수집하여 진공에서 건조시켰다. 정제 없이 N1-(2,6-디클로로피리미딘-4-일)-4-메톡시벤젠-1,2-디아민(500 mg, 조 생성물)을 회색 고체로 수득하였다. MS m/z: 315.0 [M+H]+.To a solution of the compound (400 mg, 1.27 mmol) obtained in step 1 in EtOH (20.0 mL) was added Fe (708 mg, 12.7 mmol) and NH 4 Cl (203 mg, 3.81 mmol). The mixture was stirred at 70° C. for 2 h. The mixture was filtered and the cake was collected and dried in vacuo. N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine (500 mg, crude product) was obtained as a gray solid without purification. MS m/z: 315.0 [M+H] + .
단계 3: 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1H-벤조[d][1,2,3]트리아졸의 합성Step 3: Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole
단계 2에서 수득된 화합물(500 mg, 1.75 mmol)의 AcOH(12.0 mL) 및 conc. HCl(3.00 mL) 중의 용액에 0℃에서 NaNO2(133 mg, 1.93 mmol)를 첨가하고, 혼합물을 25℃에서 2시간 동안 교반하였다. 혼합물을 여과하고, 케이크를 수집하고, 진공에서 건조시켰다. 정제 없이 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1H-벤조[d][1,2,3]트리아졸(250 mg, 844 μmol, 48.2% 수율)을 백색 고체로 수득하였다. MS m/z: 296 [M+H]+.AcOH (12.0 mL) of the compound obtained in step 2 (500 mg, 1.75 mmol) and conc. To a solution in HCl (3.00 mL) at 0° C. was added NaNO 2 (133 mg, 1.93 mmol) and the mixture was stirred at 25° C. for 2 h. The mixture was filtered and the cake was collected and dried in vacuo. 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole (250 mg, 844 μmol, 48.2% yield) without purification It was obtained as a white solid. MS m/z: 296 [M+H] + .
단계 4: 1-(2-클로로-6-(퓨란-2-일)피리미딘-4-일)-5-메톡시-1H-벤조[d][1,2,3]트리아졸의 합성Step 4: Synthesis of 1-(2-chloro-6-(furan-2-yl)pyrimidin-4-yl)-5-methoxy-1H-benzo[d][1,2,3]triazole
단계 3에서 수득된 화합물(144 mg, 742 μmol) 및 2-(퓨란-2-일)-4,4,5,5-테트라메틸-1,3,2-디옥사보로란(200 mg, 675 μmol)의 디옥산(10.0 mL) 및 H2O(2.00 mL) 중의 용액에 K2CO3(186 mg, 1.35 mmol) 및 Pd(dppf)Cl2(24.7 mg, 33.7 μmol)를 첨가하고, 혼합물을 80℃에서 2시간 동안 교반하였다. 혼합물을 물(40.0 mL) 및 에틸 아세테이트(40.0 mL)에 첨가하고, 유기층을 분리하고, 포화 염수(40.0 mL)로 세척하고, Na2SO4로 건조시킨 후 여과 농축하여 조 생성물을 수득하였다. 생성물을 실리카겔 컬럼 크로마토그래피로 정제하여(석유 에테르: EtOAc = 100:1 - 5:1), 1-(2-클로로-6-(퓨란-2-일)피리미딘-4-일)-5-메톡시-1H-벤조[d][1,2,3]트리아졸(150 mg, 457 μmol, 67.8% 수율)을 백색 고체로 수득하였다. MS m/z: 328.1 [M+H]+.The compound obtained in step 3 (144 mg, 742 μmol) and 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, To a solution of 675 μmol) 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 μmol), The mixture was stirred at 80° C. for 2 h. The mixture was added to water (40.0 mL) and ethyl acetate (40.0 mL), the organic layer was separated, washed with saturated brine (40.0 mL), dried over Na 2 SO 4 , filtered and concentrated to give the crude product. The product was purified by silica gel column chromatography (petroleum ether: EtOAc = 100:1 - 5:1), 1-(2-chloro-6-(furan-2-yl)pyrimidin-4-yl)-5- Methoxy-1H-benzo[d][1,2,3]triazole (150 mg, 457 μmol, 67.8% yield) was obtained as a white solid. MS m/z: 328.1 [M+H] + .
단계 5: 4-(퓨란-2-일)-6-(5-메톡시-1H-벤조[d][1,2,3]트리아졸-1-일)피리미딘-2-아민의 합성Step 5: Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyrimidin-2-amine
단계 4에서 수득된 화합물(140 mg, 427 μmol)의 EtOH(200 μL) 용액에 NH3·H2O(1.50 g, 8.54 mmol, 1.65 mL, 20% 순도)를 첨가하였다. 혼합물을 90℃에서 12시간 동안 교반하였다. 혼합물을 농축하여 잔사를 수득하였다. 정제 없이 4-(퓨란-2-일)-6-(5-메톡시-1H-벤조[d][1,2,3]트리아졸-1-일)피리미딘-2-아민(130 mg, 421 μmol, 98.7% 수율)을 백색 고체로 수득하였다. MS m/z: 309.2 [M+H]+.To a solution of the compound obtained in step 4 (140 mg, 427 μmol) in EtOH (200 μL) was added NH 3 ·H 2 O (1.50 g, 8.54 mmol, 1.65 mL, 20% purity). The mixture was stirred at 90° C. for 12 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 μmol, 98.7% yield) was obtained as a white solid. MS m/z: 309.2 [M+H] + .
단계 6: 1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-벤조[d][1,2,3]트리아 졸-5-올(Ex-01)의 합성Step 6: 1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-ol (Ex-01 ) synthesis
단계 5에서 수득된 화합물(120 mg, 389 μmol)의 DCM(1.00 mL) 용액에 BBr3(292 mg, 1.17 mmol, 112 μL)를 첨가하고, 혼합물을 -78℃에서 5시간 동안 교반하고 25℃로 상승하도록 두었다. 혼합물을 농축하여 잔사를 수득하였다. 조 생성물을 역상 HPLC(0.1% HCl 조건)로 정제하였다. 1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-벤조[d][1,2,3]트리아졸-5-올(Ex-01; 5.00 mg, 16.5 μmol, 4.24% 수율, 97.1% 순도)를 백색 고체로 수득하였다. 1H NMR(400 MHz DMSO-d6) δ 8.63(d, J = 8.9 Hz, 1H), 7.98(s, 1H), 7.61(s, 1H), 7.36(d, J = 1.9 Hz, 1H), 7.33(d, J = 3.4 Hz, 1H), 7.29(s, 2H), 7.23(d, J = 2.1, 9.0 Hz, 1H); MS m/z: 295.1 [M+H]+. To a DCM (1.00 mL) solution of the compound (120 mg, 389 μmol) obtained in step 5 was added BBr 3 (292 mg, 1.17 mmol, 112 μL), and the mixture was stirred at -78°C for 5 hours and at 25°C allowed to rise to The mixture was concentrated to give a residue. The crude product was purified by reverse phase HPLC (0.1% HCl conditions). 1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-ol (Ex-01; 5.00 mg , 16.5 μmol, 4.24% yield, 97.1% purity) as a white solid. 1 H NMR (400 MHz DMSO-d 6 ) δ 8.63 (d, J = 8.9 Hz, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H), 7.29 (s, 2H), 7.23 (d, J = 2.1, 9.0 Hz, 1H); MS m/z: 295.1 [M+H] + .
실시예 2: 2-[6-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]프로판-2-올(Ex-02)Example 2: 2-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl) }oxy)pyridin-2-yl]propan-2-ol (Ex-02)
Figure PCTKR2022004084-appb-I000088
Figure PCTKR2022004084-appb-I000088
화합물(Ex-02)을 하기 반응식 2에 따라서 합성하였다.Compound (Ex-02) was synthesized according to Scheme 2 below.
[반응식 2][Scheme 2]
Figure PCTKR2022004084-appb-I000089
Figure PCTKR2022004084-appb-I000089
단계 1: 2,6-디클로로-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민의 합성Step 1: Synthesis of 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine
질소 대기 하에 0℃에서 THF(700 mL) 중에 교반 혼합된 2,6-디클로로피리미딘-4-아민(34.0 g, 207 mmol)에 NaH(6.47 g, 162 mmol, 미네랄 오일 중 60% 분산)을 나누어 첨가하였다. 생성된 혼합물을 질소 대기 하에 0℃에서 30분간 교반하였다. 0℃에서 상기 혼합물에 1-플루오로-4-메톡시-2-니트로벤젠(48.5 g, 270 mmol)을 나누어 첨가하였다. 추가로 16시간 동안 실온에서 생성된 혼합물을 교반하였다. 실온에서 물(500 mL)를 첨가하여 반응을 퀀칭시키고, 생성된 혼합물을 EtOAc(3 x 1000 mL)로 추출하였다. 유기층을 모아서 염수(3 x 500 mL)로 세척하고, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시켰다. 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카 겔 컬럼 크로마토그래피로 정제하여 2,6-디클로로-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민(22 g, 30%)을 적색 고체로서 수득하였다. 1H NMR(DMSO-d6, 400 MHz) δ 10.3(s, 1H), 7.56-7.50(m, 2H), 7.36-7.33(m, 1H), 6.77(s, 1H), 3.85(s, 3H); MS m/z: 315 [M+H]+.NaH (6.47 g, 162 mmol, 60% dispersion in mineral oil) was stirred and mixed 2,6-dichloropyrimidin-4-amine (34.0 g, 207 mmol) in THF (700 mL) at 0 °C under a nitrogen atmosphere. were added in portions. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the mixture at 0° C., 1-fluoro-4-methoxy-2-nitrobenzene (48.5 g, 270 mmol) was added in portions. The resulting mixture was stirred at room temperature for an additional 16 h. The reaction was quenched by addition of water (500 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 1000 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 2,6-dichloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (22 g, 30%) as a red solid. 1 H NMR (DMSO-d 6 , 400 MHz) δ 10.3(s, 1H), 7.56-7.50(m, 2H), 7.36-7.33(m, 1H), 6.77(s, 1H), 3.85(s, 3H) ); MS m/z: 315 [M+H] + .
단계 2: N1-(2,6-디클로로피리미딘-4-일)-4-메톡시벤젠-1,2-디아민의 합성Step 2: Synthesis of N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine
단계 1에서 수득된 화합물(22.0 g, 62.8 mmol), Fe(17.5 g, 314 mmol) 및 NH4Cl(6.72 g, 126 mmol)을 EtOH(250 mL), THF(250 mL) 및 H2O(80.0 mL) 중에서 2시간 동안 80℃에서 교반하여 혼합하였다. 혼합물을 실온에서 냉각시켰다. 생성된 혼합물을 여과한 후, 필터 케이크를 EtOAc(3 x 300 mL)로 세척하고, 여액을 감압 농축시켰다. 생성된 혼합물을 물(3 x 200 mL)로 세척하여 N1-(2,6-디클로로피리미딘-4-일)-4-메톡시벤젠-1,2-디아민(16.0 g, 80.0%)을 적색 고체로서 수득하였다. 1H NMR(DMSO-d6, 400 MHz) δ 9.48(s, 1H), 6.87(d, J = 8.0 Hz, 1H), 6.45(s, 1H), 6.14(d, J = 8.0 Hz, 1H), 5.87(s, 1H), 5.12(s, 2H), 3.66(s, 3H); MS m/z: 285 [M+H]+.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. The resulting mixture was washed with water (3 x 200 mL) to give N1-(2,6-dichloropyrimidin-4-yl)-4-methoxybenzene-1,2-diamine (16.0 g, 80.0%) to red Obtained as a solid. 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 6.14 (d, J = 8.0 Hz, 1H) , 5.87(s, 1H), 5.12(s, 2H), 3.66(s, 3H); MS m/z: 285 [M+H] + .
단계 3: 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1,2,3-벤조트리아졸의 합성Step 3: Synthesis of 1-(2,6-dichloropyrimidin-4-yl)-5-methoxy-1,2,3-benzotriazole
단계 2에서 수득된 화합물(16.0 g, 50.5 mmol)을 AcOH(60.0 mL) 및 H2O(20.0 mL) 중에서 0℃에서 교반 혼합하고, NaNO2(3.83 g, 0.056 mmol)을 나누어 첨가하였다. 생성된 혼합물을 25℃에서 30분 동안 교반하였다. 실온에서 물(200 mL)를 첨가하여 반응을 퀀칭시키고, 침전된 고체를 여과하여 수집한 후 에탄올(3 x 30.0 mL)로 세척하여, 1-(2,6-디클로로피리미딘-4-일)-5-메톡시-1,2,3-벤조트리아졸(8g, 48%)을 적색 고체로서 수득하였다. 1H NMR(DMSO-d6, 400 MHz) δ 8.39(s, 1H), 8.27-8.25(d, J = 8.8 Hz, 1H), 7.71(s, 1H), 7.44(d, J = 8.8 Hz, 1H), 3.88(s, 3H); MS m/z: 296 [M+H]+.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. 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.39 (s, 1H), 8.27-8.25 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.88(s, 3H); MS m/z: 296 [M+H] + .
단계 4: 1-[2-클로로-6-(퓨란-2-일)피리미딘-4-일]-5-메톡시-1,2,3--벤조트리아졸의 합성Step 4: Synthesis of 1-[2-chloro-6-(furan-2-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
단계 3에서 수득된 화합물(8.00g, 27.0 mmol) 및 트리부틸(퓨란-2-일)스타난(9.65g, 27.0 mmol)을 DMF(80.0 mL) 중에서 교반 혼합하고, Pd(PPh3)2Cl2(3.79g, 5.40 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기 하에 25℃에서 16시간 동안 교반하였다. 물(300 mL)를 첨가하여 반응을 퀀칭시키고, 생성된 혼합물을 CH2Cl2(3 x 300 mL)로 추출하였다. 유기층을 모아서 염수(2 x 300 mL)로 세척하고, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시켰다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하고, CH2Cl2 / MeOH(10:1)로 용출시켜서 1-[2-클로로-6-(퓨란-2-일)피리미딘-4-일]-5-메톡시-1,2,3--벤조트리아졸(2.60 g, 27.9%)을 담황색 고체로서 수득하였다. 1H NMR(CDCl3, 400 MHz) δ 8.48(d, J = 8.8 Hz, 1H), 8.42(s, 1H), 7.71(s, 1H), 7.47-7.44(m, 2H), 7.33-7.30(m, 1H), 6.65-6.64(m, 1H), 3.93(s, 3H); MS m/z: 328 [M+H]+.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. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to 1-[2-chloro-6-(furan-2-yl)pyrimidin-4-yl]-5 -Methoxy-1,2,3-benzotriazole (2.60 g, 27.9%) was obtained as a pale yellow solid. 1 H NMR (CDCl 3 , 400 MHz) δ 8.48 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H), 7.71 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.30 ( m, 1H), 6.65-6.64 (m, 1H), 3.93 (s, 3H); MS m/z: 328 [M+H] + .
단계 5: 4-(퓨란-2-일)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민의 합성Step 5: Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine
단계 4에서 수득된 화합물(2.00g, 6.10 mmol)을 EtOH(20.0 mL) 중에 교반 혼합하고, MeOH(20.0 mL) 중의 NH3(g)을 첨가하였다. 질소 대기 하에 80℃에서 16시간 동안 생성된 혼합물을 교반하였다. 생성된 혼합물을 실온에서 냉각시키고, 감압 농축시켰다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하고 PE/EtOAc(1:2)로 용출시켜서 4-(퓨란-2-일)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민(940 mg, 42.5%)를 분홍색 고체로서 수득하였다. MS m/z: 309 [M+H]+ . 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] + .
단계 6: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3--벤조트리아졸-5-올(중간체 I)의 합성Step 6: Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Intermediate I)
단계 5에서 수득된 화합물(940 mg, 3.04 mmol) 및 BBr3 혼합물을 DCM(1M, 40.0 mL) 중에서 55℃에서 48시간 동안 교반하였다. 혼합물을 실온에서 냉각시키고, 0℃에서 MeOH(20.0 mL)를 첨가하였다. 생성된 혼합물을 감압 농축시킨 후, NaHCO3 포화 수용액에 부었다. 침전된 고체를 여과로 수집하고, 에틸 아세테이트로 세척하여 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3--벤조트리아졸-5-올(중간체 I; 450 mg, 42.6%)을 녹황색 고체로서 수득하였다. 1H NMR(DMSO-d6, 400 MHz) δ 8.61(d, J = 8.0 Hz, 1H), 8.00(s, 1H), 7.66-7.64(m, 1H), 7.42-7.21(m, 2H), 6.76-6.74(m, 1H), 6.75(s, 1H); MS m/z: 295 [M+H]+.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 . The precipitated solid was collected by filtration, washed with ethyl acetate and washed with 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5 -ol (intermediate I; 450 mg, 42.6%) was obtained as a greenish-yellow solid. 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.61 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.66-7.64 (m, 1H), 7.42-7.21 (m, 2H), 6.76-6.74(m, 1H), 6.75(s, 1H); MS m/z: 295 [M+H] + .
단계 7: 2-[6-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5--일]옥시)피리딘-2-일]프로판-2-올(Ex-02)의 합성Step 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)
단계 6에서 수득된 화합물(70.0 mg, 0.230 mmol) 및 2-(6-브로모피리딘-2-일)프로판-2-올(102 mg, 0.470 mmol)을 DMSO(5.00 mL) 중에 교반 혼합하고, CuI(45.0 mg, 0.230 mmol) 및 K3PO4(151 mg, 0.710 mmol)을 첨가하였다. 질소 대기 하에 110℃에서 1시간 동안 생성된 혼합물을 교반하고, 실온에서 냉각시켰다. 물(20.0 mL)를 첨가하여 반응을 퀀칭시키고, 생성된 혼합물을 CH2Cl2(3 x 20.0 mL)로 추출하였다. 유기층을 모아서 무수 Na2SO4 상에서 건조시키고, 여과 후 여액을 감압 농축시켰다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하고, PE/EtOAc(1:2)로 용출시켰다. 조 생성물을 하기 조건 하에 Prep-HPLC로 정제하였다: 컬럼 YMC-Actus Triart C18, 30 mm x 150 mm, 5 ㎛; 이동상, ACN 및 물(50 mmol/L NH4HC(38% Phase B, 7분 내에 58%까지); 검출기, UV 254&220 nm. 수집된 분획을 동결 건조하여 2-[6-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피리딘-2-일]프로판-2-올(Ex-02; 7.50 mg, 7.27%)을 백색 고체로서 수득하였다. 1H NMR(DMSO-d6, 400 MHz) δ 8.84(d, J = 9.0 Hz, 1H), 7.99(d, J = 1.8 Hz, 2H), 7.89-7.84(m, 1H), 7.66(s, 1H), 7.58-7.54(m, 1H), 7.41(d, J = 7.5 Hz, 1H), 7.36-7.35(m, 3H), 6.93(d, J = 8.1 Hz, 1H), 6.75-6.74(m, 1H), 5.18(s, 1H), 1.27(s, 6H); MS m/z: 430 [M+H]+.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. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (1:2). The crude product was purified by Prep-HPLC under the following conditions: column YMC-Actus Triart C 18 , 30 mm×150 mm, 5 μm; Mobile phase, ACN and water (50 mmol/L NH 4 HC (38% Phase B, up to 58% in 7 min); Detector, UV 254&220 nm. The collected fractions were freeze-dried to 2-[6-([1-[ 2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyridin-2-yl]propan-2-ol (Ex -02 ; 2H), 7.89-7.84 (m, 1H), 7.66 (s, 1H), 7.58-7.54 (m, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.36-7.35 (m, 3H), 6.93 (d, J = 8.1 Hz, 1H), 6.75-6.74 (m, 1H), 5.18 (s, 1H), 1.27 (s, 6H); MS m/z: 430 [M+H] + .
실시예 3: 3-[6-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아 졸-5-일}옥시)피리딘-2-일]벤조산(Ex-03)Example 3: 3-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl) }oxy)pyridin-2-yl]benzoic acid (Ex-03)
Figure PCTKR2022004084-appb-I000090
Figure PCTKR2022004084-appb-I000090
화합물(Ex-03)을 하기 반응식 3에 따라서 제조하였다.Compound (Ex-03) was prepared according to Scheme 3 below.
[반응식 3][Scheme 3]
Figure PCTKR2022004084-appb-I000091
Figure PCTKR2022004084-appb-I000091
단계 1: 메틸 3-[6-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피리딘-2-일]벤조에이트의 합성Step 1: Methyl 3-[6-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy ) Synthesis of pyridin-2-yl]benzoate
실시예 2의 단계 7에서 2-(6-브로모피리딘-2-일)프로판-2-올 대신에 제조예 1의 화합물(A)을 사용한 점을 제외하고, 실시예 2의 단계 7과 동일한 방법으로 메틸 3-[6-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피리딘-2-일]벤조에이트(35.0 mg, 19.4%)를 담황색 고체로서 수득하였다. MS m/z: 506 [M+H]+.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] + .
단계 2: 3-[6-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]벤조산(Ex-03)의 합성Step 2: 3-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl} Synthesis of oxy)pyridin-2-yl]benzoic acid (Ex-03)
상기 단계 1에서 수득된 화합물(35.0 mg, 0.069 mmol)을 THF/MeOH(4/1)(5.00 mL) 중에 교반 혼합하고, H2O(1.00 mL) 중의 NaOH(5.54 mg, 0.138 mmol) 용액을 첨가하였다. 생성된 혼합물을 25℃에서 2시간 동안 교반하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, Xselect CSH OBD 컬럼 30x150 mm 5 ㎛, n; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(25% Phase B, 7분에 45%까지); 검출기, UV 254 & 220nm. 수집된 분획을 동결 건조하여 3-[6-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]벤조산(Ex-03; 9.10 mg, 26.7%)를 황백색 고체로서 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.89(d, J = 9.0 Hz, 1H), 8.44(s, 1H), 8.09(d, J = 1.8 Hz, 1H), 8.03-7.98(m, 3H), 8.92(d, J = 7.5 Hz, 1H), 7.81(d, J = 7.5 Hz, 1H), 7.69-7.65(m, 2H), 7.50-7.45(m, 1H), 7.37-7.36(m, 3H), 7.11(d, J = 8.1 Hz, 1H), 6.77-6.75(m, 1H); MS m/z :492 [M+H]+.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 μm, n; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (25% Phase B, up to 45% in 7 min); Detector, UV 254 & 220nm. The collected fractions were freeze-dried to 3-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole- 5-yl}oxy)pyridin-2-yl]benzoic acid (Ex-03; 9.10 mg, 26.7%) was obtained as an off-white solid. 1H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.89 (d, J = 9.0 Hz, 1H), 8.44 (s, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.03 7.98 (m, 3H), 8.92 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.69-7.65 (m, 2H), 7.50-7.45 (m, 1H), 7.37 -7.36 (m, 3H), 7.11 (d, J = 8.1 Hz, 1H), 6.77-6.75 (m, 1H); MS m/z :492 [M+H] + .
실시예 4: 4-(퓨란-2-일)-6-[5-({6-[(2-메톡시에톡시)메틸]피리딘-2-일]옥시)-1H-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-04)Example 4: 4-(furan-2-yl)-6-[5-({6-[(2-methoxyethoxy)methyl]pyridin-2-yl]oxy)-1H-1,2,3 -benzotriazol-1-yl]pyrimidin-2-amine (Ex-04)
Figure PCTKR2022004084-appb-I000092
Figure PCTKR2022004084-appb-I000092
실시예 2의 단계 7에서 2-(6-브로모피리딘-2-일)프로판-2-올 대신에 제조예 2의 화합물(B)을 사용한 점을 제외하고 실시예 2의 단계 7과 동일한 방법으로 4-(퓨란-2-일)-6-[5-({6-[(2-메톡시에톡시)메틸]피리딘-2-일]옥시)-1H-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-04; 13.9 mg, 11.1%)을 황백색 고체로서 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.84(d, J = 9.0 Hz, 1H), 8.00(s, 2H),7.94-7.88(m, 1H), 7.67(s, 1H), 7.58-7.54(m, 1H), 7.36-7.35(m, 3H), 7.21(d, J = 7.2 Hz, 1H), 7.02(d, J = 7.8 Hz, 1H), 6.76-6.75(m, 1H), 4.38(s, 2H), 3.60-3.56(m, 2H), 3.47-3.45(m, 2H), 3.23(s, 3H); MS m/z: 460 [M+H]+. The same method as in Step 7 of Example 2, except that Compound (B) of Preparation Example 2 was used instead of 2-(6-bromopyridin-2-yl)propan-2-ol in Step 7 of Example 2 to 4-(furan-2-yl)-6-[5-({6-[(2-methoxyethoxy)methyl]pyridin-2-yl]oxy)-1H-1,2,3-benzotria Zol-1-yl]pyrimidin-2-amine (Ex-04; 13.9 mg, 11.1%) was obtained as an off-white solid. 1H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.84 (d, J = 9.0 Hz, 1H), 8.00 (s, 2H), 7.94-7.88 (m, 1H), 7.67 (s, 1H) ), 7.58-7.54 (m, 1H), 7.36-7.35 (m, 3H), 7.21 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.76-6.75 (m, 1H), 4.38(s, 2H), 3.60-3.56(m, 2H), 3.47-3.45(m, 2H), 3.23(s, 3H); MS m/z: 460 [M+H] + .
실시예 5: 1-[6-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]피롤리딘-3-올(Ex-05)Example 5: 1-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl) }oxy)pyridin-2-yl]pyrrolidin-3-ol (Ex-05)
Figure PCTKR2022004084-appb-I000093
Figure PCTKR2022004084-appb-I000093
실시예 2의 단계 7에서 2-(6-브로모피리딘-2-일)프로판-2-올 대신에 제조예 3의 화합물(C)를 사용한 점을 제외하고 실시예 2의 단계 7과 동일한 방법으로 1-[6-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]피롤리딘-3-올(Ex-05; 6.60 mg, 6.08%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.82(d, J = 9.0 Hz, 1H), 7.99(s, 1H), 7.95(d, J = 1.8 Hz, 1H), 7.66(s, 1H), 7.58-7.52(m, 2H), 7.36-7.35(m, 3H), 6.76-6.74(m, 1H), 6.17(s, 1H), 6.14(s, 1H), 4.89(d, J = 3.6 Hz, 1H), 4.28(brs, 1H), 3.28-3.25(m, 3H), 3.12-3.08(m, 1H), 1.94-1.90(m, 1H), 1.82-1.75(m, 1H); MS m/z: 457 [M+H]+.The same method as in Step 7 of Example 2, except that Compound (C) of Preparation Example 3 was used instead of 2-(6-bromopyridin-2-yl)propan-2-ol in Step 7 of Example 2 to 1-[6-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl}oxy)pyridin- 2-yl]pyrrolidin-3-ol (Ex-05; 6.60 mg, 6.08%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.82 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.58-7.52(m, 2H), 7.36-7.35(m, 3H), 6.76-6.74(m, 1H), 6.17(s, 1H), 6.14(s, 1H), 4.89(d) , J = 3.6 Hz, 1H), 4.28 (brs, 1H), 3.28-3.25 (m, 3H), 3.12-3.08 (m, 1H), 1.94-1.90 (m, 1H), 1.82-1.75 (m, 1H) ); MS m/z: 457 [M+H] + .
실시예 6: 2-{6-[({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)메틸]피리딘-2-일}프로판-2-올(Ex-06)Example 6: 2-{6-[({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- mono}oxy)methyl]pyridin-2-yl}propan-2-ol (Ex-06)
Figure PCTKR2022004084-appb-I000094
Figure PCTKR2022004084-appb-I000094
화합물(Ex-06)을 하기 반응식 4에 따라서 제조하였다.Compound (Ex-06) was prepared according to Scheme 4 below.
[반응식 4][Scheme 4]
Figure PCTKR2022004084-appb-I000095
Figure PCTKR2022004084-appb-I000095
단계 1: 에틸 6-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일])-1,2,3- 벤조트리아졸-5-일]옥시)메틸]피리딘-2-카르복실레이트의 합성Step 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
실시예 2의 단계 6에서 제조된 화합물(중간체 I)(80.0 mg, 0.270 mmol) 및 에틸 6-(클로로메틸)피리딘-2-카복실레이트(108 mg, 0.540 mmol)를 DMF(3.00 mL) 중에 교반하여 혼합하고, K2CO3(112 mg, 0.810 mmol)을 첨가한 후 생성된 혼합물을 16시간 동안 25℃에서 교반하였다. 반응을 물(25.0 mL)로 퀀칭시켰다. 생성된 혼합물을 EtOAc(3 x 25.0 mL)로 추출하고, 유기층을 모아서 염수(2 x 25.0 mL)로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 에틸 6-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일])-1,2,3-벤조트리아졸-5-일]옥시)메틸]피리딘-2-카르복실레이트(40.0 mg, 30.6%)를 황백색 고체로 수득하였다. MS m/z: 458 [M+H]+.The compound prepared in step 6 of Example 2 (Intermediate I) (80.0 mg, 0.270 mmol) and ethyl 6-(chloromethyl)pyridine-2-carboxylate (108 mg, 0.540 mmol) were stirred in DMF (3.00 mL). and K 2 CO 3 (112 mg, 0.810 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 hours. The reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL), and the combined organic layers were washed with brine (2 x 25.0 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to ethyl 6-[([1-[2-amino-6-(furan-2-yl) Pyrimidin-4-yl])-1,2,3-benzotriazol-5-yl]oxy)methyl]pyridine-2-carboxylate (40.0 mg, 30.6%) was obtained as an off-white solid. MS m/z: 458 [M+H] + .
단계 2: 2-{6-[({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일}옥시)메틸]피리딘-2-일}프로판-2-올(Ex-06)의 합성Step 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)
단계 1에서 수득된 화합물(40.0 mg, 0.087 mmol)을 THF(5.00 mL) 중에서 교반 혼합하고, 질소 대기하에 0℃에서 CH3MgBr(80 μL, 0.694 mmol, 1M THF 용액)를 적가하였다. 생성된 혼합물을 질소 대기하에 25℃에서 16시간 동안 교반하였다. 반응을 물(25.0 mL)로 퀀칭시켰다. 생성된 혼합물을 CH2Cl2(3 x 25.0 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:2)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, Xselect CSH OBD 컬럼 30x150 mm 5 ㎛, n; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(45% PhaseB, 7분에 65%까지); 검출기, UV 254 & 220 nm. 수집된 분획을 동결 건조하여 2-{6-[({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일}옥시)메틸]피리딘-2-일}프로판-2-올(Ex-06; 9.80 mg, 25.3%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.73(d, J = 9.0 Hz, 1H), 7.98(s, 1H), 7.87-7.80(m, 2H), 7.64-7.63(m, 2H), 7.48-7.44(m, 2H), 7.34-7.33(m, 3H), 6.75-6.74(m, 1H), 5.31(s, 2H), 5.26(s, 1H), 1.47(s, 6H); MS m/z: 444 [M+H]+.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 μL, 0.694 mmol, 1M THF solution) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. 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 μm, 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. The collected fractions were freeze-dried to 2-{6-[({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5) -yl}oxy)methyl]pyridin-2-yl}propan-2-ol (Ex-06; 9.80 mg, 25.3%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.73 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.87-7.80 (m, 2H), 7.64-7.63 ( m, 2H), 7.48-7.44(m, 2H), 7.34-7.33(m, 3H), 6.75-6.74(m, 1H), 5.31(s, 2H), 5.26(s, 1H), 1.47(s, 6H); MS m/z: 444 [M+H] + .
실시예 7: 4-(퓨란-2-일)-6-(5-페녹시-1H-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민(Ex-07)Example 7: 4-(furan-2-yl)-6-(5-phenoxy-1H-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine (Ex-07)
Figure PCTKR2022004084-appb-I000096
Figure PCTKR2022004084-appb-I000096
실시예 2의 단계 6에서 제조된 화합물(중간체 I)(110 mg, 0.370 mmol) 및 디페닐요오다늄 브로마이드(270 mg, 0.750 mmol)를 THF(5.00 mL) 중에서 교반 혼합하고, t-BuOK(125 mg, 1.12 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기하에 40℃에서 16시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 반응을 물(25.0 mL)로 퀀칭시켰다. 생성된 혼합물을 EtOAc(3 x 25.0 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18, 30 mm X 150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(64% PhaseB, 7분에 84%까지); 검출기, UV 254 & 220 nm. 수집된 분획을 동결 건조하여 4-(퓨란-2-일)-6-(5-페녹시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민(Ex-07; 8.80 mg, 6.33%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.85(d, J = 9.0 Hz, 1H), 7.99(s, 1H), 7.70(s, 1H), 7.65(s, 1H), 7.54-7.41(m, 3H), 7.35-7.34(m, 3H), 7.23-7.20(m, 1H), 7.18-7.10(m, 2H), 6.76-6.74(m, 1H); MS m/z: 371 [M+H]+.The compound (intermediate I) prepared in step 6 of Example 2 (110 mg, 0.370 mmol) and diphenyliodanium bromide (270 mg, 0.750 mmol) were stirred and mixed in THF (5.00 mL), t-BuOK ( 125 mg, 1.12 mmol) was added. The resulting mixture was stirred at 40° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and the reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C 18 , 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (64% PhaseB, up to 84% in 7 min); Detector, UV 254 & 220 nm. The collected fractions were freeze-dried to 4-(furan-2-yl)-6-(5-phenoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine (Ex-07; 8.80 mg, 6.33%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.85 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H) , 7.54-7.41 (m, 3H), 7.35-7.34 (m, 3H), 7.23-7.20 (m, 1H), 7.18-7.10 (m, 2H), 6.76-6.74 (m, 1H); MS m/z: 371 [M+H] + .
실시예 8: 4-[5-(벤질옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-08)Example 8: 4-[5-(benzyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-08 )
Figure PCTKR2022004084-appb-I000097
Figure PCTKR2022004084-appb-I000097
실시예 2의 단계 6에서 제조된 화합물(중간체 I)(80.0 mg, 0.270 mmol) 및 벤질 브로마이드(93.0 mg, 500 μmol)를 DMF(2.00 mL) 중에 교반하여 혼합하고, Cs2CO3(265 mg, 0.810 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기하에서 25℃에서 16시간 동안 교반하고, 반응을 물(25.0 mL)로 퀀칭시켰다. 생성된 혼합물을 EtOAc(3 x 25.0 mL)로 추출하고, 유기층을 모아서 염수(3 x 25.0 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜 실리카겔 컬럼 크로마토그래피로 정제하였다. 조 생성물을 하기 조건에서 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18, 30 mm X 150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(64% PhaseB, 7분에 84%까지); 검출기, UV 254 & 220 nm. 수집된 분획을 동결 건조하여 4-[5-(벤질옥시)-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-08; 10.2 mg, 9.74%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.72(d, J = 9.0 Hz, 1H), 7.98(s, 1H), 7.77(s, 1H), 7.63(s, 1H), 7.55-7.52(m, 2H), 7.46-7.33(m, 7H), 6.75-6.74(m, 1H), 5.26(s, 2H); MS m/z: 385 [M+H]+.The compound (intermediate I) prepared in step 6 of Example 2 (80.0 mg, 0.270 mmol) and benzyl bromide (93.0 mg, 500 μmol) were mixed in DMF (2.00 mL) by stirring, Cs 2 CO 3 (265 mg , 0.810 mmol) was added. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 16 h, and the reaction was quenched with water (25.0 mL). The resulting mixture was extracted with EtOAc (3 x 25.0 mL), and the combined organic layers were washed with brine (3 x 25.0 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C 18 , 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (64% PhaseB, up to 84% in 7 min); Detector, UV 254 & 220 nm. The collected fractions were freeze-dried to 4-[5-(benzyloxy)-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 08; 10.2 mg, 9.74%) as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.72 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H) , 7.55-7.52(m, 2H), 7.46-7.33(m, 7H), 6.75-6.74(m, 1H), 5.26(s, 2H); MS m/z: 385 [M+H] + .
실시예 9: 4-(퓨란-2-일)-6-[5-[(1-메틸피페리딘-3-일)옥시]-1H-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-09)Example 9: 4-(furan-2-yl)-6-[5-[(1-methylpiperidin-3-yl)oxy]-1H-1,2,3-benzotriazol-1-yl ]Pyrimidin-2-amine (Ex-09)
Figure PCTKR2022004084-appb-I000098
Figure PCTKR2022004084-appb-I000098
실시예 8에서 벤질 브로마이드 대신에 3-브로모-1-메틸피페리딘 하이드로브로마이드(528 mg, 2.04 mmol)를 사용한 것을 제외하고 실시예 8과 동일한 방법으로 4-(퓨란-2-일)-6-[5-[(1-메틸피페리딘-3-일)옥시]-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-09; 9.00 mg, 3.36%)을 백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.69(d, J = 9.0 Hz, 1H), 7.98(s, 1H), 7.72(s, 1H), 7.63(s, 1H), 7.34-7.32(m, 4H), 6.77-6.74(m, 1H), 4.67-4.55(m, 1H), 2.90-2.85(m, 1H), 2.59-2.55(m, 1H), 2.20(s, 3H), 2.19-2.15(m, 1H), 2.14-1.97(m, 2H), 1.80-1.71(m, 1H), 1.68-1.52(m, 1H), 1.45-1.36(m, 1H); MS m/z: 392 [M+H]+.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. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.69 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H) , 7.34-7.32(m, 4H), 6.77-6.74(m, 1H), 4.67-4.55(m, 1H), 2.90-2.85(m, 1H), 2.59-2.55(m, 1H), 2.20(s, 3H), 2.19-2.15 (m, 1H), 2.14-1.97 (m, 2H), 1.80-1.71 (m, 1H), 1.68-1.52 (m, 1H), 1.45-1.36 (m, 1H); MS m/z: 392 [M+H] + .
실시예 10: 메틸 2-[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]아세테이트(Ex-10)Example 10: Methyl 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- mono}oxy)pyridin-2-yl]acetate (Ex-10)
Figure PCTKR2022004084-appb-I000099
Figure PCTKR2022004084-appb-I000099
실시예 2의 단계 6에서 제조된 화합물(중간체 I)(300 mg, 1.01 mmol) 및 메틸 2-(3-브로모피리딘-2-일)아세테이트(703 mg, 3.05 mmol)를 DMSO(10 mL) 중에서 교반하여 혼합하고, CuI(19.0 mg, 1.019 mmol), 1,10-페난트롤린(183 mg, 1.01 mmol) 및 Cs2CO3(830 mg, 2.54 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기하에 110℃에서 16시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 반응을 물(100 mL)로 퀀칭시켰다. 생성된 혼합물을 EtOAc(3 x 100 mL)로 추출하고, 유기층을 모아서 염수(3 x 100 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Prep OBD C18 컬럼, 19 x 250 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(41% PhaseB, 10분에 52%까지); 검출기, UV 254&220 nm. 수집된 분획을 동결 건조하여 메틸 2-[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일}옥시)피리딘-2-일]아세테이트(Ex-10; 5.00 mg, 1.10%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.86(d, J = 9.0 Hz, 1H), 8.36-8.34(m, 1H), 7.98(s, 1H), 7.72(s, 1H), 7.64(s, 1H), 7.51-7.48(m, 1H), 7.42-7.34(m, 5H), 6.75-6.74(m, 1H), 3.96(s, 2H), 3.57(s, 3H); MS m/z: 444 [M+H]+ . The compound (intermediate I) prepared in step 6 of Example 2 (300 mg, 1.01 mmol) and methyl 2-(3-bromopyridin-2-yl)acetate (703 mg, 3.05 mmol) were mixed with DMSO (10 mL) was stirred and mixed, and CuI (19.0 mg, 1.019 mmol), 1,10-phenanthroline (183 mg, 1.01 mmol) and Cs 2 CO 3 (830 mg, 2.54 mmol) were added. The resulting mixture was stirred at 110° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and the reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography. The crude product was purified by Prep-HPLC under the following conditions: column, XBridge Prep OBD C 18 column, 19×250 mm, 5 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (41% PhaseB, 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. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.86 (d, J = 9.0 Hz, 1H), 8.36-8.34 (m, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.64(s, 1H), 7.51-7.48(m, 1H), 7.42-7.34(m, 5H), 6.75-6.74(m, 1H), 3.96(s, 2H), 3.57(s, 3H) ; MS m/z: 444 [M+H] + .
실시예 11: 2-[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-4-플루오로페닐]-2-메틸 프로판산(Ex-11)Example 11: 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl) }oxy)-4-fluorophenyl]-2-methyl propanoic acid (Ex-11)
Figure PCTKR2022004084-appb-I000100
Figure PCTKR2022004084-appb-I000100
화합물(Ex-11)을 하기 반응식 5에 따라서 제조하였다.Compound (Ex-11) was prepared according to Scheme 5 below.
[반응식 5][Scheme 5]
Figure PCTKR2022004084-appb-I000101
Figure PCTKR2022004084-appb-I000101
단계 1: 메틸 2-[3-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)-4-플루오로페닐]-2-메틸 프로파노에이트의 합성Step 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
메틸 2-(3-브로모피리딘-2-일)아세테이트 대신에 제조예 4의 화합물(D)를 사용한 것을 제외하고 실시예 10과 동일한 방법으로 메틸 2-[3-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)-4-플루오로페닐]-2-메틸 프로파노에이트(40.0 mg, 2.41%)를 황백색 고체로 수득하였다. MS m/z: 489[M+H+].Methyl 2-[3-([1-[2-] Amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)-4-fluorophenyl]-2-methyl propanoate ( 40.0 mg, 2.41%) was obtained as an off-white solid. MS m/z: 489 [M+H + ].
단계 2: 2-[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일}옥시)-4-플루오로페닐]-2-메틸 프로판산(Ex-11)의 합성Step 2: 2-[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl}oxy) Synthesis of -4-fluorophenyl]-2-methyl propanoic acid (Ex-11)
상기 단계 1에서 수득한 화합물(40.0 mg, 0.082 mmol)을 THF(4.00 mL)/MeOH(1.00 mL) 중에 교반하고, LiOH(20.0 mg, 0.820 mmol) 용액을 첨가하였다. 생성된 혼합물을 25℃에서 4시간 동안 교반하고, 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, SunFire Prep C18 OBD 컬럼, 19x150 mm 5 ㎛ 10 nm; 이동상, 물(0.05% TFA) 및 ACN(45% PhaseB, 7분에 최대 65%); 검출기, UV 254/220 nm. 수집된 분획을 동결 건조하여 2-[3-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)-4-플루오로페닐]-2-메틸 프로판산(Ex-11; 8.50 mg, 21.7%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm): 12.50(brs, 1H), 8.85(d, J = 9.2 Hz, 1H), 7.99(s, 1H), 7.64(s, 1H), 7.57-7.52(m, 2H), 7.44-7.19(m, 6H), 6.75-6.74(m, 1H), 1.45(s, 6H); MS m/z: 475 [M+H]+.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 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (45% PhaseB, up to 65% in 7 min); Detector, UV 254/220 nm. The collected fractions were freeze-dried to 2-[3-([1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5- yl]oxy)-4-fluorophenyl]-2-methyl propanoic acid (Ex-11; 8.50 mg, 21.7%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 12.50 (brs, 1H), 8.85 (d, J = 9.2 Hz, 1H), 7.99 (s, 1H), 7.64 (s, 1H) , 7.57-7.52(m, 2H), 7.44-7.19(m, 6H), 6.75-6.74(m, 1H), 1.45(s, 6H); MS m/z: 475 [M+H] + .
실시예 12: 2-{[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-5-메틸페닐]메톡시}에탄-1-올(Ex-12)Example 12: 2-{[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- mono}oxy)-5-methylphenyl]methoxy}ethan-1-ol (Ex-12)
Figure PCTKR2022004084-appb-I000102
Figure PCTKR2022004084-appb-I000102
화합물(Ex-12)를 하기 반응식 6에 따라서 제조하였다.Compound (Ex-12) was prepared according to Scheme 6 below.
[반응식 6][Scheme 6]
Figure PCTKR2022004084-appb-I000103
Figure PCTKR2022004084-appb-I000103
단계 1: 4-(퓨란-2-일)-6-[5-(3-메틸-5-[[2-(옥산-2-일옥시)에톡시]메틸]페녹시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민의 합성Step 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
메틸 2-(3-브로모피리딘-2-일)아세테이트 대신에 제조예 5의 화합물(E)를 사용한 것을 제외하고 실시예 10과 동일한 방법으로 4-(퓨란-2-일)-6-[5-(3-메틸-5-[[2-(옥산-2-일옥시)에톡시]메틸]페녹시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(25.0 mg, 1.58%)을 황백색 오일로 수득하였다. MS m/z:543 [M+H]+.4-(furan-2-yl)-6-[ 5-(3-methyl-5-[[2-(oxan-2-yloxy)ethoxy]methyl]phenoxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (25.0 mg, 1.58%) was obtained as an off-white oil. MS m/z:543 [M+H] + .
단계 2: 2-{[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-5-메틸페닐]메톡시}에탄-1-올(Ex-12)의 합성Step 2: 2-{[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl) Synthesis of }oxy)-5-methylphenyl]methoxy}ethan-1-ol (Ex-12)
상기 단계 1에서 수득된 화합물(25.0 mg, 0.032 mmol)을 MeOH(2.00 mL) 및 conc. HCl(1.00 mL)에 녹이고 25℃에서 1시간 동안 교반하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XSelect CSH 플루오로 페닐, 30 mm X 150 mm, 5 ㎛; 이동상, 물(50 mmol/L NH4HCO3) 및 ACN(40% PhaseB, 7분에 최대 60%); 검출기, UV. 수집된 분획을 동결 건조하여 2-{[3-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-5-메틸페닐]메톡시}에탄-1-올(Ex-12; 5.20 mg, 33.9%)를 황백색 고체로서 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.84(d, J = 9.0 Hz, 1H), 7.99(s, 1H), 7.69(d, J = 2.1 Hz, 1H), 7.64(s, 1H), 7.51-7.47(m, 1H), 7.35-7.34(m, 2H), 6.98(s, 1H), 6.85-6.83(m, 2H), 6.76-6.74(m, 1H), 4.65(br s, 1H), 4.46(s, 2H), 3.54-3.51(m. 4H), 2.30(s, 3H); MS m/z: 459 [M+H]+.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 μm; mobile phase, water (50 mmol/L NH 4 HCO 3 ) and ACN (40% PhaseB, up to 60% in 7 min); Detector, UV. The collected fractions were freeze-dried to 2-{[3-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole) Obtained -5-yl}oxy)-5-methylphenyl]methoxy}ethan-1-ol (Ex-12; 5.20 mg, 33.9%) as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.84 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.51-7.47(m, 1H), 7.35-7.34(m, 2H), 6.98(s, 1H), 6.85-6.83(m, 2H), 6.76-6.74(m, 1H), 4.65 (br s, 1H), 4.46 (s, 2H), 3.54-3.51 (m. 4H), 2.30 (s, 3H); MS m/z: 459 [M+H] + .
실시예 13: 2-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-N-페닐아세트아미드(Ex-13)Example 13: 2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl}oxy) -N-phenylacetamide (Ex-13)
Figure PCTKR2022004084-appb-I000104
Figure PCTKR2022004084-appb-I000104
벤질 브로마이드 대신에 제조예 6의 화합물(F)를 사용한 것을 제외하고 실시예 8과 동일한 방법으로 2-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-N-페닐아세트아미드(Ex-13; 15.2 mg, 10.4%)를 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 10.18(s, 1H), 8.76(d, J = 9.3 Hz, 1H), 7.98(s, 1H), 7.69-7.63(m, 4H), 7.53-7.50(m, 1H), 7.37-7.32(m, 4H), 7.12-7.07(m, 1H), 6.75-6.73(m, 1H), 4.88(s, 2H); MS m/z: 428 [M+H]+.2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl) in the same manner as in Example 8 except that compound (F) of Preparation 6 was used instead of benzyl bromide ]-1H-1,2,3-benzotriazol-5-yl}oxy)-N-phenylacetamide (Ex-13; 15.2 mg, 10.4%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 10.18 (s, 1H), 8.76 (d, J = 9.3 Hz, 1H), 7.98 (s, 1H), 7.69-7.63 (m, 4H), 7.53-7.50(m, 1H), 7.37-7.32(m, 4H), 7.12-7.07(m, 1H), 6.75-6.73(m, 1H), 4.88(s, 2H); MS m/z: 428 [M+H] + .
실시예 14: 4-(퓨란-2-일)-6-{5-[(5-페닐-1,2,4-옥사디아졸-3-일)옥시]-1H-1,2,3- 벤조트리아졸-1-일}피리미딘-2-아민(Ex-14)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)
Figure PCTKR2022004084-appb-I000105
Figure PCTKR2022004084-appb-I000105
벤질 브로마이드 대신에 3-클로로-5-페닐-1,2,4-옥사디아졸을 사용한 것을 제외하고 실시예 8과 동일한 방법으로 4-(퓨란-2-일)-6-{5-[(5-페닐-1,2,4-옥사디아졸-3-일)옥시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-14; 17.4 mg, 7.62%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.92(d, J = 9.0 Hz, 1H), 8.37(d, J = 2.1 Hz, 1H), 8.10(d, J = 8.7 Hz, 2H), 7.99(s, 1H), 7.89-7.85(m, 1H), 7.75-7.73(m, 1H), 7.72-7.62(m, 3H), 7.38-7.35(m, 3H), 6.76-6.74(m, 1H); MS m/z: 439 [M+H]+.4-(furan-2-yl)-6-{5-[( 5-phenyl-1,2,4-oxadiazol-3-yl)oxy]-1H-1,2,3-benzotriazol-1-yl}pyrimidin-2-amine (Ex-14; 17.4 mg , 7.62%) as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.92 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.7 Hz) , 2H), 7.99(s, 1H), 7.89-7.85(m, 1H), 7.75-7.73(m, 1H), 7.72-7.62(m, 3H), 7.38-7.35(m, 3H), 6.76-6.74 (m, 1H); MS m/z: 439 [M+H] + .
실시예 15: 2-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-1-(4-페닐피페라진-1-일)에탄-1-온(Ex-15)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)
Figure PCTKR2022004084-appb-I000106
Figure PCTKR2022004084-appb-I000106
벤질 브로마이드 대신에 제조예 7의 화합물(G)를 사용한 것을 제외하고 실시예 8과 동일한 방법으로 2-({1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}옥시)-1-(4-페닐피페라진-1-일)에탄-1-온(Ex-15; 22.4 mg, 12.9%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.71(d, J = 9.0 Hz, 1H), 7.99(s, 1H), 7.70(d, J = 2.1 Hz, 1H), 7.63(s, 1H), 7.43-7.39(m, 1H), 7.34-7.23(m, 3H), 7.27-7.22(m, 2H), 6.99(d, J = 8.1 Hz, 2H), 6.85-6.80(m, 1H), 6.75-6.74(m, 1H), 5.07(s, 2H), 3.66(br s, 4H), 3.24(br s, 2H), 3.15(br s, 2H); MS m/z: 497 [M+H]+.2-({1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl) in the same manner as in Example 8 except that compound (G) of Preparation 7 was used instead of benzyl bromide ]-1H-1,2,3-benzotriazol-5-yl}oxy)-1-(4-phenylpiperazin-1-yl)ethan-1-one (Ex-15; 22.4 mg, 12.9%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.71 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.43-7.39 (m, 1H), 7.34-7.23 (m, 3H), 7.27-7.22 (m, 2H), 6.99 (d, J = 8.1 Hz, 2H), 6.85-6.80 (m) , 1H), 6.75-6.74 (m, 1H), 5.07 (s, 2H), 3.66 (br s, 4H), 3.24 (br s, 2H), 3.15 (br s, 2H); MS m/z: 497 [M+H] + .
실시예 16: 4-(퓨란-2-일)-6-{5-[3-(1H-이미다졸-1-일)프로폭시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-16)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)
Figure PCTKR2022004084-appb-I000107
Figure PCTKR2022004084-appb-I000107
벤질 브로마이드 대신에 1-(3-브로모프로필)이미다졸(272 mg, 1.43 mmol)을 사용한 것을 제외하고는 실시예 8과 동일한 방법으로 4-(퓨란-2-일)-6-{5-[3-(1H-이미다졸-1-일)프로폭시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-16; 9.70 mg, 4.00%)을 백색 고체로서 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm):8.68(d, J = 9.0 Hz, 1H), 7.98-7.97(m, 1H), 7.63-7.62(m, 2H), 7.34-7.30(m, 4H), 6.75-6.73(m, 1H), 3.95-3.93(m, 2H), 2.99-2.95(m, 2H), 2.49-2.45(m, 2H), 1.88-1.84(m, 1H), 1.76-1.72(m, 2H), 1.27-1.18(m, 2H); MS m/z: 402 [M+H]+.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. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.68 (d, J = 9.0 Hz, 1H), 7.98-7.97 (m, 1H), 7.63-7.62 (m, 2H), 7.34 7.30(m, 4H), 6.75-6.73(m, 1H), 3.95-3.93(m, 2H), 2.99-2.95(m, 2H), 2.49-2.45(m, 2H), 1.88-1.84(m, 1H) ), 1.76-1.72 (m, 2H), 1.27-1.18 (m, 2H); MS m/z: 402 [M+H] + .
실시예 17: 4-[5-(사이클로펜틸옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-17)Example 17: 4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 17)
Figure PCTKR2022004084-appb-I000108
Figure PCTKR2022004084-appb-I000108
벤질 브로마이드 대신에 브로모사이클로펜탄(252 mg, 1.69 mmol)을 사용한 것을 제외하고는 실시예 8과 동일한 방법으로 4-[5-(사이클로펜틸옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-17; 11.7 mg, 9.00%)을 백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm): 8.67(d, J = 9.0 Hz, 1H), 7.98-7.97(m, 1H), 7.62-7.60(m, 2H), 7.33-7.26(m, 4H), 6.75-6.73(m, 1H), 5.01-4.96(m, 1H), 2.07-1.96(m, 2H), 1.81-1.60(m, 6H); MS m/z: 362 [M+H]+.4-[5-(cyclopentyloxy)-1H-1,2,3-benzotriazole in the same manner as in Example 8, except that bromocyclopentane (252 mg, 1.69 mmol) was used instead of benzyl bromide. Obtained -1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-17; 11.7 mg, 9.00%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.67 (d, J = 9.0 Hz, 1H), 7.98-7.97 (m, 1H), 7.62-7.60 (m, 2H), 7.33 7.26(m, 4H), 6.75-6.73(m, 1H), 5.01-4.96(m, 1H), 2.07-1.96(m, 2H), 1.81-1.60(m, 6H); MS m/z: 362 [M+H] + .
실시예 18: 4-(퓨란-2-일)-6-{5-[(피페리딘-4-일)메톡시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-18)Example 18: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-1H-1,2,3-benzotriazol-1-yl}pyri Midin-2-amine (Ex-18)
Figure PCTKR2022004084-appb-I000109
Figure PCTKR2022004084-appb-I000109
화합물(Ex-18)을 하기 반응식 7에 따라서 제조하였다.Compound (Ex-18) was prepared according to Scheme 7 below.
[반응식 7][Scheme 7]
Figure PCTKR2022004084-appb-I000110
Figure PCTKR2022004084-appb-I000110
단계 1: tert-부틸 4-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)메틸]피페리딘-1-카복실레이트의 합성Step 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
벤질 브로마이드 대신에 tert-부틸 4-(브로모메틸)피페리딘-1-카르복실레이트(472 mg, 1.70 mmol)을 사용한 것을 제외하고는 실시예 8과 동일한 방법으로 tert-부틸4-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)메틸]피페리딘-1-카복실레이트(80.0 mg, 21.0%)를 백색 고체로 수득하였다; MS m/z: 491 [M+H]+.In the same manner as in Example 8, tert-butyl4-[( [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)methyl]piperidine-1-carboxyl The rate (80.0 mg, 21.0%) was obtained as a white solid; MS m/z: 491 [M+H] + .
단계 2: 4-(퓨란-2-일)-6-{5-[(피페리딘-4-일)메톡시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-18)의 합성Step 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)
상기 단계 1에서 수득된 화합물(80.0 mg, 0.160 mmol)을 DCM(3.00 mL) 중에 교반 혼합하고, TFA(1.00 mL)를 적가하였다. 생성된 혼합물을 25℃에서 3시간 동안 교반하고, 감압 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼: XBridge Prep OBD C18 컬럼, 30 x 150 mm 5 ㎛; 이동상 A: 물(10 mmol/L NH4HCO3), 이동상 B: ACN; 유속: 60 mL/분; 구배: 7분에 25B에서 45B, RT1: 5.52. 수집된 분획을 동결 건조하여 4-(퓨란-2-일)-6-{5-[(피페리딘-4-일)메톡시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-18; 13.2 mg, 22.0%)을 백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.67(d, J = 12.4 Hz, 1H), 7.98-7.97(m, 1H), 7.63-7.62(m, 2H), 7.40-7.30(m, 4H), 6.75-6.73(m, 1H), 3.94(d, J = 8.4 Hz, 2H), 2.99-2.90(m, 2H), 2.60-2.51(m, 2H), 1.95-1.70(m, 3H), 1.30-1.10(m, 2H); MS m/z: 391 [M+H]+.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 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; Gradient: 25B to 45B at 7 min, RT1: 5.52. The collected fractions were freeze-dried to 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-1H-1,2,3-benzotriazole-1- Mono}pyrimidin-2-amine (Ex-18; 13.2 mg, 22.0%) was obtained as a white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.67 (d, J = 12.4 Hz, 1H), 7.98-7.97 (m, 1H), 7.63-7.62 (m, 2H), 7.40- 7.30 (m, 4H), 6.75-6.73 (m, 1H), 3.94 (d, J = 8.4 Hz, 2H), 2.99-2.90 (m, 2H), 2.60-2.51 (m, 2H), 1.95-1.70 ( m, 3H), 1.30-1.10 (m, 2H); MS m/z: 391 [M+H] + .
실시예 19: 1-[2-아미노-6-(퓨란-3-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-19)Example 19: 1- [2-amino-6- (furan-3-yl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-5-ol (Ex-19)
Figure PCTKR2022004084-appb-I000111
Figure PCTKR2022004084-appb-I000111
실시예 1의 단계 4에서 2-(퓨란-2-일)-4,4,5,5-테트라메틸-1,3,2-디옥사보로란 대신에 2-(퓨란-3-일)-4,4,5,5-테트라메틸-1,3,2-디옥사보로란을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 1-[2-아미노-6-(퓨란-3-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-19; 7.40 mg, 16.0%)을 백색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 10.08(brs, 1H), 8.63(d, J = 8.8 Hz, 1H), 8.55(s, 1H), 7.84-7.83(m, 1H), 7.65(s, 1H), 7.36-7.35(m, 1H), 7.23-7.12(m, 3H), 7.04(s, 1H); MS m/z: 295 [M+H]+.2-(furan-3-yl) instead of 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan in step 4 of Example 1 1-[2-amino-6-(furan-3-) in the same manner as in Example 1, except that -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used. yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-19; 7.40 mg, 16.0%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.08 (brs, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.55 (s, 1H), 7.84-7.83 (m, 1H), 7.65(s, 1H), 7.36-7.35(m, 1H), 7.23-7.12(m, 3H), 7.04(s, 1H); MS m/z: 295 [M+H] + .
실시예 20: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-6-올(Ex-20)Example 20: 1- [2-amino-6- (furan-2-yl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-6-ol (Ex-20)
Figure PCTKR2022004084-appb-I000112
Figure PCTKR2022004084-appb-I000112
실시예 2의 단계 1에서 1-플루오로-4-메톡시-2-니트로벤젠 대신에 2-플루오로-4-메톡시-1-니트로벤젠을 사용한 것을 제외하고, 실시예 2의 단계 1 내지 6과 동일한 방법으로 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-20; 9.70 mg, 0.42%)을 담황색 고체로 수득하였다. 1H NMR(400MHz, DMSO) δ 7.99-7.97(m, 3H), 7.59(s, 1H), 7.32-7.31(m, 1H), 7.21(s, 2H), 7.09-7.06(m, 1H), 6.74-6.73(m, 1H); MS m/z: 295[M+H]+.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 In the same manner as in 6, 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-20; 9.70) mg, 0.42%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO) δ 7.99-7.97 (m, 3H), 7.59 (s, 1H), 7.32-7.31 (m, 1H), 7.21 (s, 2H), 7.09-7.06 (m, 1H), 6.74-6.73 (m, 1H); MS m/z: 295 [M+H] + .
실시예 21: 4-(퓨란-2-일)-6-{6-[3-(이미다졸-1-일)프로폭시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-21)Example 21: 4-(furan-2-yl)-6-{6-[3-(imidazol-1-yl)propoxy]-1H-1,2,3-benzotriazol-1-yl} Pyrimidin-2-amine (Ex-21)
Figure PCTKR2022004084-appb-I000113
Figure PCTKR2022004084-appb-I000113
실시예 20의 화합물(100 mg, 0.340 mmol) 및 1-(3-브로모프로필)이미다졸(96.0 mg, 0.510 mmol)을 DMF(1.00 mL) 중에서 교반하여 혼합하고, 실온에서 K2CO3(140 mg, 1.02 mmol)를 나누어 첨가하였다. 생성된 혼합물을 질소 대기하에 100℃에서 1.5시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 원하는 생성물을 LCMS로 확인할 수 있었다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다(컬럼: Kinetex EVO C18 컬럼, 30x150, 5 ㎛; 이동상 A: 물(10 mmol/L NH4HCO3), 이동상 B: ACN; 유속: 60 mL/분). 수집된 분획을 동결 건조하여 4-(퓨란-2-일)-6-{6-[3-(이미다졸-1-일)프로폭시]-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-21; 10.7 mg, 7.00%)을 황백색 고체로 수득하였다. 1H NMR(400MHz, DMSO-d6) δ 8.14-8.08(m, 2H), 7.98(s, 1H), 7.66-7.62(m, 2H), 7.38-7.32(m, 3H), 7.22-7.17(m, 2H), 6.90(s, 1H), 6.74(s, 1H), 4.24-4.19(m, 2H), 4.15-4.11(m, 2H), 2.33-2.23(m, 2H); MS m/z: 403 [M+H]+.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 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL /minute). The collected fractions were freeze-dried to 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. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14-8.08 (m, 2H), 7.98 (s, 1H), 7.66-7.62 (m, 2H), 7.38-7.32 (m, 3H), 7.22-7.17 ( m, 2H), 6.90(s, 1H), 6.74(s, 1H), 4.24-4.19(m, 2H), 4.15-4.11(m, 2H), 2.33-2.23(m, 2H); MS m/z: 403 [M+H] + .
실시예 22: 4-[6-(사이클로펜틸옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-22)Example 22: 4-[6-(cyclopentyloxy)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex- 22)
Figure PCTKR2022004084-appb-I000114
Figure PCTKR2022004084-appb-I000114
1-(3-브로모프로필)이미다졸 대신에 브로모사이클로펜탄을 사용한 것을 제외하고, 실시예 21과 동일한 방법으로 4-[6-(사이클로펜틸옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-22; 10.9 mg, 8.78%)을 담황색 고체로 수득하였다. 1H NMR(400 MHz, DMSO-d6) δ 8.13(s, 1H), 8.13(d, J = 3.2 Hz, 1H), 8.04(s, 1H), 7.62(s, 1H), 7.33(s, 3H), 7.14-7.11(m, 1H), 7.14-7.11(m, 1H), 6.75-6.76(m, 1H), 5.15-5.11(m, 1H), 2.33-2.32(m, 2H), 2.09-2.00(m, 4H), 1.79-1.71(m, 1H); MS m/z: 363 [M+H]+.4-[6-(cyclopentyloxy)-1H-1,2,3-benzo in the same manner as in Example 21, except that bromocyclopentane was used instead of 1-(3-bromopropyl)imidazole. Triazol-1-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-22; 10.9 mg, 8.78%) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13(s, 1H), 8.13(d, J = 3.2 Hz, 1H), 8.04(s, 1H), 7.62(s, 1H), 7.33(s, 3H), 7.14-7.11(m, 1H), 7.14-7.11(m, 1H), 6.75-6.76(m, 1H), 5.15-5.11(m, 1H), 2.33-2.32(m, 2H), 2.09- 2.00 (m, 4H), 1.79-1.71 (m, 1H); MS m/z: 363 [M+H] + .
실시예 23: 4-(퓨란-2-일)-6-{6-[2-(피페리딘-4-일)에톡시]-1H-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-23)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)
Figure PCTKR2022004084-appb-I000115
Figure PCTKR2022004084-appb-I000115
화합물(Ex-23)을 하기 반응식 8에 따라서 제조하였다.Compound (Ex-23) was prepared according to Scheme 8 below.
[반응식 8][Scheme 8]
Figure PCTKR2022004084-appb-I000116
Figure PCTKR2022004084-appb-I000116
단계 1: tert-부틸 4-[2-([3-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)에틸]피페리딘-1-카르복실레이트의 합성Step 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
실시예 20의 화합물(100 mg, 0.340 mmol) 및 tert-부틸 4-(2-브로모에틸)피페리딘-1-카르복실레이트(148 mg, 0.510 mmol)를 DMF(1.00 mL) 중에서 교반하여 혼합하고, 실온에서 K2CO3(140 mg, 1.02 mmol)를 나누어 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 1시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 원하는 생성물을 LCMS로 확인할 수 있었다. 생성뒨 혼합물에 물(3.00 mL)을 첨가하고, 생성된 혼합물을 CH2Cl2(3 x 3.00 mL)로 추출하였으며, 유기층을 모아서 물(3 x 2.00 mL)로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 tert-부틸 4-[2-([3-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)에틸]피페리딘-1-카르복실레이트(100 mg, 58.0%)를 황색 고체로 수득하였다. MS m/z: 506 [M+H]+.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. Water (3.00 mL) was added to the resulting mixture, and the resulting mixture was extracted with CH 2 Cl 2 (3 x 3.00 mL), the combined organic layers were washed with water (3 x 2.00 mL), and anhydrous Na 2 SO 4 dried with After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography, followed by tert-butyl 4-[2-([3-[2-amino-6-(furan-) 2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)ethyl]piperidine-1-carboxylate (100 mg, 58.0%) as a yellow solid obtained. MS m/z: 506 [M+H] + .
단계 2: 4-(퓨란-2-일)-6-{6-[2-(피페리딘-4-일)에톡시]-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-23)의 합성Step 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)
상기 단계 1에서 수득된 화합물(100 mg, 0.240 mmol)을 DCM(1.0 0mL) 중에 교반하고, 용액에 실온에서 TFA(0.330 mL)를 적가하였다. 생성된 혼합물을 실온에서 1시간 동안 교반하였다. 원하는 생성물을 LCMS로 확인할 수 있었다. 조 생성물을 하기 조건에서 정제하였다(컬럼: Kinetex EVO C18 컬럼, 30x150, 5 ㎛; 이동상 A : 물(10 mmol/L NH4HCO3), 이동상 B: ACN; 유속: 60 mL/분). 수집된 분획을 동결 건조하여 4-(퓨란-2-일)-6-{6-[2-(피페리딘-4-일)에톡시]-1,2,3-벤조트리아졸-1-일}피리미딘-2-아민(Ex-23; 7.80 mg, 7.78%)을 황백색 고체로 수득하였다. 1H NMR(400MHz, DMSO-d6) δ 8.13(s, 1H), 8.13(d, J = 3.2Hz, 1H), 8.04(s, 1H), 7.62(s, 1H), 7.33(s, 3H), 7.14-7.11(m, 1H), 7.14-7.11(m, 1H), 6.75-6.76(m, 1H), 5.15-5.11(m, 1H), 2.33-2.32(m, 2H), 2.09-2.00(m, 4H), 1.79-1.71(m, 1H); MS m/z: 406 [M+H]+.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 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min). The collected fractions were freeze-dried to 4-(furan-2-yl)-6-{6-[2-(piperidin-4-yl)ethoxy]-1,2,3-benzotriazole-1- Mono}pyrimidin-2-amine (Ex-23; 7.80 mg, 7.78%) was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13(s, 1H), 8.13(d, J = 3.2Hz, 1H), 8.04(s, 1H), 7.62(s, 1H), 7.33(s, 3H) ), 7.14-7.11(m, 1H), 7.14-7.11(m, 1H), 6.75-6.76(m, 1H), 5.15-5.11(m, 1H), 2.33-2.32(m, 2H), 2.09-2.00 (m, 4H), 1.79-1.71 (m, 1H); MS m/z: 406 [M+H] + .
실시예 24: 4-[5-(4-벤질피페라진-1-카르보닐)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-24)Example 24: 4-[5-(4-benzylpiperazine-1-carbonyl)-1H-1,2,3-benzotriazol-1-yl]-6-(furan-2-yl)pyrimidine -2-amine (Ex-24)
Figure PCTKR2022004084-appb-I000117
Figure PCTKR2022004084-appb-I000117
화합물(Ex-24)을 하기 반응식 9에 따라서 제조하였다.Compound (Ex-24) was prepared according to Scheme 9 below.
[반응식 9][Scheme 9]
Figure PCTKR2022004084-appb-I000118
Figure PCTKR2022004084-appb-I000118
단계 1 내지 5: 메틸 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-카르복실레이트의 합성Steps 1 to 5: Synthesis of methyl 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylate
실시예 2의 단계 1에서 1-플루오로-4-메톡시-2-니트로벤젠 대신에 메틸 4-플루오로-3-니트로벤조에이트를 사용한 것을 제외하고 실시예 2의 단계 1 내지 실시예 2의 단계 5와 동일한 방법으로 메틸 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-카르복실레이트(800 mg, 35.5%)를 분홍색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.88(d, J = 8.0 Hz, 1H), 8.75(s, 1H), 8.22-8.19(m, 1H), 7.97(s, 1H), 7.61(s, 1H), 7.36(s, 2H), 7.34-7.33(m, 1H), 6.74-6.72(m, 1H), 3.92(s, 3H); MS m/z: 337 [M+H]+.Steps 1 to 2 of Example 2, except that methyl 4-fluoro-3-nitrobenzoate was used instead of 1-fluoro-4-methoxy-2-nitrobenzene in Step 1 of Example 2 Methyl 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylate (800 mg, 35.5%) as a pink solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ(ppm): 8.88(d, J = 8.0 Hz, 1H), 8.75(s, 1H), 8.22-8.19(m, 1H), 7.97(s, 1H), 7.61(s, 1H), 7.36(s, 2H), 7.34-7.33(m, 1H), 6.74-6.72(m, 1H), 3.92(s, 3H); MS m/z: 337 [M+H] + .
단계 6: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-카르복실산의 합성Step 6: Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylic acid
상기 단계 5에서 수득된 화합물(2.00 g, 5.94 mmol)을 THF(20.0 mL) 중에 교반 혼합하고, H2O(4.00 mL) 중 LiOH(1.40 g, 58.5 mmol)를 첨가하였다. 생성된 혼합물을 25℃에서 16시간 동안 교반하고, 진공하에 농축시켰다. 조 생성물을 역상 컬럼 크로마토그래피로 정제하였다(컬럼, C18 실리카겔, 80g, 40-60 ㎛, 60A; 이동상, 물(10 mmol/L NH4HCO3) 및 ACN(0% ACN, 30분에 최대 100%까지); 검출기, UV 220&254 nm). 수집된 분획을 농축하여 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-카르복실산(900 mg, 42.3%)을 황백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.66(d, J = 8.0 Hz, 1H), 8.57(s, 1H), 8.28-8.25(m, 1H), 7.97(s, 1H), 7.62(s, 1H), 7.32(s, 2H), 6.73-6.10(m, 1H); MS m/z: 323 [M+H]+.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 μm, 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). The collected fractions were concentrated and 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazole-5-carboxylic acid (900 mg, 42.3 %) as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ(ppm): 8.66(d, J = 8.0 Hz, 1H), 8.57(s, 1H), 8.28-8.25(m, 1H), 7.97(s, 1H), 7.62(s, 1H), 7.32(s, 2H), 6.73-6.10(m, 1H); MS m/z: 323 [M+H] + .
단계 7: 4-[5-(4-벤질피페라진-1-카르보닐)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-24)의 합성Step 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)
상기 단계 6에서 수득된 화합물(110 mg, 0.340 mmol) 및 벤질피페라진(72.0 mg, 0.410 mmol)을 DMF(3.00 mL) 중에서 교반하여 혼합하고, HATU(456 mg, 1.19 mmol) 및 DIEA(132 mg, 1.02 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 3시간 동안 교반하였다. 혼합물을 물(50.0 mL)에 붓고, 생성된 혼합물을 EtOAc(60.0 mL)로 추출하였다. 유기층을 모아서 염수(50.0 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18, 30 mm X 150 mm, 5 ㎛; 이동상, 물(50 mmol/L NH4HCO3) 및 ACN(48% PhaseB, 7분에 최대 68%); 검출기, UV 254&220 nm. 생성물 분획을 동결 건조하여 4-[5-(4-벤질피페라진-1-카르보닐)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-24; 9.10 mg, 5.33%)을 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.86(d, J = 8.4 Hz, 1H), 8.26(s, 1H), 7.99(s, 1H), 7.72(d, J = 8.8 Hz, 1H), 7.65(s, 1H), 7.36-7.25(m, 8H), 6.75-6.74(m, 1H）, 3.76-3.68(m, 2H), 3.52(s, 2H), 3.39-3.31(m, 2H), 2.49-2.32(m, 4H); MS m/z: 481 [M+H]+.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 μm; mobile phase, water (50 mmol/L NH 4 HCO 3 ) and ACN (48% PhaseB, up to 68% in 7 min); Detector, UV 254&220 nm. 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. 1 H-NMR (400 MHz, DMSO-d 6 ) δ(ppm): 8.86(d, J = 8.4 Hz, 1H), 8.26(s, 1H), 7.99(s, 1H), 7.72(d, J = 8.8 Hz, 1H), 7.65(s, 1H), 7.36-7.25(m, 8H), 6.75-6.74(m, 1H), 3.76-3.68(m, 2H), 3.52(s, 2H), 3.39-3.31 (m, 2H), 2.49-2.32 (m, 4H): MS m/z: 481 [M+H] + .
실시예 25: {1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일}메틸 N-(티오펜-3-일)카르바메이트(Ex-25)Example 25: {1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl}methyl N-(thi Offen-3-yl)carbamate (Ex-25)
Figure PCTKR2022004084-appb-I000119
Figure PCTKR2022004084-appb-I000119
화합물(Ex-25)을 하기 반응식 10에 따라서 제조하였다.Compound (Ex-25) was prepared according to Scheme 10 below.
[반응식 10][Scheme 10]
Figure PCTKR2022004084-appb-I000120
Figure PCTKR2022004084-appb-I000120
단계 1: [1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]메탄올의 합성Step 1: Synthesis of [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methanol
실시예 24의 단계 5에서 수득된 화합물(500 mg, 1.48 mmol) 및 LiAlH4(110 mg, 2.90 mmol)을 THF(10.0 mL) 중에서 질소 대기하에 실온에서 15분 동안 교반하였다. 반응을 실온에서 물/얼음으로 퀀칭시켰다. 혼합물을 물(90.0 mL)에 붓고 CH2Cl2(80 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하여, [1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]메탄올(300 mg, 60.9%)을 백색 고체로 수득하였다. MS m/z: 309 [M+H]+.The compound obtained in step 5 of Example 24 (500 mg, 1.48 mmol) and LiAlH 4 (110 mg, 2.90 mmol) were stirred in THF (10.0 mL) under nitrogen atmosphere at room temperature for 15 minutes. The reaction was quenched with water/ice at room temperature. The mixture was poured into water (90.0 mL) and extracted with CH 2 Cl 2 (80 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methanol (300 mg, 60.9%) as a white solid. MS m/z: 309 [M+H] + .
단계 2: [1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]메틸 N-(티오펜-3-일)카르바메이트(Ex-25)의 합성Step 2: [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methyl N-(thiophen-3) Synthesis of -yl) carbamate (Ex-25)
상기 단계 1에서 수득된 화합물(50.0 mg, 0.160 mmol) 및 3-이소시아네이토티오펜(44.0 mg, 0.350 mmol)을 DMF(2.00 mL) 중에서 교반하여 혼합하고, DIEA(68.0 mg, 0.520 mmol)를 첨가하였다. 생성된 혼합물을 질소 대기하에 실온에서 3시간 동안 교반하였다. 혼합물을 물(80.0 mL)에 붓고 EtOAc(80.0 mL)로 추출하고, 유기층을 모아서 염수(80.0 mL)로 세척한 후 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(44% PhaseB, 7분에 최대 64%). 생성물 분획을 동결 건조하여 [1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]메틸 N-(티오펜-3-일)카르바메이트(Ex-25; 5.50 mg, 7.67%)를 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.13(s, 1H), 8.83(d, J = 8.8 Hz, 1H), 8.27(s, 1H), 7.99-7.98(m, 1H), 7.81-7.78(m, 1H), 7.65(s, 1H), 7.45-7.43(m, 1H), 7.35-7.34(m, 3H), 7.24(s, 1H), 7.03-7.02(m, 1H), 6.75-6.74(m, 1H), 5.36(s, 2H); MS m/z: 434 [M+H]+.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 . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30x150 mm, 5 μm; Mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (44% PhaseB, up to 64% in 7 min). The product fractions were lyophilized to [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methyl N-(thi Offen-3-yl)carbamate (Ex-25; 5.50 mg, 7.67%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.13 (s, 1H), 8.83 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 7.99-7.98 (m, 1H), 7.81-7.78(m, 1H), 7.65(s, 1H), 7.45-7.43(m, 1H), 7.35-7.34(m, 3H), 7.24(s, 1H), 7.03-7.02(m, 1H), 6.75-6.74 (m, 1H), 5.36 (s, 2H); MS m/z: 434 [M+H] + .
실시예 26: [1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-일]메틸3,4-디하이드로-1H-이소퀴놀린-2-카르복실레이트(Ex-26)Example 26: [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-yl]methyl3,4- Dihydro-1H-isoquinoline-2-carboxylate (Ex-26)
Figure PCTKR2022004084-appb-I000121
Figure PCTKR2022004084-appb-I000121
실시예 25의 단계 1에서 수득된 화합물(100 mg, 0.320 mmol), CDI(105 mg, 0.648 mmol) 및 TEA(131 mg, 1.29 mmol)를 DMF(3.00 mL) 중에 교반하여 혼합하고, 생성된 혼합물을 질소 대기하에 실온에서 30분 동안 교반하였다. 테트라히드로이소퀴놀린(86.0 mg, 0.640 mmol)을 첨가하고, 생성된 혼합물을 질소 대기하에 60℃에서 1시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 혼합물을 물(60.0 mL)에 붓고 EtOAc(60.0 mL)로 추출하고, 유기층을 모아서 염수(60.0 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여액을 감압 농축하고, 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18, 30 mm x150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(59% PhaseB, 7분에 79%까지); 검출기, UV 254&220 nm. 생성물 분획을 동결 건조하여 [1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]메틸 3,4-디하이드로-1H-이소퀴놀린-2-카르복실레이트(Ex-26; 14.4 mg, 9.40%)를 백색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 8.21(d, J = 8.4 Hz, 1H), 8.23(s, 1H), 7.98(s, 1H), 7.77(d, J = 8.8 Hz, 1H), 7.65(s, 1H), 7.34-7.33(m, 3H), 7.19-7.17(m, 4H), 6.75-6.74(m, 1H), 5.34(s, 2H), 4.68-4.57(m, 2H), 3.75-3.63(m, 2H), 2.84-2.81(m, 2H); MS m/z: 468 [M+H]+.Compound obtained in step 1 of Example 25 (100 mg, 0.320 mmol), CDI (105 mg, 0.648 mmol) and TEA (131 mg, 1.29 mmol) were stirred in DMF (3.00 mL) to mix, and the resulting mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. Tetrahydroisoquinoline (86.0 mg, 0.640 mmol) was added, the resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 1 h, and the mixture was cooled to room temperature. The mixture was poured into water (60.0 mL) and extracted with EtOAc (60.0 mL), the combined organic layers were washed with brine (60.0 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C 18 , 30 mm×150 mm, 5 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (59% PhaseB, to 79% in 7 min); Detector, UV 254&220 nm. The product fractions were freeze-dried to [1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]methyl 3,4- Dihydro-1H-isoquinoline-2-carboxylate (Ex-26; 14.4 mg, 9.40%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.21 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.65(s, 1H), 7.34-7.33(m, 3H), 7.19-7.17(m, 4H), 6.75-6.74(m, 1H), 5.34(s, 2H), 4.68-4.57 (m, 2H), 3.75-3.63 (m, 2H), 2.84-2.81 (m, 2H); MS m/z: 468 [M+H] + .
실시예 27: 1-[2-아미노-6-(퓨란-2-일)-5-(피리딘-4-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-27)Example 27: 1-[2-amino-6-(furan-2-yl)-5-(pyridin-4-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole- 5-All (Ex-27)
Figure PCTKR2022004084-appb-I000122
Figure PCTKR2022004084-appb-I000122
화합물(Ex-27)를 하기 반응식 11에 따라서 제조하였다.Compound (Ex-27) was prepared according to Scheme 11 below.
[반응식 11][Scheme 11]
Figure PCTKR2022004084-appb-I000123
Figure PCTKR2022004084-appb-I000123
Figure PCTKR2022004084-appb-I000124
Figure PCTKR2022004084-appb-I000124
Figure PCTKR2022004084-appb-I000125
Figure PCTKR2022004084-appb-I000125
단계 1 내지 3: 1-[5-브로모-6-클로로-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Steps 1 to 3: Synthesis of 1-[5-bromo-6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
실시예 2의 단계 1에서 2,6-디클로로피리미딘-4-아민 대신에 제조예 8의 화합물(H)(26.5 g, 104 mmol)을 사용한 것을 제외하고 실시예 2의 단계 1 내지 3과 동일한 방법으로 1-[5-브로모-6-클로로-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(20.0 g, 62.0%)을 갈색을 띤 고체로 수득하였다. MS m/z: 386 [M+H]+.The same as in Steps 1 to 3 of Example 2, except that Compound (H) (26.5 g, 104 mmol) of Preparation Example 8 was used instead of 2,6-dichloropyrimidin-4-amine in Step 1 of Example 2 Method 1- [5-bromo-6-chloro-2- (methylsulfanyl) pyrimidin-4-yl] -5-methoxy-1,2,3-benzotriazole (20.0 g, 62.0%) was obtained as a brownish solid. MS m/z: 386 [M+H] + .
단계 4: 1-[6-클로로-2-(메틸설파닐)-5-(피리딘-4-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Step 4: 1-[6-chloro-2-(methylsulfanyl)-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole synthesis
단계 3에서 수득된 화합물(20.0 g, 51.7 mmol) 및 피리딘-4-일 보론산(5.09 g, 41.4 mmol)을 디옥산(300 mL) 및 H2O(50.0 mL) 중에 혼합하고, K2CO3(21.6 g, 156 mmol) 및 Pd(dppf)Cl2(7.57g, 10.3 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 2시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 혼합물을 물(500 mL)로 희석하고 EtOAc(3 x 600 mL)로 추출하고, 유기층을 모아서 무수 황산나트륨상에서 건조시키고 감압 농축시켰다. 조 생성물을 EA/PE(1/2)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-클로로-2-(메틸설파닐)-5-(피리딘-4-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(3.00g, 14.0%)을 보라색 고체로 수득하였다. MS m/z: 385 [M+H]+.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. The crude product was eluted with EA/PE (1/2) and purified by silica gel column chromatography to 1-[6-chloro-2-(methylsulfanyl)-5-(pyridin-4-yl)pyrimidine-4- yl]-5-methoxy-1,2,3-benzotriazole (3.00 g, 14.0%) was obtained as a purple solid. MS m/z: 385 [M+H] + .
단계 5: 1-[6-(퓨란-2-일)-2-(메틸설파닐)-5-(피리딘-4-일))피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Step 5: 1-[6-(furan-2-yl)-2-(methylsulfanyl)-5-(pyridin-4-yl))pyrimidin-4-yl]-5-methoxy-1,2 Synthesis of ,3-benzotriazole
Figure PCTKR2022004084-appb-I000126
Figure PCTKR2022004084-appb-I000126
단계 4에서 수득된 화합물(3.00 g, 7.79 mmol) 및 퓨란-2-일 보론산(872 mg, 7.79 mmol)을 디옥산(50.0 mL) 및 H2O(10.0 mL) 중에 혼합하고, Cs2CO3(7.61 g, 23.4 mmol), Xphos(743 mg, 1.56 mmol) 및 XPhos Pd G3(659 mg, 0.780 mmol)을 첨가하였다. 생성된 혼합물을 질소 대기하에 8℃에서 2시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 물(60.0 mL)로 희석하고 EtOAc(3 x 80.0 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨상에서 건조시키고 감압 농축시켰다. 조 생성물을 EtOAc/PE(1/2)로 용출시켜 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-(퓨란-2-일)-2-(메틸설파닐)-5-(피리딘-4-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(1.20 g, 35.1%)을 황색 고체로서 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.83-8.81(m, 2H), 8.03-8.00(m, 1H), 7.80(s, 1H), 7.57-7.56(m, 1H), 7.44-7.30(m, 3H), 6.60(s, 2H), 3.85(s, 3H), 2.68(s, 3H); MS m/z: 417 [M+H]+.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. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.83-8.81 (m, 2H), 8.03-8.00 (m, 1H), 7.80 (s, 1H), 7.57-7.56 (m, 1H) ), 7.44-7.30 (m, 3H), 6.60 (s, 2H), 3.85 (s, 3H), 2.68 (s, 3H); MS m/z: 417 [M+H] + .
단계 6: 1-[6-(퓨란-2-일)-2-메탄설포닐-5-(피리딘-4-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Step 6: 1-[6-(furan-2-yl)-2-methanesulfonyl-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1,2,3- Synthesis of benzotriazole
단계 5에서 수득된 화합물(1.20 g, 2.88 mmol)을 MeOH(20.0 mL) 중에 교반 혼합하고, H2O(10.0 mL) 중 칼륨 퍼옥시모노설페이트(H3K5O18S4)(5.31 g, 8.64 mmol) 용액을 첨가하였다. 생성된 혼합물을 25℃에서 4시간 동안 교반하였다. 반응을 Na2S2O3 포화 수용액으로 퀀칭하고, 생성된 혼합물을 EtOAc(3 x 100 mL)로 추출하였다. 유기층을 모아서 NaHCO3 포화 수용액으로 세척하고, 무수 Na2SO4로 건조하였다. 여과 후, 여액을 감압 농축하여 1-[6-(퓨란-2-일)-2-메탄설포닐-5-(피리딘-4-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(1.00 g, 미정제)을 황색 고체로 수득하였다. MS m/z: 449 [M+H]+.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 . After filtration, the filtrate was concentrated under reduced pressure to 1-[6-(furan-2-yl)-2-methanesulfonyl-5-(pyridin-4-yl)pyrimidin-4-yl]-5-methoxy-1 ,2,3-benzotriazole (1.00 g, crude) was obtained as a yellow solid. MS m/z: 449 [M+H] + .
단계 7: 4-(퓨란-2-일)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)-5-(피리딘-4-일)피리미딘-2-아민의 합성Step 7: 4-(furan-2-yl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)-5-(pyridin-4-yl)pyrimidin-2- Synthesis of amines
단계 6에서 수득된 화합물(1.00 g, 2.23 mmol)을 THF(5.00 mL) 중에서 교반하고, NH3·H2O(5.00 mL)를 첨가하였다. 생성된 혼합물을 25℃에서 2시간 동안 교반하였다. 반응을 물(100 mL)로 퀀칭시키고, 생성된 혼합물을 EtOAc(3 x 100 mL)로 추출하였다. 유기층을 모아서 염수(2 x 100 mL)로 세척하고 무수 Na2SO4로 건조시켰다. 여과 후 여과액을 감압 농축하고, 잔사를 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 4-(퓨란-2-일)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)-5-(피리딘-4-일)피리미딘-2-아민(220 mg, 23.0%)을 황백색 고체로 수득하였다. MS m/z: 386 [M+H]+.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 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography, followed by 4-(furan-2-yl)-6-(5-methoxy-1,2). Obtained ,3-benzotriazol-1-yl)-5-(pyridin-4-yl)pyrimidin-2-amine (220 mg, 23.0%) as an off-white solid. MS m/z: 386 [M+H] + .
단계 8: 1-[2-아미노-6-(퓨란-2-일)-5-(피리딘-4-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-올(Ex-27)의 합성Step 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)
단계 7에서 수득된 화합물(25.0 mg, 0.065 mmol) 및 BBr3을 DCM(1M)(2 mL) 중에서 질소 대기하에 25℃에서 2시간 동안 교반하였다. 반응을 MeOH(1 mL)로 퀀칭하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x15 0mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(20% PhaseB, 7분에 최대 40%); 검출기, UV 254&220 nm. 수집된 분획을 동결 건조하여 1-[2-아미노-6-(퓨란-2-일)-5-(피리딘-4-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-올(Ex-27; 5.00 mg, 20.7%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 9.85(s, 1H), 8.45(d, J = 4.5 Hz, 2H), 7.95(d, J = 8.7 Hz, 1H), 7.72(s, 1H), 7.44(s, 2H), 7.22(d, J = 4.5 Hz, 2H), 7.16-7.11(m, 2H), 6.51-6.49(m, 1H), 6.25-6.24(m, 1H); MS m/z: 372 [M+H]+.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 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (20% PhaseB, up to 40% in 7 min); Detector, UV 254&220 nm. The collected fractions were freeze-dried to 1-[2-amino-6-(furan-2-yl)-5-(pyridin-4-yl)pyrimidin-4-yl]-1,2,3-benzotriazole 5-ol (Ex-27; 5.00 mg, 20.7%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 9.85 (s, 1H), 8.45 (d, J = 4.5 Hz, 2H), 7.95 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.44 (s, 2H), 7.22 (d, J = 4.5 Hz, 2H), 7.16-7.11 (m, 2H), 6.51-6.49 (m, 1H), 6.25-6.24 (m, 1H) ); MS m/z: 372 [M+H] + .
실시예 28: 4-[5-(사이클로펜틸옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)-5-(피리딘-4-일)피리미딘-2-아민(Ex-28)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)
Figure PCTKR2022004084-appb-I000127
Figure PCTKR2022004084-appb-I000127
실시예 27의 화합물(35.0 mg, 0.094 mmol) 및 브로모사이클로펜탄(42.0 mg, 0.280 mmol)을 DMF(3.00 mL) 중에 교반 혼합하고, Cs2CO3(77.0 mg, 0.230 mmol)을 첨가하였다. 생성된 혼합물을 60℃에서 2시간 동안 교반하고, MeOH(2.00 mL)로 반응을 퀀칭시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(38% PhaseB, 10분에 최대 49%); 검출기, UV 254&220 nm. 수집된 분획을 동결 건조하여 4-[5-(사이클로펜틸옥시)-1H-1,2,3-벤조트리아졸-1-일]-6-(퓨란-2-일)-5-(피리딘-4-일)피리미딘-2-아민(Ex-28; 17.1 mg, 40.9%)을 백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.46(d, J = 4.5 Hz, 2H), 8.01(d, J = 9.0 Hz, 1H), 7.72(d, J = 1.6 Hz, 1H), 7.46(s, 2H), 7.40(d, J = 2.1 Hz, 1H), 7.22(d, J = 4.5 Hz, 2H), 7.20-7.17(m, 1H), 6.51-6.50(m, 1H), 6.25-6.24(m, 1H), 1.97-1.90(m, 2H), 1.75-1.57(m, 6H); MS m/z: 440 [M+H]+.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 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (38% PhaseB, up to 49% in 10 min); Detector, UV 254&220 nm. The collected fractions were freeze-dried to 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. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.46 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 1.6 Hz) , 1H), 7.46 (s, 2H), 7.40 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 4.5 Hz, 2H), 7.20-7.17 (m, 1H), 6.51-6.50 (m, 1H), 6.25-6.24 (m, 1H), 1.97-1.90 (m, 2H), 1.75-1.57 (m, 6H); MS m/z: 440 [M+H] + .
실시예 29: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일)-1H-1,3-벤조디아졸-5-올(Ex-29)Example 29: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1H-1,3-benzodiazole-5- All (Ex-29)
Figure PCTKR2022004084-appb-I000128
Figure PCTKR2022004084-appb-I000128
화합물(Ex-29)을 하기 반응식 12에 따라서 제조하였다.Compound (Ex-29) was prepared according to Scheme 12 below.
[반응식 12][Scheme 12]
Figure PCTKR2022004084-appb-I000129
Figure PCTKR2022004084-appb-I000129
단계 1: 6-(퓨란-2-일)-N-(4-메톡시-2-니트로페닐)-2-(메틸설파닐)피리미딘-4-아민의 합성Step 1: Synthesis of 6-(furan-2-yl)-N-(4-methoxy-2-nitrophenyl)-2-(methylsulfanyl)pyrimidin-4-amine
제조예 9에서 수득된 화합물(I)(4.10 g, 19.8 mmol)을 THF(40.0 mL) 중에 교반 혼합하고, NaH(1.58 g, 39.6 mmol, 미네랄 오일 중 60% 분산)를 질소 대기하에 0℃에서 나누어 첨가하였다. 생성된 혼합물을 질소 대기하에 0℃에서 1시간 동안 교반하고, 0℃에서 1-플루오로-4-메톡시-2-니트로벤젠(6.70 g, 39.6 mmol)을 첨가하였다. 생성된 혼합물을 60℃에서 추가로 5시간 동안 교반하고, 반응을 물(100 mL)로 퀀칭시켰다. 혼합물을 EtOAc(3 x 300 mL)로 추출하고, 무수 Na2SO4로 건조하고 감압 농축하였다. 침전된 고체를 여과하여 수집하고, 헥산(3 x 100 mL)으로 세척하였다. 생성된 고체를 적외선 하에서 건조시켜서 6-(퓨란-2-일)-N-(4-메 톡시-2-니트로페닐)-2-(메틸설파닐)피리미딘-4-아민(5.50 g, 72.9%)을 적색 고체로 수득하였다. MS m/z: 359 [M+H]+.Compound (I) obtained in Preparation Example 9 (4.10 g, 19.8 mmol) was stirred and mixed in THF (40.0 mL), and NaH (1.58 g, 39.6 mmol, 60% dispersion in mineral oil) was dissolved in a nitrogen atmosphere at 0° C. were added in portions. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 h, and 1-fluoro-4-methoxy-2-nitrobenzene (6.70 g, 39.6 mmol) was added at 0° C. The resulting mixture was stirred at 60° C. for an additional 5 h and the reaction was quenched with water (100 mL). The mixture was extracted with EtOAc (3 x 300 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexanes (3 x 100 mL). The resulting solid was dried under infrared light to 6-(furan-2-yl)-N-(4-methoxy-2-nitrophenyl)-2-(methylsulfanyl)pyrimidin-4-amine (5.50 g, 72.9 %) as a red solid. MS m/z: 359 [M+H] + .
단계 2: N1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-4-메톡시벤젠-1,2-디아민의 합성Step 2: Synthesis of N1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-4-methoxybenzene-1,2-diamine
상기 단계 1에서 수득된 화합물(5.50 g, 15.3 mmol) 및 Pd/C(800 mg, 10%)의 혼합물을 EtOAc(50.0 mL) 중에서 수소 대기 하에 25℃에서 6시간 동안 교반하였다. 생성된 혼합물을 여과하고, 필터 케이크를 EtOAc(3 x 300 mL)로 세척하고, 여액을 감압 농축시켜서 N1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-4-메톡시벤젠-1,2-디아민(4.00 g, 72.2%)을 자주색 고체로 수득하였다. MS m/z: 329 [M+H]+.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] + .
단계 3: 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-2-(피리딘-4-일)-1,3-벤조디아졸의 합성Step 3: 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3- Synthesis of benzodiazoles
상기 단계 2에서 수득된 화합물(1.50 g, 4.56 mmol) 및 4-포르밀 피리딘(587 mg, 5.48 mmol)을 DMF(30.0 mL) 중에서 교반 혼합하고, Na2S2O5(4.30 g, 22.8 mmol)을 첨가하였다. 최종 반응 혼합물에 140℃에서 3시간 동안 마이크로파를 조사하였다. 이어서 혼합물을 실온으로 냉각시키고, 생성된 혼합물을 물(400 mL)에 붓고, EtOAc(3 x 400 mL)로 추출하였다. 유기층을 모아서 염수(2 x 300 mL)로 세척하고, 무수 Na2SO4로 건조하고, 여과하여 감압 농축시켰다. 잔사를 PE/EtOAc(1:5)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-2-(피리딘-4-일)-1,3-벤조디아졸(800 mg, 40.5%)을 진황색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 8.68-8.67(m, 2H), 8.03(s, 1H), 7.64-7.57(m, 1H), 7.50-7.49(m, 2H), 7.43-7.42(m, 2H), 7.27-7.26(m, 1H), 7.10-7.07(m, 1H), 6.84-6.78(m, 1H), 3.86(s, 3H), 2.23(s, 3H); MS m/z: 416 [M+H]+.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. The residue was eluted with PE/EtOAc (1:5) and purified by silica gel column chromatography to 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5- Methoxy-2-(pyridin-4-yl)-1,3-benzodiazole (800 mg, 40.5%) was obtained as a deep yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.68-8.67 (m, 2H), 8.03 (s, 1H), 7.64-7.57 (m, 1H), 7.50-7.49 (m, 2H) ), 7.43-7.42(m, 2H), 7.27-7.26(m, 1H), 7.10-7.07(m, 1H), 6.84-6.78(m, 1H), 3.86(s, 3H), 2.23(s, 3H) ); MS m/z: 416 [M+H] + .
단계 4: 1-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-5-메톡시-2-(피리딘-4-일)-1,3-벤조디아졸의 합성Step 4: 1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3-benzodia synthesis of sol
단계 3에서 수득한 화합물(800 mg, 1.92 mmol) 및 칼륨 퍼옥시모노설페이트(H3K5O18S4)(9.40 g, 15.4 mmol)를 MeOH(30.0 mL) 및 H2O(15.0 mL) 중에서 3시간 동안 25℃에서 교반 혼합하였다. 반응을 티오황산나트륨 용액(200 mL)으로 퀀칭시키고, 생성된 혼합물을 물(100 mL)에 붓고, CH2Cl2(3 x 200 mL)로 추출하였다. 유기층을 모아서 중탄산 나트륨 용액(2 x 100 mL)으로 세척하고, 무수 Na2SO4상에서 건조하고, 여과하고 감압 농축하여 1-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-5-메톡시-2-(피리딘-4-일)-1,3-벤조디아졸(900 mg, 93.0%)을 황백색 고체로 수득하였다. MS m/z: 448 [M+H]+. Compound obtained in step 3 (800 mg, 1.92 mmol) and potassium peroxymonosulfate (H 3 K 5 O 18 S 4 ) (9.40 g, 15.4 mmol) were mixed with MeOH (30.0 mL) and H 2 O (15.0 mL) The mixture was stirred and mixed at 25° C. for 3 hours. The reaction was quenched with sodium thiosulfate solution (200 mL) and the resulting mixture was poured into water (100 mL) and extracted with CH 2 Cl 2 (3×200 mL). The combined organic layers were washed with sodium bicarbonate solution (2 x 100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to 1-[6-(furan-2-yl)-2-methanesulfonylpyrimidine. -4-yl]-5-methoxy-2-(pyridin-4-yl)-1,3-benzodiazole (900 mg, 93.0%) was obtained as an off-white solid. MS m/z: 448 [M+H] + .
단계 5: 4-(퓨란-2-일)-6-[5-메톡시-2-(피리딘-4-일)-1,3-벤조디아졸-1-일]피리미딘-2-아민의 합성Step 5: of 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-yl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine synthesis
상기 단계 4에서 수득한 화합물(900 mg, 2.01 mmol) 및 NH3·H2O(10.0 mL)를 THF(10.0 mL) 중에서 25℃에서 3시간 동안 교반하고, 생성된 혼합물을 감압 농축시켰다. 잔사를 CH2Cl2/MeOH(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 4-(퓨란-2-일)-6-[5-메톡시-2-(피리딘-4-일)-1,3-벤조디아졸-1-일]피리미딘-2-아민(500 mg, 60.1%)을 갈색 고체로 수득하였다. MS m/z: 385 [M+H]+.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. MS m/z: 385 [M+H] + .
단계 6: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일)-1,3-벤조디아졸-5-올(Ex-29)의 합성Step 6: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzodiazol-5-ol (Ex -29) synthesis
상기 단계 5에서 수득된 화합물(100 mg, 0.260 mmol) 및 BBr3를 DCM(1 M, 2.00 mL) 중에 25℃에서 5시간 동안 교반 혼합하였다. 반응을 MeOH(2.00 mL)로 퀀칭시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, Xselect CSH OBD 컬럼 30 x 150 mm 5 ㎛, n; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(15% PhaseB, 9분에 최대 45%까지); 검출기, UV 254 nm. 수집된 분획을 동결 건조하여 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일)-1,3-벤조디아졸-5-올(Ex-29; 5.30 mg, 5.45%)을 황백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.43 (s, 1H), 8.66-8.64 (m, 2H), 7.90 (s, 1H), 7.59-7.57 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 2H), 6.90-6.87 (m, 1H), 6.86 (s, 1H), 6.70-6.69 (m, 1H); MS m/z: 371 [M+H]+.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 μm, n; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (15% PhaseB, up to 45% in 9 min); Detector, UV 254 nm. The collected fractions were freeze-dried to 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzodiazole-5 -ol (Ex-29; 5.30 mg, 5.45%) was obtained as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.43 (s, 1H), 8.66-8.64 (m, 2H), 7.90 (s, 1H), 7.59-7.57 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 2H), 6.90-6.87 (m, 1H), 6.86 (s) , 1H), 6.70-6.69 (m, 1H); MS m/z: 371 [M+H] + .
실시예 30: 4-(퓨란-2-일)-6-{5-[(피페리딘-4-일)메톡시]-2-(피리딘-4-일)-1H-1,3-벤조디아졸-1-일}피리미딘-2-아민(Ex-30)Example 30: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-2-(pyridin-4-yl)-1H-1,3-benzo Diazol-1-yl}pyrimidin-2-amine (Ex-30)
Figure PCTKR2022004084-appb-I000130
Figure PCTKR2022004084-appb-I000130
화합물(Ex-30)을 하기 반응식 13에 따라서 제조하였다.Compound (Ex-30) was prepared according to Scheme 13 below.
[반응식 13][Scheme 13]
Figure PCTKR2022004084-appb-I000131
Figure PCTKR2022004084-appb-I000131
단계 1: tert-부틸 4-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일)-1,3-벤조디아졸-5-일]옥시)메틸]피페리딘-1-카르복실레이트의 합성Step 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
실시예 29의 화합물(120 mg, 0.320 mmol) 및 tert-부틸 4-(브로모메틸)피페리딘-1-카르복실레이트(180 mg, 0.640 mmol)를 DMF(3.00 mL) 중에 교반한 혼합물에 Cs2CO3(263 mg, 0.810 mmol)을 첨가하였다. 생성된 혼합물을 1시간 동안 60℃에서 교반하였다. 생성된 혼합물을 물(100 mL)에 붓고 CH2Cl2(3 x 100 mL)로 추출하였다. 유기층을 모아서 염수(2 x 100 mL)로 세척하고, 무수 Na2SO4로 건조시키고, 여과하여 감압 하에서 농축시켜 tert-부틸 4-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일)-1,3-벤조디아졸-5-일]옥시)메틸]피페리딘-1-카르복실레이트(110 mg, 52.6%)를 갈색 고체로 수득하였다. MS m/z: 568 [M+H]+.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). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure, tert-butyl 4-[([1-[2-amino-6-(furan-2)) -yl)pyrimidin-4-yl]-2-(pyridin-4-yl)-1,3-benzodiazol-5-yl]oxy)methyl]piperidine-1-carboxylate (110 mg, 52.6%) as a brown solid. MS m/z: 568 [M+H] + .
단계 2: 4-(퓨란-2-일)-6-{5-(피페리딘-4-일메톡시)-2-(피리딘-4-일)-1,3-벤조디아졸-1-일}피리미딘-2-아민(Ex-30)의 합성Step 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)
단계 1에서 수득된 화합물(100 mg, 0.170 mmol)을 TFA(1.00 mL) 및 DCM(3.00 mL) 중에서 30 분 동안 25℃에서 교반하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Prep OBD C18 컬럼, 30 x 150 mm 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(15% PhaseB, 9분에 45%까지); 검출기, UV 254 nm. 수집된 분획을 동결건조하여 4-(퓨란-2-일)-6-[5-(피페리딘-4-일메톡시)-2-(피리딘-4-일)-1,3-벤조디아졸-1-일]피리미딘-2-아민(Ex-30; 12.6 mg, 15.2%)을 백색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 8.67-8.65(m, 2H), 7.90(d, J = 2.4 Hz, 1H), 7.64-7.59(m, 3H), 7.36(d, J = 10.2 Hz, 1H), 7.22(d, J = 4.0 Hz, 1H), 7.17(s, 2H), 7.02(d, J = 11.3 Hz, 1H), 6.87(s, 1H), 6.70-6.69(m, 1H), 3.89-3.85(m, 2H), 3.05-2.96(m, 2H), 2.54-2.52(m, 1H), 2.49-2.47(m, 1H), 1.95-1.85(m, 1H), 1.83-1.72(m, 2H), 1.25-1.15(m, 2H); MS m/z: 468 [M+H]+.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 μm; 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. The collected fractions were lyophilized to 4-(furan-2-yl)-6-[5-(piperidin-4-ylmethoxy)-2-(pyridin-4-yl)-1,3-benzodiazole -1-yl]pyrimidin-2-amine (Ex-30; 12.6 mg, 15.2%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.67-8.65 (m, 2H), 7.90 (d, J = 2.4 Hz, 1H), 7.64-7.59 (m, 3H), 7.36 ( d, J = 10.2 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.17 (s, 2H), 7.02 (d, J = 11.3 Hz, 1H), 6.87 (s, 1H), 6.70- 6.69(m, 1H), 3.89-3.85(m, 2H), 3.05-2.96(m, 2H), 2.54-2.52(m, 1H), 2.49-2.47(m, 1H), 1.95-1.85(m, 1H) ), 1.83-1.72 (m, 2H), 1.25-1.15 (m, 2H); MS m/z: 468 [M+H] + .
실시예 31: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-[(피리딘-4-일)메틸]-1H-1,3-벤조디아졸-5-올(Ex-31)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)
Figure PCTKR2022004084-appb-I000132
Figure PCTKR2022004084-appb-I000132
화합물(Ex-31)을 하기 반응식 14에 따라서 제조하였다.Compound (Ex-31) was prepared according to Scheme 14 below.
[반응식 14][Scheme 14]
Figure PCTKR2022004084-appb-I000133
Figure PCTKR2022004084-appb-I000133
단계 1: N-(2-[[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]아미노]-5-메톡시페닐)-2-(피리딘-4-일)아세트아미드의 합성Step 1: N-(2-[[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]amino]-5-methoxyphenyl)-2-(pyridin-4 -yl) Synthesis of acetamide
실시예 29의 단계 2에서 수득된 화합물(8.00 g, 24.4 mmol) 및 4-아세틸피리딘 하이드로클로라이드(5.50 g, 31.7 mmol)를 DMF(70.0 mL) 중에 교반한 혼합물에 HATU(11.1 g, 29.2 mmol) 및 DIEA(9.40 g, 73.1 mmol)를 첨가하였다. 얻어진 혼합물을 1시간 동안 25℃에서 교반하였다. 생성된 혼합물을 물(400 mL)에 붓고 EtOAc(3 x 400 mL)로 추출하였다. 유기층을 모으고 염수(2 x 400 mL)로 세척하고, 무수 Na2SO4로 건조시킨 후, 여과하고 감압 농축시켰다. 잔사를 CH2Cl2/MeOH(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 N-(2-[[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]아미노]-5-메톡시페닐)-2-(피리딘-4-일)아세트아미드(8.00 g, 67.5%)를 갈색 오일로 수득하였다. MS m/z: 448 [M+H]+.To a stirred mixture of the compound obtained in step 2 of Example 29 (8.00 g, 24.4 mmol) and 4-acetylpyridine hydrochloride (5.50 g, 31.7 mmol) in DMF (70.0 mL) HATU (11.1 g, 29.2 mmol) and DIEA (9.40 g, 73.1 mmol) were added. The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was poured into water (400 mL) and extracted with EtOAc (3 x 400 mL). The organic layers were combined, washed with brine (2 x 400 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was eluted with CH 2 Cl 2 /MeOH (10:1) and purified by silica gel column chromatography to obtain N-(2-[[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine- Obtained 4-yl]amino]-5-methoxyphenyl)-2-(pyridin-4-yl)acetamide (8.00 g, 67.5%) as a brown oil. MS m/z: 448 [M+H] + .
단계 2: 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-2-(피리딘-4-일메틸)-1,3-벤조디아졸의 합성 Step 2: 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3 -Synthesis of benzodiazole
단계 1에서 수득된 화합물(8.00 g, 17.9 mmol)을 AcOH(40.0 mL) 중에 질소 대기 하에서 혼합하고, 최종 반응 혼합물에 1시간 동안 120℃에서 마이크로파를 조사하였다. 혼합물을 실온으로 냉각시켰다. 이어서, 혼합물을 CH2Cl2/MeOH(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-2-(피리딘-4-일메틸)-1,3-벤조디아졸(5.20 g, 63.0%)을 갈색 오일로 수득하였다. 1H-NMR(300 MHz, DMSO-d6) δ(ppm): 8.76-8.78(m, 2H), 8.16(s, 1H), 7.64-7.52(m, 3H), 7.28-7.24(m, 3H), 6.99-6.95(m, 1H), 6.81-6.79(m, 1H), 4.56(s, 2H), 3.88(s, 3H); MS m/z: 430 [M+H]+.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. 1 H-NMR (300 MHz, DMSO-d 6 ) δ (ppm): 8.76-8.78 (m, 2H), 8.16 (s, 1H), 7.64-7.52 (m, 3H), 7.28-7.24 (m, 3H) ), 6.99-6.95 (m, 1H), 6.81-6.79 (m, 1H), 4.56 (s, 2H), 3.88 (s, 3H); MS m/z: 430 [M+H] + .
단계 3: 1-[6-(퓨란-2-일)-2-메탄설피닐피리미딘-4-일]-5-메톡시-2-(피리딘-4-일메틸)-1,3-벤조디아졸의 합성Step 3: 1-[6-(furan-2-yl)-2-methanesulfinylpyrimidin-4-yl]-5-methoxy-2-(pyridin-4-ylmethyl)-1,3-benzo Synthesis of diazoles
단계 2에서 수득된 화합물(5.20 g, 12.1 mmol) 및 m-CPBA(1.00 g, 6.05 mmol)를 DCM(50.0 mL) 중에서 25 분 동안 0℃에서 교반하였다. 잔사를 CH2Cl2/MeOH(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-(퓨란-2-일)-2-메탄설피닐피리미딘-4-일]-5-메톡시-2-(피리딘-4-일메틸)-1,3-벤조디아졸(2.00 g, 34.9%)을 갈색 오일로 수득하였다. MS m/z: 446 [M+H]+.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] + .
단계 4: 4-(퓨란-2-일)-6-[5-메톡시-2-(피리딘-4-일메틸)-1,3-벤조디아졸-1-일]피리미딘-2-아민의 합성Step 4: 4-(furan-2-yl)-6-[5-methoxy-2-(pyridin-4-ylmethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine synthesis of
단계 3에서 수득된 화합물(2.00 g, 4.48 mmol)을 THF(20.0 mL) 및 NH3·H2O(20.0 mL) 중에서 5시간 동안 25℃에서 교반하였다. 이어서 혼합물을 CH2Cl2/MeOH(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 4-(퓨란-2-일)-6-[5-메톡시-2-(피리딘-4-일메틸)-1,3-벤조디아졸-1-일]피리미딘-2-아민(700 mg, 36.8%)을 갈색 고체로 수득하였다. 1H-NMR(300 MHz, DMSO-d6) δ(ppm): 8.45-8.43(m, 2H), 7.95-7.94(m, 1H), 7.58-7.55(m, 1H), 7.30-7.21(m, 6H), 7.17(s, 1H), 7.00-6.92(m, 1H), 6.73-6.71(m, 1H), 4.60(s, 2H), 3.81(s, 3H); MS m/z: 399 [M+H]+.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. 1 H-NMR (300 MHz, DMSO-d 6 ) δ (ppm): 8.45-8.43 (m, 2H), 7.95-7.94 (m, 1H), 7.58-7.55 (m, 1H), 7.30-7.21 (m) , 6H), 7.17 (s, 1H), 7.00-6.92 (m, 1H), 6.73-6.71 (m, 1H), 4.60 (s, 2H), 3.81 (s, 3H); MS m/z: 399 [M+H] + .
단계 5: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일메틸)-11H-,3-벤조디아졸-5-올(Ex-31)의 합성Step 5: 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-ylmethyl)-11H-,3-benzodiazol-5-ol Synthesis of (Ex-31)
단계 4에서 수득된 화합물(50.0 mg, 0.120 mmol) 및 BBr3을 DCM(1.00 mL) 중에서 1시간 동안 25℃에서 교반하여 혼합하였다. 반응은 MeOH(1.00 mL)로 퀀칭하였다. 생성된 혼합물은 감압 농축시켰다. 조 생성물은 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(20% PhaseB, 7분에 50%까지); 검출기, UV 254 nm. 수집된 분획을 동결건조하여 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일메틸)-1,3-벤조디아졸-5-올(Ex-31; 5.30 mg, 10.8%)을 황백색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 9.28(s, 1H), 8.44-8.42(m, 2H), 7.93(s, 1H), 7.45(d, J = 8.8 Hz, 1H), 7.28-7.27(m, 1H), 7.22-7.20(m, 2H), 7.14(s, 2H), 7.00-6.96(m, 2H), 6.79(d, J = 11.2 Hz, 1H), 6.72-6.70(m, 1H), 4.57(s, 2H); MS m/z: 385 [M+H]+.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 μm; 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. The collected fractions were lyophilized to 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-2-(pyridin-4-ylmethyl)-1,3-benzodiazole- 5-ol (Ex-31; 5.30 mg, 10.8%) was obtained as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.28 (s, 1H), 8.44-8.42 (m, 2H), 7.93 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.28-7.27 (m, 1H), 7.22-7.20 (m, 2H), 7.14 (s, 2H), 7.00-6.96 (m, 2H), 6.79 (d, J = 11.2 Hz, 1H), 6.72 -6.70 (m, 1H), 4.57 (s, 2H); MS m/z: 385 [M+H] + .
실시예 32: 4-(퓨란-2-일)-6-{5-[(피페리딘-4-일)메톡시]-2-[(피리딘-4-일)메틸]-1H-1,3-벤조디아졸-1-일}피리미딘-2-아민(Ex-32)Example 32: 4-(furan-2-yl)-6-{5-[(piperidin-4-yl)methoxy]-2-[(pyridin-4-yl)methyl]-1H-1, 3-benzodiazol-1-yl}pyrimidin-2-amine (Ex-32)
Figure PCTKR2022004084-appb-I000134
Figure PCTKR2022004084-appb-I000134
화합물(Ex-32)을 하기 반응식 15에 따라서 제조하였다.Compound (Ex-32) was prepared according to Scheme 15 below.
[반응식 15][Scheme 15]
Figure PCTKR2022004084-appb-I000135
Figure PCTKR2022004084-appb-I000135
단계 1: tert-부틸 4-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일메틸)-1,3-벤조디아졸-5-일]옥시)메틸]피페리딘-1-카르복실레이트의 합성Step 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
실시예 31의 화합물(200 mg, 0.520 mmol) 및 tert-부틸 4-(브로모메틸)피페리딘-1-카르복실레이트(434 mg, 1.56 mmol)를 아세톤(6.00 mL) 중에 교반한 혼합물에 K2CO3(215 mg, 1.56 mmol)을 첨가하였다. 생성된 혼합물을 48시간 동안 100℃에서 교반하였다. 혼합물을 실온으로 냉각시켰다. 이어서, 혼합물을 CH2Cl2/MeOH(10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 tert-부틸 4-[([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-2-(피리딘-4-일메틸)-1,3-벤조디아졸-5-일]옥시)메틸]피페리딘-1-카르복실레이트(110 mg, 27.3%)를 갈색 오일로 수득하였다. MS m/z: 582 [M+H]+.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. The mixture was then purified by silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (10:1) to tert-butyl 4-[([1-[2-amino-6-(furan-2-yl)pyri) midin-4-yl]-2-(pyridin-4-ylmethyl)-1,3-benzodiazol-5-yl]oxy)methyl]piperidine-1-carboxylate (110 mg, 27.3%) was obtained as a brown oil. MS m/z: 582 [M+H] + .
단계 2: 4-(퓨란-2-일)-6-[5-(피페리딘-4-일메톡시)-2-(피리딘-4-일메틸)-1,3-벤조디아졸-1-일]피리미딘-2-아민(Ex-32)의 합성Step 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)
단계 1에서 수득된 화합물(100 mg, 0.170 mmol)을 TFA(2.00 mL) 및 DCM(2.00 mL) 중에서 30 분 동안 25℃에서 교반하였다. 생성된 혼합물을 감압 하에서 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x150 mm, 5 μm; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(30% PhaseB, 7분에 60%까지); 검출기, UV 254 nm. 수집된 분획을 동결건조하여 4-(퓨란-2-일)-6-[5-(피페리딘-4-일메톡시)-2-(피리딘-4-일메틸)-1,3-벤조디아졸-1-일]피리미딘-2-아민(Ex-32; 5.20 mg, 6.27%)을 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.43-8.42(m, 2H), 7.93(s, 1H), 7.53(d, J = 8.8 Hz, 1H), 7.28-7.14(m, 6H), 7.03(s, 1H), 6.98-6.91(m, 1H), 6.72-6.70(m, 1H), 4.57(s, 2H), 3.85-3.83(m, 2H), 2.96-2.93(m, 2H), 2.49-2.46(m, 2H), 1.88-1.83(m, 1H), 1.82-1.72(m, 2H), 1.23-1.11(m, 2H); MS m/z: 482 [M+H]+.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 μm; 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. The collected fractions were lyophilized to 4-(furan-2-yl)-6-[5-(piperidin-4-ylmethoxy)-2-(pyridin-4-ylmethyl)-1,3-benzodia Zol-1-yl]pyrimidin-2-amine (Ex-32; 5.20 mg, 6.27%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.43-8.42 (m, 2H), 7.93 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.28-7.14 ( m, 6H), 7.03(s, 1H), 6.98-6.91(m, 1H), 6.72-6.70(m, 1H), 4.57(s, 2H), 3.85-3.83(m, 2H), 2.96-2.93( m, 2H), 2.49-2.46 (m, 2H), 1.88-1.83 (m, 1H), 1.82-1.72 (m, 2H), 1.23-1.11 (m, 2H); MS m/z: 482 [M+H] + .
실시예 33: 4-(퓨란-2-일)-6-[5-(1H-피라졸-4-일옥시)-1H-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-33)Example 33: 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1H-1,2,3-benzotriazol-1-yl]pyrimidin- 2-amine (Ex-33)
Figure PCTKR2022004084-appb-I000136
Figure PCTKR2022004084-appb-I000136
화합물(Ex-33)을 하기 반응식 16에 따라서 제조하였다.Compound (Ex-33) was prepared according to Scheme 16 below.
[반응식 16][Scheme 16]
Figure PCTKR2022004084-appb-I000137
Figure PCTKR2022004084-appb-I000137
단계 1 내지 4: 5-브로모-1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸의 합성Steps 1 to 4: Synthesis of 5-bromo-1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazole
6-클로로-2-(메틸설파닐)피리미딘-4-아민(33.0 g, 188 mmol) 및 6-브로모 1-플루오로-2-니트로벤젠(50.0 g, 227 mmol)을 출발물질로 하여 실시예 2의 단계 1 내지 4와 동일한 방법으로 5-브로모-1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸(28.0 g, 78.1%)을 흑색 고체로 수득하였다. MS m/z: 388 [M+H]+. 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] + .
단계 5:Step 5: 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1,2,3-벤조트리아졸의 합성1-[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
단계 4에서 수득된 화합물(16.0 g, 41.2 mmol) 및 비스(피나콜라토)디보론(21.0 g, 82.9 mmol)을 디옥산(160 mL) 중에 교반한 혼합물에 CH3COOK(12.0 g, 122 mmol) 및 Pd(PPh3)2Cl2(2.89 g, 4.11 mmol)을 첨가하였다. 생성된 혼합물을 4시간 동안 80℃에 질소 대기 하에서 교반하였다. 혼합물은 실온으로 냉각되도록 방치하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 잔사는 PE/EtOAc(2:1)으로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여, 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1,2,3-벤조트리아졸(5.00 g, 25.1%)을 황색 고체로 수득하였다. MS m/z: 436 [M+H]+.To a stirred mixture of the compound obtained in step 4 (16.0 g, 41.2 mmol) and bis(pinacolato)diboron (21.0 g, 82.9 mmol) in dioxane (160 mL) CH 3 COOK (12.0 g, 122 mmol) ) and Pd(PPh 3 ) 2 Cl 2 (2.89 g, 4.11 mmol) were added. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 4 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was eluted with PE/EtOAc (2:1), purified by silica gel column chromatography, and 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzotriazole (5.00 g, 25.1%) was obtained as a yellow solid did. MS m/z: 436 [M+H] + .
단계 6: 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일 보론산의 합성Step 6: Synthesis of 1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl boronic acid
단계 5에서 수득된 화합물(5.00 g, 11.5 mmol)을 THF(50.0 mL) 및 HCl(6M, 50.0 mL) 중에서 2시간 동안 80℃에서 교반하였다. 혼합물은 실온으로 냉각되도록 방치하였다. 혼합물을 물(150 mL)에 첨가하였다. 침전된 고체는 여과하여 수집하고 물(50.0 mL)로 세척하여, 1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일보론산(1.80 g, 44.4%)을 황백색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 8.65(s, 1H), 8.50(d, J = 8.4 Hz, 1H), 8.38(s, 2H), 8.16(d, J = 8.0 Hz, 1H), 8.10(s, 1H), 8.08(s, 1H), 7.58-7.57(m, 1H), 6.82-6.80(m, 1H), 2.74(s, 3H); MS m/z: 354 [M+H]+. 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. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.65 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.38 (s, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.10(s, 1H), 8.08(s, 1H), 7.58-7.57(m, 1H), 6.82-6.80(m, 1H), 2.74(s, 3H); MS m/z: 354 [M+H] + .
단계 7: tert-부틸 4-([1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 합성Step 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
단계 6에서 수득된 화합물(1.80 g, 5.09 mmol) 및 tert-부틸 4-히드록시피라졸-1-카르복실레이트(1.80 g, 10.2 mmol)를 DCM(100 mL) 중에 교반하여 혼합하고, Cu(OAc)2(1.80 g, 10.2 mmol) 및 TEA(1.50 g, 15.3 mmol)를 첨가하였다. 생성된 혼합물 16시간 동안 실온에서 O2 대기 하에서 교반하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 tert-부틸 4-([1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(500 mg, 18.4%)를 황백색 고체로 수득하였다. 1H-NMR(400 MHz, DMSO-d6) δ(ppm): 8.53(d, J = 8.4 Hz, 1H), 8.34(s, 1H), 8.09(s, 2H), 7.94(s, 1H), 7.85(s, 1H), 7.67-7.64(m, 1H), 7.59-7.58(m, 1H), 6.82-6.81(m, 1H), 2.72(s, 3H), 1.59(s, 9H); MS m/z: 492 [M+H]+.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. The residue was eluted with PE/EtOAc (1:1), purified by silica gel column chromatography, and tert-butyl 4-([1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine- 4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (500 mg, 18.4%) was obtained as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.53 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.09 (s, 2H), 7.94 (s, 1H) , 7.85(s, 1H), 7.67-7.64(m, 1H), 7.59-7.58(m, 1H), 6.82-6.81(m, 1H), 2.72(s, 3H), 1.59(s, 9H); MS m/z: 492 [M+H] + .
단계 8:Step 8: tert-부틸 4-([1-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 합성tert-Butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyra Synthesis of sol-1-carboxylate
단계 7에서 수득된 화합물(260 mg, 0.520 mmol)을 DCM(10.0 mL) 중에 교반한 용액에 m-CPBA(365 mg, 2.11 mmol)를 첨가하였다. 생성된 혼합물은 2시간 동안 실온에서 교반하였다. 반응은 Na2S2O3 포화 수용액 (40.0 mL)으로 실온에서 퀀칭하였다. 생성된 혼합물은 CH2Cl2(80 mL)로 추출하였다. 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 농축하여, tert-부틸 4-([1-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(230 mg, 74.8%)를 황백색 고체로 수득하였다. MS m/z: 524 [M+H]+.To a stirred solution of the compound obtained in step 7 (260 mg, 0.520 mmol) in DCM (10.0 mL) was added m-CPBA (365 mg, 2.11 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous Na 2 S 2 O 3 (40.0 mL) at room temperature. The resulting mixture was extracted with CH 2 Cl 2 (80 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and tert-butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzo Triazol-5-yl]oxy)pyrazole-1-carboxylate (230 mg, 74.8%) was obtained as an off-white solid. MS m/z: 524 [M+H] + .
단계 9: tert-부틸 4-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 합성Step 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
단계 8에서 수득된 화합물(230 mg, 0.430 mmol)을 THF(3.00 mL) 중에 교반시킨 혼합물에 NH3·H2O(3.00 mL)를 첨가하였다. 생성된 혼합물을 3시간 동안 25℃에서 교반하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 tert-부틸 4-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(120 mg, 53.4%)를 백색 고체로 수득하였다. MS m/z: 461 [M+H]+.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] + .
단계 10:Step 10: 4-(퓨란-2-일)-6-[5-(1H-피라졸-4-일옥시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-33)의 합성4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex- 33) Synthesis of
단계 9에서 수득된 화합물(60.0 mg, 0.130 mmol)을 DCM(4.00 mL) 중에 교반시킨 혼합물에 TFA(1.00 mL)를 적가하였다. 생성된 혼합물은 1시간 동안 25℃에서 교반하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18 ExRS, 30 mm X 150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(40% PhaseB, 7분에 60%까지); 검출기, UV &254/220 nm. 생성물 분획은 동결건조시켜 4-(퓨란-2-일)-6-[5-(1H-피라졸-4-일옥시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-33; 9.20 mg, 19.5%)을 백색 고체로 수득하였다. 1H-NMR(300 MHz, DMSO-d6) δ(ppm): 12.91(s, 1H), 8.80-8.77(m, 1H), 7.98(s, 1H), 7.90(s, 1H), 7.62(s, 1H), 7.54(s, 2H), 7.52-7.51(m, 1H),7.34(d, J = 2.7 Hz, 3H), 6.75-6.73(m, 1H); MS m/z: 361 [M+H]+.To a stirred mixture of the compound obtained in step 9 (60.0 mg, 0.130 mmol) in DCM (4.00 mL) was added TFA (1.00 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C18 ExRS, 30 mm X 150 mm, 5 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (40% PhaseB, to 60% in 7 min); Detector, UV &254/220 nm. The product fractions were lyophilized to 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin- The 2-amine (Ex-33; 9.20 mg, 19.5%) was obtained as a white solid. 1 H-NMR (300 MHz, DMSO-d 6 ) δ (ppm): 12.91 (s, 1H), 8.80-8.77 (m, 1H), 7.98 (s, 1H), 7.90 (s, 1H), 7.62 ( s, 1H), 7.54 (s, 2H), 7.52-7.51 (m, 1H), 7.34 (d, J = 2.7 Hz, 3H), 6.75-6.73 (m, 1H); MS m/z: 361 [M+H] + .
실시예 34: 1-{2-아미노-6-[(퓨란-2-일)메틸]피리미딘-4-일}-1H-1,2,3-벤조트리아졸-5-올(Ex-34)Example 34: 1-{2-amino-6-[(furan-2-yl)methyl]pyrimidin-4-yl}-1H-1,2,3-benzotriazol-5-ol (Ex-34 )
Figure PCTKR2022004084-appb-I000138
Figure PCTKR2022004084-appb-I000138
화합물(Ex-34)을 하기 반응식 17에 따라서 제조하였다.Compound (Ex-34) was prepared according to Scheme 17 below.
[반응식 17][Scheme 17]
Figure PCTKR2022004084-appb-I000139
Figure PCTKR2022004084-appb-I000139
단계 1 내지 3: 1-[6-클로로-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Steps 1 to 3: Synthesis of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
실시예 2의 단계 1에서 2,6-디클로로피리미딘-4-아민 대신에 6-클로로-2-(메틸설파닐)피리미딘-4-아민을 사용한 것을 제외하고, 실시예 2의 단계 1 내지 3과 동일한 방법으로 1-[6-클로로-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(12.0 g, 44.5%)을 갈색 고체로 수득하였다. MS m/z: 308 [M+H]+.Steps 1 to 2 of Example 2, except that 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine was used instead of 2,6-dichloropyrimidin-4-amine in Step 1 of Example 2 In the same manner as in 3, 1- [6-chloro-2- (methylsulfanyl) pyrimidin-4-yl] -5-methoxy-1,2,3-benzotriazole (12.0 g, 44.5%) was browned obtained as a solid. MS m/z: 308 [M+H] + .
단계 4:Step 4: 5-메톡시-1-[2-(메틸설파닐)-6-(트리메틸스탄닐)피리미딘-4-일]-1,2,3-벤조트리아졸의 합성Synthesis of 5-methoxy-1-[2-(methylsulfanyl)-6-(trimethylstannyl)pyrimidin-4-yl]-1,2,3-benzotriazole
단계 3에서 수득된 화합물(12.0 g, 39.0 mmol) 및 헥사메틸디스탄난(19.2 g, 58.5 mmol)을 톨루엔(200 mL) 중에 교반한 혼합물에 Pd(PPh3)4(9.01g, 7.79 mmol)을 첨가하였다. 생성된 혼합물을 16시간 동안 100℃에 질소 대기 하에서 교반하였다. 혼합물은 실온으로 냉각되도록 방치하였다. 조 생성물은 PE/EtOAc(2:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 5-메톡시-1-[2-(메틸설파닐)-6-(트리메틸스탄닐)피리미딘-4-일]-1,2,3-벤조트리아졸(3.00 g, 15.0%)을 백색 고체로 수득하였다. 1H-NMR(CDCl3, 400 MHz) δ(ppm): 8.50(d, J = 8.0 Hz, 1H), 8.11(s, 1H), 7.48(s, 1H), 7.30(d, J = 8.0 Hz, 1H), 3.95(s, 3H), 2.72(s, 3H), 0.46(s, 9H); MS m/z: 438 [M+H]+.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. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 8.50 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.48 (s, 1H), 7.30 (d, J = 8.0 Hz) , 1H), 3.95 (s, 3H), 2.72 (s, 3H), 0.46 (s, 9H); MS m/z: 438 [M+H] + .
단계 5:Step 5: 1-[6-(퓨란-2-카르보닐)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Synthesis of 1-[6-(furan-2-carbonyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
단계 4에서 수득된 화합물(3.00 g, 6.87 mmol) 및 푸로일 클로라이드(4.19 g, 34.4 mmol)를 톨루엔(60.0 mL) 중에 교반한 화합물에 Pd(PPh3)4(1.59 g, 1.37 mmol)을 첨가하였다. 생성된 혼합물을 16시간 동안 100℃에 질소 대기 하에서 교반하였다. 혼합물은 실온으로 냉각되도록 방치하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-(퓨란-2-카르보닐)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(1.20 g, 42.7%)을 담황색 고체로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm): 8.40(d, J = 8.0 Hz, 1H), 8.28 -8.27(m, 2H), 8.08-8.06(m, 1H), 7.84-7.82(m, 1H), 7.48-7.47(m, 1H), 6.89-6.88(m, 1H), 3.91(s, 3H), 2.78(s, 3H); MS m/z: 368 [M+H]+.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. The residue was eluted with PE/EtOAc (1:1), purified by silica gel column chromatography, and 1-[6-(furan-2-carbonyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5 -Methoxy-1,2,3-benzotriazole (1.20 g, 42.7%) was obtained as a pale yellow solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.40 (d, J = 8.0 Hz, 1H), 8.28 -8.27 (m, 2H), 8.08-8.06 (m, 1H), 7.84 7.82(m, 1H), 7.48-7.47(m, 1H), 6.89-6.88(m, 1H), 3.91(s, 3H), 2.78(s, 3H); MS m/z: 368 [M+H] + .
단계 6:Step 6: 퓨란-2-일[6-(5-메톡시-1,2,3-벤조트리아졸-1-일)-2-(메틸설파닐)피리미딘-4-일]메탄올의 합성Synthesis of furan-2-yl[6-(5-methoxy-1,2,3-benzotriazol-1-yl)-2-(methylsulfanyl)pyrimidin-4-yl]methanol
단계 5에서 수득된 화합물(1.20 g, 3.26 mmol)을 MeOH(60.0 mL) 중에 교반한 혼합물에 NaBH4(1.20g, 31.7 mmol)를 0℃에서 나누어 첨가하였다. 생성된 혼합물을 16시간 동안 25℃에서 교반하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 퓨란-2-일[6-(5-메톡시-1,2,3-벤조트리아졸-1-일)-2-(메틸설파닐)피리미딘-4-일]메탄올(700 mg, 52.2%)을 담황색 고체로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm): 8.41(d, J = 8.0 Hz, 1H), 8.22(s, 1H), 7.69-7.63(m, 2H), 7.44-7.41(m, 1H), 6.61-6.60(m, 1H), 6.45-6.40(m, 2H), 5.76-5.73(m, 1H), 3.90(s, 3H), 2.65(s, 3H); MS m/z: 370 [M+H]+ .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. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.41 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.69-7.63 (m, 2H), 7.44-7.41 ( m, 1H), 6.61-6.60 (m, 1H), 6.45-6.40 (m, 2H), 5.76-5.73 (m, 1H), 3.90 (s, 3H), 2.65 (s, 3H); MS m/z: 370 [M+H] + .
단계 7:Step 7: 1-[6-(퓨란-2-일메틸)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Synthesis of 1-[6-(furan-2-ylmethyl)-2-(methylsulfanyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
단계 6에서 수득된 화합물(700 mg, 1.89 mmol)을 트리에톡시실란(20.0 mL) 중에 교반한 용액에 TFA(20.0 mL)를 0℃에 질소 대기 하에서 적가하였다. 생성된 혼합물은 2시간 동안 25℃에 질소 대기 하에서 교반하였다. 조 생성물은 PE/EtOAc(2:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-[6-(퓨란-2-일메틸)-2-(메틸설파닐)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(200 mg, 26.9%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm): 8.39(d, J = 8.0 Hz, 1H), 7.75(s, 1H), 7.68-7.64(m, 2H), 7.43-7.39(m, 1H), 6.47-6.46(m, 1H), 6.40-6.38(m, 1H), 4.26(s, 2H), 3.90(s, 3H), 2.67(s, 3H); MS m/z: 354 [M+H]+.To a stirred solution of the compound obtained in step 6 (700 mg, 1.89 mmol) in triethoxysilane (20.0 mL), TFA (20.0 mL) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 25° C. under a nitrogen atmosphere. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to 1-[6-(furan-2-ylmethyl)-2-(methylsulfanyl)pyrimidin-4-yl]- 5-Methoxy-1,2,3-benzotriazole (200 mg, 26.9%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.39 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.68-7.64 (m, 2H), 7.43-7.39 ( m, 1H), 6.47-6.46 (m, 1H), 6.40-6.38 (m, 1H), 4.26 (s, 2H), 3.90 (s, 3H), 2.67 (s, 3H); MS m/z: 354 [M+H] + .
단계 8:Step 8: 1-[6-(퓨란-2-일메틸)-2-메탄설포닐피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Synthesis of 1-[6-(furan-2-ylmethyl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
단계 7에서 수득된 화합물(200 mg, 0.560 mmol)을 DCM(20.0 mL) 중에 교반한 혼합물에 m-CPBA(390 mg, 2.26 mmol)를 첨가하였다. 생성된 혼합물은 3시간 동안 25℃에서 교반하였다. 반응은 Na2S2O3 포화 수용액으로 퀀칭하였다. 생성된 혼합물은 CH2Cl2(2 x 20.0 mL)로 추출하였다. 유기층을 모아서 NaHCO3 포화 수용액으로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 농축시켜서 1-[6-(퓨란-2-일메틸)-2-메탄설포닐피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸(150 mg, 48.1%)을 황백색 고체로 수득하였다. MS m/z: 386 [M+H]+.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 . After filtration, the filtrate was concentrated under reduced pressure to 1-[6-(furan-2-ylmethyl)-2-methanesulfonylpyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole (150 mg, 48.1%) was obtained as an off-white solid. MS m/z: 386 [M+H] + .
단계 9: 4-(퓨란-2-일메틸)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민의 합성Step 9: Synthesis of 4-(furan-2-ylmethyl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine
단계 8에서 수득된 화합물(150 mg, 0.270 mmol)을 THF(3.00 mL) 중에 교반한 혼합물에 NH3·H2O(3.00 mL)를 첨가하였다. 생성된 혼합물은 2시간 동안 25℃에서 교반하였다. 생성된 혼합물은 물(20.0 mL)로 희석하였다. 생성된 혼합물을 EtOAc(3 x 20.0 mL)로 추출하였다. 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 4-(퓨란-2-일메틸)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민(50.0 mg, 51.2%)을 황백색 고체로 수득하였다. 1H-NMR(DMSO-d6, 400 MHz) δ(ppm): 8.66(d, J = 8.0 Hz, 1H), 7.64-7.61(m, 2H), 7.33(d, J = 8.0 Hz, 1H), 7.26(s, 2H), 7.17(s, 1H), 6.44-6.43(m, 1H), 6.34-6.33(m, 1H), 4.05(s, 2H), 3.90(s, 3H); MS m/z: 323 [M+H]+.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. The residue was eluted with PE/EtOAc (1:1), purified by silica gel column chromatography, and 4-(furan-2-ylmethyl)-6-(5-methoxy-1,2,3-benzotriazole-1 -yl)pyrimidin-2-amine (50.0 mg, 51.2%) was obtained as an off-white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.66 (d, J = 8.0 Hz, 1H), 7.64-7.61 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H) , 7.26(s, 2H), 7.17(s, 1H), 6.44-6.43(m, 1H), 6.34-6.33(m, 1H), 4.05(s, 2H), 3.90(s, 3H); MS m/z: 323 [M+H] + .
단계 10: 1-[2-아미노-6-(퓨란-2-일메틸)피리미딘-4-일]-1,2,3-벤조트리아졸-5-올(Ex-34)의 합성Step 10: Synthesis of 1-[2-amino-6-(furan-2-ylmethyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-34)
단계 9에서 수득된 화합물(50.0 mg, 0.150 mmol) 및 BBr3을 DCM(1M)(3.00 mL) 중에서 1시간 동안 25℃에 질소 대기 하에서 교반하여 혼합하였다. 반응은 MeOH(1 mL)를 0℃에서 첨가하여 퀀칭하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(25% PhaseB, 7분에서 45%까지); 검출기, UV 254/220 nm. 수집된 분획을 동결건조하여 1-[2-아미노-6-(퓨란-2-일메틸)피리미딘-4-일]-1,2,3-벤조트리아졸-5-올(Ex-34; 7.30 mg, 14.9%)을 엷은 황색 고체로 수득하였다. 1H-NMR(DMSO-d6, 300 MHz) δ(ppm): 8.60(d, J = 9.0 Hz, 1H), 7.59(s, 1H), 7.35(d, J = 2.1 Hz, 1H), 7.22(d, J = 9.0Hz, 1H), 7.14(s, 1H), 6.43(d, J = 1.8 Hz, 1H), 6.33(d, J = 3.3 Hz, 1H), 4.03(s, 2H); MS m/z: 309 [M+H]+.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 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (25% PhaseB, 7 min to 45%); Detector, UV 254/220 nm. The collected fractions were lyophilized to 1-[2-amino-6-(furan-2-ylmethyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-34; 7.30 mg, 14.9%) was obtained as a pale yellow solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.60 (d, J = 9.0 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.14 (s, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.33 (d, J = 3.3 Hz, 1H), 4.03 (s, 2H); MS m/z: 309 [M+H] + .
실시예 35: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-인돌-5-올(Ex-35)Example 35: 1- [2-amino-6- (furan-2-yl) pyrimidin-4-yl] -1H-indol-5-ol (Ex-35)
Figure PCTKR2022004084-appb-I000140
Figure PCTKR2022004084-appb-I000140
화합물(Ex-35)을 하기 반응식 18에 따라서 제조하였다.Compound (Ex-35) was prepared according to Scheme 18 below.
[반응식 18][Scheme 18]
Figure PCTKR2022004084-appb-I000141
Figure PCTKR2022004084-appb-I000141
단계 1: 4-클로로-6-(퓨란-2-일)피리미딘-2-아민의 합성Step 1: Synthesis of 4-chloro-6-(furan-2-yl)pyrimidin-2-amine
4,6-디클로로피리딘-2-아민(1.00 g, 6.09 mmol)을 DMF(10 mL) 중에 교반한 용액을 아르곤으로 5분 동안 탈기(degas)하였다. Dikis(0.210 g, 0.300 mmol)를 실온에서 가하고 5분 동안 교반하였다. 트리부틸(퓨란-2-일)스탄난(2.17 g, 6.09 mmol)을 가하고 80℃에서 16시간 동안 교반하였다. 16 시간 후, 반응물을 실온으로 냉각시키고, 물로 희석하고, 에틸 아세테이트(2 x 100 mL)로 추출하였다. 유기층을 모으고 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물을 실리카겔(100-200 메쉬) 컬럼 크로마토그래피로 정제하고, 생성물을 헥산 중 15-20% EtOAc로 용출하여 4-클로로-6-(퓨란-2-일)피리미딘-2-아민(0.500 g, 41.0%)을 수득하였다. MS m/z: 196.2 [M+H]+.A stirred solution of 4,6-dichloropyridin-2-amine (1.00 g, 6.09 mmol) in DMF (10 mL) was degassed with argon for 5 min. Dikis (0.210 g, 0.300 mmol) was added at room temperature and stirred for 5 minutes. Tributyl(furan-2-yl)stannane (2.17 g, 6.09 mmol) was added and stirred at 80° C. for 16 hours. After 16 h, the reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography, and the product was eluted with 15-20% EtOAc in hexanes to 4-chloro-6-(furan-2-yl)pyrimidin-2-amine (0.500). g, 41.0%). MS m/z: 196.2 [M+H] + .
단계 2: 4-(퓨란-2-일)-6-요오드피리미딘-2-아민의 합성Step 2: Synthesis of 4-(furan-2-yl)-6-iodopyrimidin-2-amine
단계 1에서 수득된 화합물(1.00 g, 5.11 mmol)을 교반한 용액에 HI(37.0 mL)를 가하고 반응물을 50℃에서 16시간 동안 교반하였다. 16시간 후, 반응물을 얼음물(50.0 mL)에 붓고 고체를 여과하여 진공 하에서 건조시켜 4-(퓨란-2-일)-6-요오드피리미딘-2-아민(1.00 g, 68.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d) δ 7.95(s, 1H), 7.31(d, J = 2.8 Hz, 2H), 6.71(q, 1H); MS m/z: 288.17 [M-H]+.HI (37.0 mL) was added to a stirred solution of the compound obtained in step 1 (1.00 g, 5.11 mmol), and the reaction was stirred at 50° C. for 16 hours. After 16 hours, the reaction was poured into ice water (50.0 mL), the solid was filtered and dried under vacuum to give 4-(furan-2-yl)-6-iodopyrimidin-2-amine (1.00 g, 68.0%). . 1 H NMR (400 MHz, DMSO-d) δ 7.95 (s, 1H), 7.31 (d, J = 2.8 Hz, 2H), 6.71 (q, 1H); MS m/z: 288.17 [MH] + .
단계 3: 4-(퓨란-2-일)-6-(5-메톡시-1H-인돌-1-일)피리미딘-2-아민의 합성Step 3: Synthesis of 4-(furan-2-yl)-6-(5-methoxy-1H-indol-1-yl)pyrimidin-2-amine
단계 2에서 수득된 화합물(0.5g, 1.74 mmol)의 DMF(5 mL) 용액에 CuI(0.013g, 0.06 mmol), K2CO3(0.36g, 2.61 mmol) 및 5-메톡시-1H-인돌(0.120 g, 0.870 mmol)을 첨가하였다. 반응물을 125℃에서 16시간 동안 교반하였다. 16시간 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 50.0 mL)로 추출하였다. 유기층을 모으고 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물은 실리카겔(100-200 메쉬) 컬럼 크로마토그래피로 정제하고 생성물을 헥산 중 15% EtOAc으로 용출하여 4-(퓨란-2-일)-6-(5-메톡시-1H-인돌-1-일)피리미딘-2-아민(0.150 g, 28.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d) δ 8.76(d, J = 9.2 Hz, 1H), 8.17(d, J = 3.6Hz, 1H), 7.92(s, 1H), 7.31(t, 2H), 8.76(d, J = 2.4 Hz, 1H) 6.95(s, 1H) 6.89(d, J = 2.4 Hz, J = 2.8 Hz 1H) 6.72(d, J = 2 Hz, 2H) 3.34(s, 3H).In a DMF (5 mL) solution of the compound obtained in step 2 (0.5 g, 1.74 mmol), CuI (0.013 g, 0.06 mmol), K 2 CO 3 (0.36 g, 2.61 mmol) and 5-methoxy-1H-indole (0.120 g, 0.870 mmol) was added. The reaction was stirred at 125° C. for 16 h. After 16 h, the reaction was diluted with water and extracted with ethyl acetate (2 x 50.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted with 15% EtOAc in hexanes to 4-(furan-2-yl)-6-(5-methoxy-1H-indole-1- Yield) pyrimidin-2-amine (0.150 g, 28.0%) was obtained. 1 H NMR (400 MHz, DMSO-d) δ 8.76 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 3.6 Hz, 1H), 7.92 (s, 1H), 7.31 (t, 2H), 8.76 (d, J = 2.4 Hz, 1H) 6.95 (s, 1H) 6.89 (d, J = 2.4 Hz, J = 2.8 Hz 1H) 6.72 (d, J = 2 Hz, 2H) 3.34 (s, 3H).
단계 4: 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-인돌-5-올(Ex-35)의 합성 Step 4: Synthesis of 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indol-5-ol (Ex-35)
단계 3에서 수득된 화합물(0.125 g, 0.400 mmol)을 DCM(1.25 mL) 중 -78℃에서 냉각 교반한 용액에, BBr3(DCM 중 1M, 5.00 mL)을 적가하고 반응물을 실온에서 4시간 동안 교반하였다. 반응물을 NaHCO3로 희석하고 에틸 아세테이트(2 x 50.0 mL)로 추출하였다. 유기층을 모으고 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물을 prep HPLC로 정제하여 1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-인돌-5-올(Ex-35; 18.0 mg, 15.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d) δ 8.65(d, J = 8.8 Hz, 1H), 8.36(s, 1H), 8.10(d, J = 3.6 Hz, 1H), 7.91(s, 1H), 7.25(d, J = 3.2 Hz, 1H) 7.18(s, 1H) 6.93(m, 3H) 6.77(m, 2H) 6.63(d, J = 3.2 Hz, 1H); MS m/z: 293.19 [M+H]+.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. The crude product was purified by prep HPLC to 1-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indol-5-ol (Ex-35; 18.0 mg, 15.0%) was obtained. 1 H NMR (400 MHz, DMSO-d) δ 8.65 (d, J = 8.8 Hz, 1H), 8.36 (s, 1H), 8.10 (d, J = 3.6 Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 3.2 Hz, 1H) 7.18 (s, 1H) 6.93 (m, 3H) 6.77 (m, 2H) 6.63 (d, J = 3.2 Hz, 1H); MS m/z: 293.19 [M+H] + .
실시예 36: 4-[7-(벤질옥시)-[1,2,4]트리아졸로[4,3-a]피리딘-3-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-36)Example 36: 4-[7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-6-(furan-2-yl)pyrimidine-2 -Amine (Ex-36)
Figure PCTKR2022004084-appb-I000142
Figure PCTKR2022004084-appb-I000142
화합물(Ex-36)을 하기 반응식 19에 따라서 제조하였다.Compound (Ex-36) was prepared according to Scheme 19 below.
[반응식 19][Scheme 19]
Figure PCTKR2022004084-appb-I000143
Figure PCTKR2022004084-appb-I000143
단계 1: 4-(벤질옥시)-2-클로로피리딘의 합성Step 1: Synthesis of 4-(benzyloxy)-2-chloropyridine
2-클로로-4-플루오로피리딘(2.00 g, 15.4 mmol)을 DMF(20.0 mL) 중에 0℃에서 냉각시켜 교반한 용액에 NaH(0.670 g, 16.9 mmol, 미네랄 오일 중 60% 분산)를 가하고 20분 동안 교반하였다. 벤질알코올(1.82 g, 16.9 mmol)을 가하고, 실온에서 6시간 동안 더 교반하였다. 6 시간 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 150 mL)로 추출하였다. 유기층을 모아 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물은 실리카겔(100-200 메쉬) 컬럼 크로마토그래피로 정제하고 생성물을 헥산 중 4% EtOAc에서 용출시켜 4-(벤질옥시)-2-클로로피리딘(1.80 g, 53.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d) δ 8.24(d, J = 5.6 1H), 7.48(m, 4H), 7.33(m, 1H), 7.24(m, 1H), 7.09(t, 1H) 5.25(s, 2H).To a stirred solution of 2-chloro-4-fluoropyridine (2.00 g, 15.4 mmol) in DMF (20.0 mL) at 0 °C was added NaH (0.670 g, 16.9 mmol, 60% dispersion in mineral oil) and 20 stirred for minutes. Benzyl alcohol (1.82 g, 16.9 mmol) was added, and the mixture was further stirred at room temperature for 6 hours. After 6 h, the reaction was diluted with water and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted in 4% EtOAc in hexanes to give 4-(benzyloxy)-2-chloropyridine (1.80 g, 53.0%). 1 H NMR (400 MHz, DMSO-d) δ 8.24 (d, J = 5.6 1H), 7.48 (m, 4H), 7.33 (m, 1H), 7.24 (m, 1H), 7.09 (t, 1H) 5.25 (s, 2H).
단계 2: 4-(벤질옥시)-2-히드라진일피리딘의 합성Step 2: Synthesis of 4-(benzyloxy)-2-hydrazinylpyridine
단계 1에서 수득된 화합물(1.80 g, 8.21 mmol)을 피리딘(54.0 mL) 중에 교반한 용액에 히드라진 수화물(0.820 g, 16.4 mmol)을 가하고 120℃에서 32시간 동안 교반하였다. 32 시간 후, 반응물을 얼음물(50 mL)에 붓고 및 고체를 여과하고, 진공 하에서 건조시켜 4-(벤질옥시)-2-히드라진일피리딘(1.50 g, 85.0%)을 수득하였다. MS m/z: 216.2 [M+H]+.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] + .
단계 3: 7-(벤질옥시)-[1,2,4]트리아졸로[4,3-a]피리딘의 합성Step 3: Synthesis of 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine
트리메틸 오르토포르메이트(0.500 g, 46.5 mmol) 중 4-(벤질옥시)-2-히드라진일피리딘(1.00 g, 4.65 mmol)의 용액을 130℃에서 2시간 동안 교반하였다. 2 h 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 100 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨에 건조시키고, 진공 하에서 농축시켜 7-(벤질옥시)-[1,2,4]트리아졸로[4,3-a]피리딘(0.500 g, 47.0%)을 수득하였다. MS m/z: 226.24 [M+H]+.A solution of 4-(benzyloxy)-2-hydrazinylpyridine (1.00 g, 4.65 mmol) in trimethyl orthoformate (0.500 g, 46.5 mmol) was stirred at 130° C. for 2 h. After 2 h, the reaction was diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine (0.500 g, 47.0%). MS m/z: 226.24 [M+H] + .
단계 4: 4-[7-(벤질옥시)-[1,2,4]트리아졸로[4,3-a]피리딘-3-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-36)의 합성Step 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)
단계 3에서 수득된 화합물(0.420 g, 1.86 mmol)을 DMSO(4.20 mL) 중에 교반한 용액에, 4-(퓨란-2-일)-6-요오도피리미딘-2-아민(0.80 g, 2.79 mmol), PPh3(97.0 mg, 0.370 mmol), K2CO3(510 mg, 3.73 mmol), 및 CuI(70.0 mg, 0.37 mmol)를 가하고, 반응물을 15분 동안 탈기하였다. 반응물을 140℃에서 1시간 동안 마이크로파에서 교반하였다. 반응 완료 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 50.0 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물은 실리카겔(100-200 메쉬) 컬럼 크로마토그래피로 정제하고 생성물을 DCM 중 1% MeOH에 용출시켜 4-[7-(벤질옥시)-[1,2,4]트리아졸로[4,3-a]피리딘-3-일]-6-(퓨란-2-일)피리미딘-2-아민(Ex-36; 200 mg, 28.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d6) δ 9.79(d, J = 7.6 1H), 7.96(s, 1H), 7.74(s, 1H), 7.55(d, J = 6.8 2H), 7.45(m, 4H), 7.28(d, J = 2.8 1H), 7.10(s, 2H) 6.94(d, J = 6, 1H), 6.73(s, 1H), 5.29(s, 2H); MS m/z: 385.34 [M+H]+.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). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted in 1% MeOH in DCM to 4-[7-(benzyloxy)-[1,2,4]triazolo[4,3- A]pyridin-3-yl]-6-(furan-2-yl)pyrimidin-2-amine (Ex-36; 200 mg, 28.0%) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (d, J = 7.6 1H), 7.96 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 6.8 2H), 7.45 (m) , 4H), 7.28 (d, J = 2.8 1H), 7.10 (s, 2H) 6.94 (d, J = 6, 1H), 6.73 (s, 1H), 5.29 (s, 2H); MS m/z: 385.34 [M+H] + .
실시예 37: 3-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-[1,2,4]트리아졸로[4,3-a]피리딘-7-올(Ex-37)Example 37: 3- [2-amino-6- (furan-2-yl) pyrimidin-4-yl] - [1,2,4] triazolo [4,3-a] pyridin-7-ol ( Ex-37)
Figure PCTKR2022004084-appb-I000144
Figure PCTKR2022004084-appb-I000144
실시예 36의 화합물(150 mg, 0.390 mmol)을 메탄올(1.50 mL) 중에 교반한 용액에, 10% Pd/C(50% 수분, 150 mg)을 가하고 실온에서 2시간 동안 H2 대기 하에서 교반하였다. 2 h 후, 반응물을 셀라이트 베드(Celite bed)를 통과시켜 여과하고 메탄올로 세척하였다. 유기층을 진공 하에서 농축시켜서 조 생성물을 얻고 prep HPLC로 정제하여 3-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-[1,2,4]트리아졸로[4,3-a]피리딘-7-올(Ex-37; 18.0 mg, 15.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d6) δ 9.74(d, J = 7.6 1H), 8.37(s, 1H), 7.94(s, 1H), 7.70(s, 1H), 7.26(d, J=3.2 1H), 7.03(s, 2H), 6.90(s, 1H) 6.79(m, 2H); MS m/z: 295.26 [M+H]+.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. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (d, J = 7.6 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.26 (d, J= 3.2 1H), 7.03(s, 2H), 6.90(s, 1H) 6.79(m, 2H); MS m/z: 295.26 [M+H] + .
실시예 38: 3-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1H-인다졸-6-올(Ex-38)Example 38: 3-[2-amino-6-(furan-2-yl)pyrimidin-4-yl]-1H-indazol-6-ol (Ex-38)
Figure PCTKR2022004084-appb-I000145
Figure PCTKR2022004084-appb-I000145
화합물(Ex-38)을 하기 반응식 20에 따라서 제조하였다.Compound (Ex-38) was prepared according to Scheme 20 below.
[반응식 20][Scheme 20]
Figure PCTKR2022004084-appb-I000146
Figure PCTKR2022004084-appb-I000146
단계 1: 6-((tert-부틸디메틸실릴)옥시)-1H-인다졸의 합성Step 1: Synthesis of 6-((tert-butyldimethylsilyl)oxy)-1H-indazole
1H-인다졸-6-올(2.00 g, 14.9 mmol)을 DMF(20.0 mL) 중에 0℃에서 냉각하여 교반한 용액에, 이미다졸(2.00 g, 29.8 mmol)을 가하고 5분 동안 동일한 온도에서 교반하였다. TBDMS-Cl(3.37 g, 22.4 mmol)을 가하고 반응물을 실온에서 16시간 동안 교반하였다. 16시간 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 100 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 6-((tert-부틸디메틸실릴)옥시)-1H-인다졸(3.50 g, 94.0%)을 수득하였다. MS m/z: 249.27 [M+H]+.To a stirred solution of 1H-indazol-6-ol (2.00 g, 14.9 mmol) in DMF (20.0 mL) at 0° C., imidazole (2.00 g, 29.8 mmol) was added and stirred at the same temperature for 5 minutes. did. TBDMS-Cl (3.37 g, 22.4 mmol) was added and the reaction stirred at room temperature for 16 h. After 16 h, the reaction was diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 6-((tert-butyldimethylsilyl)oxy)-1H-indazole (3.50 g, 94.0%). MS m/z: 249.27 [M+H] + .
단계 2: 6-((tert-부틸디메틸실릴)옥시)-3-요오드-1H-인다졸의 합성Step 2: Synthesis of 6-((tert-butyldimethylsilyl)oxy)-3-iodine-1H-indazole
단계 1에서 수득된 화합물(3.50 g, 14.1 mmol)을 교반한 용액에 t-BuOK(2.50 g, 22.6 mmol) 및 I2(5.73 g, 22.6 mmol)를 가하고 반응물을 실온에서 16시간 동안 교반하였다. 16시간 후, 반응물을 포화 소듐 티오설페이트 용액으로 희석하고 에틸 아세테이트(2 x 100 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 6-((tert-부틸디메틸실릴)옥시)-3-요오드-1H-인다졸(3.50 g, 66.0%)을 수득하였다. MS m/z: 375.11 [M+H]+.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] + .
단계 3: 6-((tert-부틸디메틸실릴)옥시)-3-(트리부틸스탄닐)-1H-인다졸의 합성Step 3: Synthesis of 6-((tert-butyldimethylsilyl)oxy)-3-(tributylstannyl)-1H-indazole
단계 2에서 수득된 화합물(4.00 g, 10.7 mmol)을 THF(40 mL) 중에 0℃에서 냉각시킨 용액에 NaH(850 mg, 12.8 mmol, 미네랄 오일 중 60% 분산)를 가하고 반응물을 15 분 동안 교반하고 -10℃로 더 냉각시켰다. 이 용액에 i-PrMgCl(THF 중 2M 용액, 6.41 mL)을 적가하고 30분 동안 동일한 온도에서 교반하였다. 30분 후, Bu3SnCl(4.50 g, 13.9 mmol)을 -10℃에서 가하고 20 분 동안 동일한 온도에서 교반한 후 이어서 실온에서 30 분 동안 교반하였다. 30 분 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 200 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물을 실리카겔(100-200 메쉬) 컬럼 크로마토그래피로 정제하고 생성물을 헥산 중 5% EtOAc로 용출하여 6-((tert-부틸디메틸실릴)옥시)-3-(트리부틸스탄닐)-1H-인다졸(1.00 g, 17.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d6) δ 12.93(s, 1H) 7.52(d, J = 12 1H) 6.89(s, 1H) 6.67(d, J = 8.8 1H), 1.60(m, 6H), 1.35(m, 7H), 1.17(m, 6H), 0.98(s, 9H) 0.86(t, 8H) 0.22(s, 6H).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. To this solution, i-PrMgCl (2M solution in THF, 6.41 mL) was added dropwise and stirred at the same temperature for 30 minutes. After 30 minutes, Bu 3 SnCl (4.50 g, 13.9 mmol) was added at -10°C and stirred at the same temperature for 20 minutes, followed by stirring at room temperature for 30 minutes. After 30 min, the reaction was diluted with water and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted with 5% EtOAc in hexanes to 6-((tert-butyldimethylsilyl)oxy)-3-(tributylstannyl)-1H- Indazole (1.00 g, 17.0%) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.93 (s, 1H) 7.52 (d, J = 12 1H) 6.89 (s, 1H) 6.67 (d, J = 8.8 1H), 1.60 (m, 6H) , 1.35 (m, 7H), 1.17 (m, 6H), 0.98 (s, 9H) 0.86 (t, 8H) 0.22 (s, 6H).
단계 4: 4-(6-((tert-부틸디메틸실릴)옥시)-1H-인다졸-3-일)-6-(퓨란-2-일)피리미딘-2-아민의 합성Step 4: Synthesis of 4-(6-((tert-butyldimethylsilyl)oxy)-1H-indazol-3-yl)-6-(furan-2-yl)pyrimidin-2-amine
단계 3에서 수득된 화합물(600 mg, 1.11 mmol)을 DMF(6.00 mL) 중에 교반한 용액에 팔라듐(II)비스(트리페닐포스핀) 디클로라이드(0.078g, 110 μmol) 및 TEA(0.44 mL)를 가하고 반응물을 아르곤 하에서 15 분 동안 탈기하였다. 반응물에 4-(퓨란-2-일)-6-요오드피리미딘-2-아민(320 mg, 1.11 mmol)을 가하고 반응물을 90℃에서 6시간 동안 교반하였다. 6시간 후, 반응물을 물로 희석하고 에틸 아세테이트(2 x 50.0 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물은 실리카겔(100-200 메쉬) 컬럼 크로마토그래피로 정제하고 생성물을 헥산 중 20% EtOAc로 용출하여 4-(6-((tert-부틸디메틸실릴)옥시)-1H-인다졸-3-일)-6-(퓨란-2-일)피리미딘-2-아민(120 mg, 26.0%)을 수득하였다. MS m/z: 408.35 [M+H]+.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 μmol) 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). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography and the product was eluted with 20% EtOAc in hexanes to 4-(6-((tert-butyldimethylsilyl)oxy)-1H-indazol-3-yl )-6-(furan-2-yl)pyrimidin-2-amine (120 mg, 26.0%) was obtained. MS m/z: 408.35 [M+H] + .
단계 5: 3-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-인다졸-6-올(Ex-38)의 합성Step 5: Synthesis of 3-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-indazol-6-ol (Ex-38)
단계 4에서 수득된 화합물(100 mg, 0.280 mmol)을 THF(1.25 mL) 중에 교반한 용액을 0℃로 냉각시키고 TBAF(1M THF 용액)(300 μL)를 적가하였다. 반응물을 0℃에서 30 분 동안 교반하였다. 30 분 후, 반응물을 물로 희석시키고 에틸 아세테이트(2 x 20.0 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨으로 건조시키고, 진공 하에서 농축시켜 조 생성물을 수득하였다. 조 생성물은 prep HPLC 정제하여 3-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-인다졸-6-올(Ex-38; 15.0 mg, 20.0%)을 수득하였다. 1H NMR(400 MHz, DMSO-d6) δ 13.11(s, 1H) 9.72(s, 1H) 8.48(d, J = 8.8 1H) 8.14(s, 1H) 7.91(s, 1H) 7.57(s, 1H) 7.20(d, J = 3.2 1H), 6.83(d, J = 1.2 1H), 6.77(m, 2H), 6.70(q, 1H); MS m/z: 294.34 [M+H]+.A stirred solution of the compound obtained in step 4 (100 mg, 0.280 mmol) in THF (1.25 mL) was cooled to 0° C. and TBAF (1 M THF solution) (300 μL) was added dropwise. The reaction was stirred at 0° C. for 30 min. After 30 min, the reaction was diluted with water and extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by prep HPLC to 3-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-indazol-6-ol (Ex-38; 15.0 mg, 20.0%) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.11(s, 1H) 9.72(s, 1H) 8.48(d, J = 8.8 1H) 8.14(s, 1H) 7.91(s, 1H) 7.57(s, 1H) 7.20 (d, J = 3.2 1H), 6.83 (d, J = 1.2 1H), 6.77 (m, 2H), 6.70 (q, 1H); MS m/z: 294.34 [M+H] + .
실시예 39: 4-(퓨란-2-일)-6-[6-(1H-피라졸-4-일옥시)-1H-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-39)Example 39: 4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1H-1,2,3-benzotriazol-1-yl]pyrimidin- 2-amine (Ex-39)
Figure PCTKR2022004084-appb-I000147
Figure PCTKR2022004084-appb-I000147
화합물(Ex-39)을 하기 반응식 21에 따라서 제조하였다.Compound (Ex-39) was prepared according to Scheme 21 below.
[반응식 21][Scheme 21]
Figure PCTKR2022004084-appb-I000148
Figure PCTKR2022004084-appb-I000148
단계 1: tert-부틸 4-히드록시피라졸-1-카르복실레이트의 합성Step 1: Synthesis of tert-butyl 4-hydroxypyrazole-1-carboxylate
tert-부틸 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)피라졸-1-카르복실레이트(20.0 g, 68.0 mmol) 및 NaOH(5.44 g, 136 mmol)을 THF(150 mL) 중에 교반한 혼합물에 H2O2(15.4 g, 136 mmol, 30%)를 0℃에 질소 대기 하에서 적가하였다. 생성된 혼합물을 2시간 동안 25℃에 질소 대기 하에서 교반하였다. 생성된 혼합물을 DCM(250 mL)으로 희석하였다. 혼합물을 HCl 수용액으로 pH 2로 산성화시켰다. 유기층을 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 하에서 농축시켜 tert-부틸 4-히드록시피라졸-1-카르복실레이트(8.00 g, 57.5%)를 황백색 고체로 수득하였다. MS m/z: 185 [M+H]+.tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (20.0 g, 68.0 mmol) and NaOH ( To a stirred mixture of 5.44 g, 136 mmol) in THF (150 mL) was added H 2 O 2 (15.4 g, 136 mmol, 30%) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 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. MS m/z: 185 [M+H] + .
단계 2:Step 2: tert-부틸 4-(3-아미노-4-니트로페녹시)피라졸-1-카르복실레이트의 합성Synthesis of tert-butyl 4-(3-amino-4-nitrophenoxy)pyrazole-1-carboxylate
단계 1에서 수득된 화합물(8.00 g, 43.4 mmol) 및 5-플루오로-2-니트로아닐린(6.78 g, 43.4 mmol)을 DMF(100 mL) 중에 교반한 혼합물에 K2CO3(15.0g, 109 mmol)를 첨가하였다. 생성된 혼합물을 16시간 동안 80℃에 질소 대기 하에서 교반하였다. 혼합물은 실온으로 냉각되도록 방치하였다. 반응은 물(300 mL)로 퀀칭하였다. 생성된 혼합물을 EtOAc(3 x 300 mL)로 추출하였다. 유기층을 모아서 염수(3 x 300 mL)로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여, tert-부틸 4-(3-아미노-4-니트로페녹시)피라졸-1-카르복실레이트(2.10 g, 13.6%)를 황색 고체로 수득하였다. MS m/z: 321 [M+H]+.To a stirred mixture of the compound obtained in step 1 (8.00 g, 43.4 mmol) and 5-fluoro-2-nitroaniline (6.78 g, 43.4 mmol) in DMF (100 mL) K 2 CO 3 (15.0 g, 109) mmol) was added. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. The reaction was quenched with water (300 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography, followed by tert-butyl 4-(3-amino-4-nitrophenoxy)pyrazole-1-carboxylate (2.10 g, 13.6). %) as a yellow solid. MS m/z: 321 [M+H] + .
단계 3:Step 3: tert-부틸 4-(3,4-디아미노페녹시)피라졸-1-카르복실레이트의 합성Synthesis of tert-butyl 4-(3,4-diaminophenoxy)pyrazole-1-carboxylate
단계 2에서 수득된 화합물(2.10 g, 6.56 mmol)을 메탄올(50.0 mL) 중에 교반한 혼합물에 Pd/C(500 mg, 10%)를 약간씩 첨가하였다. 생성된 혼합물을 2시간 동안 25℃에 수소 대기 하에서 교반하였다. 생성된 혼합물을 여과하고, 여액을 감압 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여, tert-부틸 4-(3,4-디아미노페녹시)피라졸-1-카르복실레이트(1.50 g, 70.9%)를 담황색 고체로 수득하였다. MS m/z: 291 [M+H]+.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] + .
단계 4: tert-부틸 4-(1H-1,2,3-벤조트리아졸-5-일옥시)피라졸-1-카르복실레이트의 합성Step 4: Synthesis of tert-butyl 4-(1H-1,2,3-benzotriazol-5-yloxy)pyrazole-1-carboxylate
단계 3에서 수득된 화합물(1.50 g, 5.16 mmol)을 AcOH(25.0 mL) 중에 교반한 혼합물에 H2O(5.00 mL) 중 NaNO2(534 mg, 7.75 mmol)의 용액을 질소 대기 하에 0℃에서 적가하였다. 생성된 혼합물은 1시간 동안 25℃에 질소 대기 하에서 교반하였다. 반응은 0℃에서 물로 퀀칭하였다. 침전된 고체를 여과로 수집하고 물로 세척하여, tert-부틸 4-(1H-1,2,3-벤조트리아졸-5-일옥시)피라졸-1-카르복실레이트(700 mg, 40.5%)를 농황색 고체로 수득하였다. MS m/z: 302 [M+H]+.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] + .
단계 5:Step 5: tert-부틸 4-([1-[6-클로로-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[6-클로로-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 혼합물의 합성tert-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
단계 4에서 수득된 화합물(700 mg, 2.32 mmol)을 DMF(20.0 mL) 중에 교반한 혼합물에 NaH(102 mg, 2.55 mmol, 미네랄 오일 중 60% 분산)를 질소 대기 하에 0℃에서 나누어 첨가하였다. 생성된 혼합물을 30 분 동안 0℃에 질소 대기 하에서 교반하였다. 상기 혼합물에 4,6-디클로로-2-(메틸설파닐)피리미딘(498 mg, 2.55 mmol)을 첨가하였다. 생성된 혼합물을 추가로 2시간 동안 25℃에서 교반하였다. 반응은 물(200 mL)로 퀀칭하였다. 생성된 혼합물은 EtOAc(3 x 200 mL)로 추출하였다. 유기층을 모아서 염수(3 x 200 mL)로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 tert-부틸 4-([1-[6-클로로-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[6-클로로-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(500 mg, 42.2%)의 혼합물을 황백색 고체로 수득하였다. MS m/z: 460 [M+H]+.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). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1), purified by silica gel column chromatography, and 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- A mixture of yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (500 mg, 42.2%) was obtained as an off-white solid. MS m/z: 460 [M+H] + .
단계 6: tert-부틸 4-([1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 혼합물의 합성Step 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
단계 5에서 수득된 혼합물(500 mg, 1.08 mmol)을 DMF(20.0 mL) 중에 교반한 혼합물에 트리부틸(퓨란-2-일)스탄난(582 mg, 1.63 mmol) 및 Pd(PPh3)2Cl2(915 mg, 1.30 mmol)를 첨가하였다. 생성된 혼합물을 2시간 동안 25℃에 질소 대기 하에서 교반하였다. 반응은 물(200 mL)로 퀀칭하였다. 생성된 혼합물을 EtOAc(3 x 200 mL)로 추출하였다. 유기층을 모아서 염수(3 x 200 mL)로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 하에서 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여, tert-부틸 4-([1-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[6-(퓨란-2-일)-2-(메틸설파닐)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(300 mg, 50.5%)의 혼합물을 황백색 고체로 수득하였다. MS m/z: 492 [M+H]+. To a stirred mixture of the mixture obtained in step 5 (500 mg, 1.08 mmol) in DMF (20.0 mL) tributyl(furan-2-yl)stannane (582 mg, 1.63 mmol) and Pd(PPh 3 ) 2 Cl 2 (915 mg, 1.30 mmol) was added. The resulting mixture was stirred for 2 h at 25° C. under a nitrogen atmosphere. The reaction was quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography, followed by tert-butyl 4-([1-[6-(furan-2-yl)-2-(methylsulfanyl)pyrimidine). -4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[6-(furan-2-yl) A mixture of -2-(methylsulfanyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (300 mg, 50.5%) It was obtained as an off-white solid. MS m/z: 492 [M+H] + .
단계 7:Step 7: tert-부틸 4-([1-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 혼합물의 합성tert-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
단계 6에서 수득된 혼합물(300 mg, 0.610 mmol)을 DCM(15.0 mL) 중에 교반한 혼합물에 m-CPBA(316 mg, 1.83 mmol)를 적가하였다. 생성된 혼합물을 12시간 동안 25℃에서 교반하였다. 반응은 Na2S2O3 포화 수용액으로 퀀칭하였다. 생성된 혼합물을 CH2Cl2(2 x 100 mL)로 추출하였다. 유기층을 모아서 포화 NaHCO3 포화 수용액으로 세척하고, 무수 Na2SO4로 건조시켰다. 여과 후, 여과물을 감압 하에서 농축시켜서 tert-부틸 4-([1-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[6-(퓨란-2-일)-2-메탄설포닐피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(300 mg, 미정제)의 혼합물을 담황색 고체로 수득하였다. MS m/z: 524 [M+H]+.To a stirred mixture of the mixture obtained in step 6 (300 mg, 0.610 mmol) in DCM (15.0 mL) was added dropwise m-CPBA (316 mg, 1.83 mmol). The resulting mixture was stirred at 25° C. for 12 h. 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 (2×100 mL). The combined organic layers were washed with saturated aqueous NaHCO 3 , and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and tert-butyl 4-([1-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl]-1,2,3-benzo triazol-5-yl]oxy)pyrazole-1-carboxylate and tert-butyl 4-([3-[6-(furan-2-yl)-2-methanesulfonylpyrimidin-4-yl] A mixture of -1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (300 mg, crude) was obtained as a pale yellow solid. MS m/z: 524 [M+H] + .
단계 8:Step 8: tert-부틸 4-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트의 혼합물의 합성tert-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
단계 7에서 수득된 혼합물(300 mg, 0.570 mmol)을 THF(5.00 mL) 중에 교반한 혼합물에 NH3·H2O(5.00 mL)를 적가하였다. 생성된 혼합물을 4시간 동안 25℃에서 교반하였다. 반응은 물(100 mL)로 퀀칭하였다. 생성된 혼합물은 EtOAc(3 x 100 mL)으로 추출하였다. 유기층을 모아서 무수 Na2SO4로 건조시켰다. 여과 후, 여액을 감압 농축시켰다. 잔사는 PE/EtOAc(1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 tert-부틸 4-([1-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트 및 tert-부틸 4-([3-[2-아미노-6-(퓨란-2-일)피리미딘-4-일]-1,2,3-벤조트리아졸-5-일]옥시)피라졸-1-카르복실레이트(120 mg, 40.9%)의 혼합물을 황백색 고체로 수득하였다. MS m/z: 461 [M+H]+.To a stirred mixture of the mixture obtained in step 7 (300 mg, 0.570 mmol) in THF (5.00 mL) was added NH 3 ·H 2 O (5.00 mL) dropwise. The resulting mixture was stirred at 25° C. for 4 h. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was 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 and tert-butyl 4-([3-[2-amino-6-(furan-2-yl)pyri) A mixture of midin-4-yl]-1,2,3-benzotriazol-5-yl]oxy)pyrazole-1-carboxylate (120 mg, 40.9%) was obtained as an off-white solid. MS m/z: 461 [M+H] + .
단계 9:Step 9: 4-(퓨란-2-일)-6-[6-(1H-피라졸-4-일옥시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-39)의 합성4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidin-2-amine (Ex- 39) synthesis
단계 8에서 수득된 혼합물(120 mg, 0.26 mmol)을 DCM(4.00 mL) 중에서 교반 혼합하고, TFA(1.00 mL)를 적가하였다. 생성된 혼합물을 1시간 동안 25℃에서 교반하였다. 생성된 혼합물은 진공 하에서 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18 ExRS, 30 mm X 150 mm, 5 ㎛; 이동상, 물(10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN(38% PhaseB, 9분에 53%까지); 검출기, UV 254&220 nm. 수집된 분획을 동결건조하여 4-(퓨란-2-일)-6-[5-(1H-피라졸-4-일옥시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(9.20 mg, 9.76%) 및 4-(퓨란-2-일)-6-[6-(1H-피라졸-4-일옥시)-1,2,3-벤조트리아졸-1-일]피리미딘-2-아민(Ex-39; 10.5 mg, 22.1%)을 백색 고체로 수득하였다. 1H-NMR(300 MHz, DMSO-d6) δ(ppm): 12.89(s, 1H), 8.43(d, J = 2.1Hz, 1H), 8.16(d, J = 9.0 Hz, 1H), 7.98(s, 1H), 7.89(s, 1H), 7.62(s, 1H), 7.54(s, 1H), 7.34-7.20(m, H), 6.75-6.74(m, 1H); MS m/z: 361 [M+H]+.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 μm; 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. The collected fractions were lyophilized to 4-(furan-2-yl)-6-[5-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazol-1-yl]pyrimidine -2-amine (9.20 mg, 9.76%) and 4-(furan-2-yl)-6-[6-(1H-pyrazol-4-yloxy)-1,2,3-benzotriazole-1 -yl]pyrimidin-2-amine (Ex-39; 10.5 mg, 22.1%) was obtained as a white solid. 1 H-NMR (300 MHz, DMSO-d 6 ) δ (ppm): 12.89 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.89(s, 1H), 7.62(s, 1H), 7.54(s, 1H), 7.34-7.20(m, H), 6.75-6.74(m, 1H); MS m/z: 361 [M+H] + .
실시예 40: 1-[2-아미노-6-(2-메틸-1,3-티아졸-5-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-40)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)
Figure PCTKR2022004084-appb-I000149
Figure PCTKR2022004084-appb-I000149
제조예 10의 화합물 J를 출발물질로 하여 하기 반응식 22에 따라서 화합물(Ex-40)을 합성하였다.Compound (Ex-40) was synthesized according to Scheme 22 below using compound J of Preparation 10 as a starting material.
[반응식 22][Scheme 22]
Figure PCTKR2022004084-appb-I000150
Figure PCTKR2022004084-appb-I000150
단계 1: 1-[2-클로로-6-(2-메틸-1,3-티아졸-5-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Step 1: 1-[2-Chloro-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole synthesis of
제조예 10에서 제조된 화합물 J (3.0g, 7.09 mmol, 1.00당량, 70%) 및 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1,3-티아졸 (798 mg, 3.54 mmol, 0.50당량)을 디옥산 (15 mL) 및 H2O (3 mL) 중에 교반 혼합하고, Pd(dppf)Cl2CH2Cl2 (1.1g, 1.41 mmol, 0.2당량) 및 K2CO3 (3.9g, 28.36 mmol, 4당량)를 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 16시간 동안 교반하였다. 혼합물을 실온으로 냉각시킨 다음 감압 농축시켰다. 조 생성물을 하기 조건에서 역 플래쉬 크로마토그래피로 정제하였다: 컬럼, C18 실리카겔, 80g, 20-35 ㎛; 이동상, 물, 0.05% TFA 및 ACN (30분 내에 0% ~ 100% 구배); 검출기, UV 254/220 nm. 용액을 감압 농축하여 1-[2-클로로-6-(2-메틸-1,3-티아졸-5-일)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸 (600 mg, 15.33%)을 황백색(off white) 고체로 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.96 (s, 1H), 8.79 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 2.77 (s, 3H); MS m/z: 359 [M+H]+.Compound J (3.0 g, 7.09 mmol, 1.00 eq, 70%) prepared in Preparation Example 10 and 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)-1,3-thiazole (798 mg, 3.54 mmol, 0.50 equiv) was stirred mixed in dioxane (15 mL) and H 2 O (3 mL), Pd(dppf)Cl 2 CH 2 Cl 2 (1.1 g, 1.41 mmol, 0.2 equiv) and K 2 CO 3 (3.9 g, 28.36 mmol, 4 equiv) were added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by reverse flash chromatography under the following conditions: column, C 18 silica gel, 80 g, 20-35 μm; mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient in 30 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. 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.96 (s, 1H), 8.79 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 2.77 (s, 3H); MS m/z: 359 [M+H] + .
단계 2: 4-(5-메톡시-1,2,3-벤조트리아졸-1-일)-6-(2-메틸-1,3-티아졸-5-일)피리미딘-2-아민의 합성Step 2: 4-(5-Methoxy-1,2,3-benzotriazol-1-yl)-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-2-amine synthesis of
단계 1에서 수득된 화합물 (600 mg, 1.67 mmol, 1.00당량) 및 NH3.H2O를 MeOH (7 M, 5 mL) 및 EtOH (5 mL) 중에서 질소 대기하에 80℃에서 16시간 동안 교반 하였다. 혼합물을 실온으로 냉각시킨 후, 감압 농축하였다. 조 생성물을 하기 조건에서 역 플래쉬 크로마토그래피로 정제하였다: 컬럼, C18 실리카겔, 80g, 20-35 ㎛; 이동상, 물 (10 mmol/L NH4HCO3) 및 ACN (30분에 0% ~ 100% 구배); 검출기, UV 254/220 nm. 혼합물을 감압 농축하여 4-(5-메톡시-1,2,3-벤조트리아졸-1-일)-6-(2-메틸-1,3-티아졸-5-일)피리미딘-2-아민 (100 mg, 14.10%)을 황백색 고체로 수득하였다. MS m/z: 340 [M+H]+ 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 μm; mobile phase, water (10 mmol/L NH 4 HCO 3 ) and ACN (0% to 100% gradient in 30 min); Detector, UV 254/220 nm. The mixture was concentrated under reduced pressure to 4-(5-methoxy-1,2,3-benzotriazol-1-yl)-6-(2-methyl-1,3-thiazol-5-yl)pyrimidine-2 -Amine (100 mg, 14.10%) was obtained as an off-white solid. MS m/z: 340 [M+H] +
단계 3: 1-[2-아미노-6-(2-메틸-1,3-티아졸-5-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-40)의 합성Step 3: 1-[2-amino-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazole-5- Synthesis of ol (Ex-40)
단계 2에서 수득된 화합물 (100 mg, 0.236 mmol, 1.00당량, 80%) 및 BBr3를 DCM (1M, 3.00 mL) 중에서 25℃에서 1시간 동안 교반하였다. 반응을 MeOH (50 mL)로 퀀칭시키고, 생성된 혼합물을 감압 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼: YMC-Actus Triart C18, 30 mm X 150 mm, 5 ㎛; 이동상 A: 물 (50MMOL/L NH4HCO3), 이동상 B: ACN; 유속: 60 mL/분; 구배: 9 분에 25B에서 45B, 254nm; RT1: 7.93. 수집된 분획을 동결 건조하여 1-[2-아미노-6-(2-메틸-1,3-티아졸-5-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올 (Ex-40; 5.4 mg, 6.92%)을 황백색 고체로서 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.01 (s, 1H), 8.64 (s, 1H), 8.62 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 7.37 (s, 1H), 7.32 (s, 2H), 7.22 (d, J = 11.2 Hz, 1H), 2.72 (s, 3H); MS m/z: 326 [M+H]+.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 μm; 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. The collected fractions were freeze-dried to 1-[2-amino-6-(2-methyl-1,3-thiazol-5-yl)pyrimidin-4-yl]-1H-1,2,3-benzotria Zol-5-ol (Ex-40; 5.4 mg, 6.92%) was obtained as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.01 (s, 1H), 8.64 (s, 1H), 8.62 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H) , 7.37 (s, 1H), 7.32 (s, 2H), 7.22 (d, J = 11.2 Hz, 1H), 2.72 (s, 3H); MS m/z: 326 [M+H] + .
실시예 41: 1-{2-아미노-[4,5'-비피리미딘]-6-일}-1H-1,2,3-벤조트리아졸-5-올(Ex-41)Example 41: 1-{2-amino-[4,5'-bipyrimidin]-6-yl}-1H-1,2,3-benzotriazol-5-ol (Ex-41)
Figure PCTKR2022004084-appb-I000151
Figure PCTKR2022004084-appb-I000151
실시예 40의 단계 1에서 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1,3-티아졸 대신에 피리미딘-4-일 보론산을 사용한 것을 제외하고, 실시예 40과 동일한 방법으로 1-{2-아미노-[4,5'-비피리미딘]-6-일}-1H-1,2,3-벤조트리아졸-5-올(Ex-41; 14.06%)을 백색 고체로서 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 9.52 (s, 2H), 9.34 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.47 (s, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.26-7.23 (m, 1H); MS m/z: 307 [M+H]+.Pyri instead of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole in step 1 of Example 40 1-{2-amino-[4,5'-bipyrimidin]-6-yl}-1H-1,2,3 in the same manner as in Example 40, except that midin-4-yl boronic acid was used -Benzotriazol-5-ol (Ex-41; 14.06%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.04 (s, 1H), 9.52 (s, 2H), 9.34 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H) , 8.02 (s, 1H), 7.47 (s, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.26-7.23 (m, 1H); MS m/z: 307 [M+H] + .
실시예 42: 1-[2-아미노-6-(3-아미노아제티딘-1-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-42)Example 42: 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex- 42)
Figure PCTKR2022004084-appb-I000152
Figure PCTKR2022004084-appb-I000152
제조예 10의 화합물 J를 출발물질로 하여 하기 반응식 23에 따라서 화합물(Ex-42)을 합성하였다.Compound (Ex-42) was synthesized according to Scheme 23 below using compound J of Preparation 10 as a starting material.
[반응식 23][Scheme 23]
Figure PCTKR2022004084-appb-I000153
Figure PCTKR2022004084-appb-I000153
단계 1: tert-부틸 N-[1-[2-클로로-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-4-일]아제티딘-3-일]카바메이트의 합성Step 1: tert-Butyl N-[1-[2-chloro-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]azetidine-3- General] synthesis of carbamates
제조예 10의 화합물 J (1.5g, 5.06 mmol, 1.00당량) 및 tert-부틸 N-(아제티딘-3)-일)카바메이트 하이드로클로라이드 (1.0g, 5.06 mmol, 1당량)을 DMF (15 mL) 중에 교반 혼합하고, DIEA (2.6g, 20.26 mmol, 4당량)을 첨가하였다. 생성된 혼합물을 25℃에서 5분 동안 교반하고, 조 생성물을 하기 조건에서 역 플래쉬 크로마토그래피로 정제하였다: 컬럼, C18 실리카겔, 330g, 20-35 ㎛; 이동상, 물, 0.05% TFA 및 ACN (30분에 0%에서 100% 구배); 검출기, UV 254/220 nm. 이어서, 혼합물을 감압 농축하고, 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼: YMC-Actus Triart C18, 30 mm X 150 mm, 5 ㎛; 이동상 A: 물 (50 mmol/L NH4HCO3), 이동상 B: ACN; 유속: 60 mL/분; 구배: 18B에서 35B까지 12분, 254nm; RT1: 10.47. 혼합물을 감압 농축하여 tert-부틸 N-[1-[2-클로로-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-4-일]아제티딘-3-일]카바메이트 (첫번째 이성질체 용리)(150 mg, 6.31%)를 백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.27 (d, J = 8.8 Hz, 1H), 7.72-7.70 (m, 1H), 7.63-7.62 (m, 1H), 7.38-7.35 (m, 1H), 6.94 (m, 1H), 4.56-4.47 (m, 1H), 4.45-4.30 (m, 2H), 4.05-4.00 (m, 2H), 3.88 (s, 3H), 1.41 (s, 9H); MS m/z: 432 [M+H]+ . Compound J of Preparation 10 (1.5 g, 5.06 mmol, 1.00 equiv) and tert-butyl N-(azetidin-3)-yl)carbamate hydrochloride (1.0 g, 5.06 mmol, 1 equiv) were mixed with DMF (15 mL) ), and DIEA (2.6 g, 20.26 mmol, 4 eq) was added. The resulting mixture was stirred at 25° C. for 5 minutes, and the crude product was purified by reverse flash chromatography under the following conditions: column, C 18 silica gel, 330 g, 20-35 μm; mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient at 30 min); Detector, UV 254/220 nm. Then, the mixture was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: Column: YMC-Actus Triart C 18 , 30 mm X 150 mm, 5 μm; mobile phase A: water (50 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; Gradient: 12 min from 18B to 35B, 254 nm; RT1: 10.47. The mixture was concentrated under reduced pressure, and tert-butyl N-[1-[2-chloro-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]azetidine- 3-yl]carbamate (eluting the first isomer) (150 mg, 6.31%) was obtained as a white solid. 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.27 (d, J = 8.8 Hz, 1H), 7.72-7.70 (m, 1H), 7.63-7.62 (m, 1H), 7.38-7.35 (m, 1H), 6.94 (m, 1H), 4.56-4.47 (m, 1H), 4.45-4.30 (m, 2H), 4.05-4.00 (m, 2H), 3.88 (s, 3H), 1.41 (s) , 9H); MS m/z: 432 [M+H] + .
단계 2: tert-부틸 N-[1-[2-아미노-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-4-일]아제티딘-3-일]카바메이트의 합성Step 2: tert-Butyl N-[1-[2-amino-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]azetidine-3- General] synthesis of carbamates
단계 1에서 수득된 화합물 (150 mg, 0.34 mmol, 1.00당량) 및 NH3(g)을 MeOH (7M, 3 mL) 및 EtOH (2 mL) 중에서 질소 대기하에 100℃에서 5일 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 감압 농축한 후, 조 생성물을 하기 조건에서 역 플래쉬 크로마토그래피로 정제하였다: 컬럼, C18 실리카겔, 40g, 20-35 ㎛; 이동상, 물, 0.05% TFA 및 ACN (30분에 0%에서 100% 구배); 검출기, UV 254/220 nm. 수집된 분획을 동결 건조하여 tert-부틸 N-[1-[2-아미노-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-4-일]아제티딘-3-일]카바메이트 (95 mg, 64.26%)를 분홍색 고체로 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.61 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.58 (s, 1H), 7.27-7.25 (m, 1H), 6.85 (brs, 2H), 6.31 (s, 1H), 4.47-4.44 (m, 1H), 4.31-4.27 (m, 2H), 3.90-3.87 (m, 2H); MS m/z: 413 [M+H]+ . 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 μm; mobile phase, water, 0.05% TFA and ACN (0% to 100% gradient at 30 min); Detector, UV 254/220 nm. The collected fractions were freeze-dried to obtain tert-butyl N-[1-[2-amino-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]ase Tidin-3-yl]carbamate (95 mg, 64.26%) was obtained as a pink solid. 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.61 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.58 (s, 1H), 7.27-7.25 (m) , 1H), 6.85 (brs, 2H), 6.31 (s, 1H), 4.47-4.44 (m, 1H), 4.31-4.27 (m, 2H), 3.90-3.87 (m, 2H); MS m/z: 413 [M+H] + .
단계 3: 1-[2-아미노-6-(3-아미노아제티딘-1-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-42)의 합성Step 3: 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-42 ) synthesis
단계 2에서 수득된 화합물 (95 mg, 0.23 mmol, 1.00당량) 및 BBr3을 DCM (1M, 3.00 mL) 중에 25℃에서 1시간 동안 교반하였다. 반응을 MeOH (50 mL)로 퀀칭시키고, 생성된 혼합물을 감압 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30x150 mm, 5 ㎛; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3.H2O) 및 ACN (10% PhaseB, 7분에 30%까지); 검출기, 254 nm. 수집된 분획을 동결 건조하여 1-[2-아미노-6-(3-아미노아제티딘-1-일)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올 (Ex-42; 6 mg, 9.64%)을 황백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.57 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.15 (d, J = 11.2 Hz, 1H), 6.68 (s, 2H), 6.28 (s, 1H), 4.29-4.19 (m, 2H), 3.89-3.81 (m, 1H), 3.66-3.66 (m, 2H); MS, m/z: 299 [M+H]+ 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 μm; 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. The collected fractions were freeze-dried to 1-[2-amino-6-(3-aminoazetidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-benzotriazol-5-ol (Ex-42; 6 mg, 9.64%) was obtained as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.57 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.15 (d, J = 11.2 Hz, 1H), 6.68 (s, 2H), 6.28 (s, 1H), 4.29-4.19 (m, 2H), 3.89-3.81 (m, 1H), 3.66-3.66 (m, 2H); MS, m/z: 299 [M+H] +
실시예 43: 1-[2-아미노-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-1H-1,2,3-벤조트리아졸-5-올(Ex-43)Example 43: 1- [2-amino-6- (3,3-difluorocyclobutyl) pyrimidin-4-yl] -1H-1,2,3-benzotriazol-5-ol (Ex- 43)
Figure PCTKR2022004084-appb-I000154
Figure PCTKR2022004084-appb-I000154
화합물(Ex-43)을 하기 반응식 24에 따라서 합성하였다.Compound (Ex-43) was synthesized according to Scheme 24 below.
[반응식 24][Scheme 24]
Figure PCTKR2022004084-appb-I000155
Figure PCTKR2022004084-appb-I000155
단계 1: 2-클로로-6-(3,3-디플루오로사이클로부틸)-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민의 합성Step 1: Synthesis of 2-chloro-6-(3,3-difluorocyclobutyl)-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine
제조예 11의 화합물 K (2.3g, 10.47 mmol, 1.00당량)를 THF (25 mL) 중에 교반한 혼합물에 NaH (837 mg, 20.94 mmol, 2.00당량, 60%)를 질소 대기하에 0℃에서 나누어 첨가하였다. 생성된 혼합물을 질소 대기하에 0℃에서 1시간 동안 교반하였다. 상기 혼합물에 1-플루오로-4-메톡시-2-니트로벤젠 (3.5g, 20.94 mmol, 2.00당량)을 0℃에서 첨가하였다. 생성된 혼합물을 60℃에서 추가로 3시간 동안 교반하고, 반응을 물 (300 mL)로 퀀칭시켰다. 혼합물을 에틸 아세테이트 (3 x 300 mL)로 추출하고 무수 Na2SO4로 건조하고 감압 농축하였다. 잔사를 PE/EtOAc (5:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-6-(3,3-디플루오로사이클로부틸)-N-(4-메톡시-2-니트로페닐)피리미딘-4-아민(1.5g, 37.17%)을 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.99 (s, 1H), 7.55-7.49 (m, 2H), 7.36-7.32 (m, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.43-3.38 (m, 1H), 2.91-2.75 (m, 4H); MS m/z: 371 [M+H]+.To a mixture of compound K of Preparation 11 (2.3 g, 10.47 mmol, 1.00 equiv) was stirred in THF (25 mL), NaH (837 mg, 20.94 mmol, 2.00 equiv, 60%) was added portionwise at 0 °C under a nitrogen atmosphere. did. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour. To this mixture was added 1-fluoro-4-methoxy-2-nitrobenzene (3.5 g, 20.94 mmol, 2.00 equiv) at 0 °C. The resulting mixture was stirred at 60° C. for an additional 3 h and the reaction was quenched with water (300 mL). The mixture was extracted with ethyl acetate (3 x 300 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to 2-chloro-6-(3,3-difluorocyclobutyl)-N-(4-methoxy-2-nitrophenyl). ) pyrimidin-4-amine (1.5 g, 37.17%) was obtained as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.99 (s, 1H), 7.55-7.49 (m, 2H), 7.36-7.32 (m, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.43-3.38 (m, 1H), 2.91-2.75 (m, 4H); MS m/z: 371 [M+H] + .
단계 2: N1-[2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-4-메톡시벤젠-1,2-디아민의 합성Step 2: Synthesis of N1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-4-methoxybenzene-1,2-diamine
단계 1에서 수득된 화합물 (1.5g, 4.04 mmol, 1.00당량)을 EtOH (15 mL) 및 H2O (3 mL) 중에 교반한 혼합물에 Fe (1.1g, 20.23 mmol, 5당량) 및 NH4Cl (649 mg, 12.13 mmol, 3당량)을 첨가하였다. 생성된 혼합물을 80℃에서 16시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 여과하여 필터 케이크를 에틸 아세테이트 (3 x 700 mL)로 세척하였다. 여액을 감압 농축하여 N1-[2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-4-메톡시벤젠-1,2-디아민 (1.5g, 93.57%)을 황백색 고체로 수득하였다. MS m/z: 341 [M+H]+.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). The filtrate was concentrated under reduced pressure to N1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-4-methoxybenzene-1,2-diamine (1.5g, 93.57% ) was obtained as an off-white solid. MS m/z: 341 [M+H] + .
단계 3: 1-[2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸의 합성Step 3: Synthesis of 1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-5-methoxy-1,2,3-benzotriazole
단계 2에서 수득된 화합물 (1.5g, 4.40 mmol, 1.00당량)을 AcOH (15 mL) 및 H2O (5 mL) 중에 교반한 혼합물에 NaNO2 (334 mg, 4.84 mmol, 1.1당량)를 0℃에서 나누어 첨가하였다. 생성된 혼합물을 25℃에서 30분 동안 교반하고, 반응을 실온에서 물 (800 mL)을 첨가하여 퀀칭하였다. 침전된 고체를 여과하여 수집하고 H2O (100 mL)로 세척하여, 1-[2-클로로-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-5-메톡시-1,2,3-벤조트리아졸 (900 mg, 56.96%)을 황백색 고체로 수득하였다. 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.49 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.49 (s, 1H), 7.37-7.34 (m, 1H), 3.96 (s, 3H), 3.61-3.54 (m, 1H), 3.11-3.02 (m, 4H); MS m/z: 352 [M+H]+.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). The precipitated solid was collected by filtration and washed with H 2 O (100 mL), 1-[2-chloro-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-5-me Toxy-1,2,3-benzotriazole (900 mg, 56.96%) was obtained as an off-white solid. 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 8.49 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.49 (s, 1H), 7.37-7.34 (m, 1H) , 3.96 (s, 3H), 3.61-3.54 (m, 1H), 3.11-3.02 (m, 4H); MS m/z: 352 [M+H] + .
단계 4: 4-(3,3-디플루오로사이클로부틸)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민의 합성Step 4: Synthesis of 4-(3,3-difluorocyclobutyl)-6-(5-methoxy-1,2,3-benzotriazol-1-yl)pyrimidin-2-amine
단계 3에서 수득된 화합물 (900 mg, 2.55 mmol, 1.00당량) 및 NH3 (g)를 MeOH (7 M, 5 mL) 및 EtOH (5 mL) 중에서 질소 대기하에 80℃에서 3시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 감압 농축하였다. 잔사를 PE/EtOAc (2:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 4-(3,3-디플루오로사이클로부틸)-6-(5-메톡시-1,2,3-벤조트리아졸-1-일)피리미딘-2-아민 (360 mg, 37.60%)을 황백색 고체로 수득하였다. 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.49-8.46 (m, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.30-7.26 (m, 1H), 5.31 (s, 2H), 3.95 (s, 3H), 3.42-3.38 (m, 1H), 3.07-2.92 (m, 4H); MS m/z: 333 [M+H]+.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. 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 8.49-8.46 (m, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.30-7.26 (m, 1H), 5.31 ( s, 2H), 3.95 (s, 3H), 3.42-3.38 (m, 1H), 3.07-2.92 (m, 4H); MS m/z: 333 [M+H] + .
단계 5: 1-[2-아미노-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-1,2,3-벤조트리아졸-5-올(Ex-43)의 합성Step 5: of 1-[2-amino-6-(3,3-difluorocyclobutyl)pyrimidin-4-yl]-1,2,3-benzotriazol-5-ol (Ex-43) synthesis
단계 4에서 수득된 화합물 (150 mg, 0.45 mmol, 1.00당량) 및 BBr3을 DCM (1M, 5 mL) 중에서 25℃에서 10분 동안 교반하였다. 반응을 MeOH (5 mL)로 퀀칭하고, 조 생성물을 하기 조건에서 역 플래쉬 크로마토그래피로 정제하였다: 컬럼, C18 실리카겔, 80g, 20-35 ㎛; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3.H2O) 및 ACN (30분에 0%에서 100% 구배). 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18 ExRS, 30 x 250, 5 ㎛; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3.H2O) 및 ACN (42% PhaseB, 7분에 65%까지); 검출기, UV 254 nm. 수집된 분획을 동결 건조하여 1-[2-아미노-6-(3,3-디플루오로사이클로부틸)피리미딘-4-일]-1,2,3-벤조트리아졸-5-올 (Ex-43; 9.3 mg, 6.45%)을 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.99 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.24-7.19 (m, 3H), 3.52-3.46 (m, 1H), 2.97-2.88 (m, 4H); MS m/z: 319 [M+H]+.The compound obtained in step 4 (150 mg, 0.45 mmol, 1.00 equiv) and BBr 3 were stirred in DCM (1M, 5 mL) at 25° C. for 10 min. The reaction was quenched with MeOH (5 mL), and the crude product was purified by reverse flash chromatography under the following conditions: column, C 18 silica gel, 80 g, 20-35 μm; Mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (0% to 100% gradient in 30 min). The crude product was purified by Prep-HPLC under the following conditions: column, YMC-Actus Triart C 18 ExRS, 30×250, 5 μm; 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. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.99 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.30 (s, 1H) , 7.24-7.19 (m, 3H), 3.52-3.46 (m, 1H), 2.97-2.88 (m, 4H); MS m/z: 319 [M+H] + .
실시예 44: 3-[2-아미노-6-(5-히드록시-1H-1,2,3-벤조트리아졸-1-일)피리미딘-4-일]-2-메틸벤조니트릴(Ex-44)Example 44: 3-[2-amino-6-(5-hydroxy-1H-1,2,3-benzotriazol-1-yl)pyrimidin-4-yl]-2-methylbenzonitrile (Ex -44)
Figure PCTKR2022004084-appb-I000156
Figure PCTKR2022004084-appb-I000156
실시예 40의 단계 1에서 2-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1,3-티아졸 대신에 3-아미노-2-메틸페닐 보론산을 사용한 것을 제외하고, 실시예 40과 동일한 방법으로 3-[2-아미노-6-(5-히드록시-1H-1,2,3-벤조트리아졸-1-일)피리미딘-4-일]-2-메틸벤조니트릴(Ex-44; 18.5 mg, 30.26%)을 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 7.93-7.91 (m, 1H), 7.82-7.80 (m, 1H), 7.55-7.52 (m, 1H), 7.40-7.37 (m, 4H), 7.26-7.23 (m, 1H), 2.59 (s, 3H); MS m/z: 344 [M+H]+.3 instead of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole in step 1 of Example 40 - 3-[2-amino-6-(5-hydroxy-1H-1,2,3-benzotriazole-1-) in the same manner as in Example 40, except that amino-2-methylphenyl boronic acid was used yl)pyrimidin-4-yl]-2-methylbenzonitrile (Ex-44; 18.5 mg, 30.26%) was obtained. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.03 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 7.93-7.91 (m, 1H), 7.82-7.80 ( m, 1H), 7.55-7.52 (m, 1H), 7.40-7.37 (m, 4H), 7.26-7.23 (m, 1H), 2.59 (s, 3H); MS m/z: 344 [M+H] + .
실험예 1: A2AR cAMP 기능 에세이Experimental Example 1: A2AR cAMP function assay
본원 화합물의 A2A 수용체 길항 활성을 평가하기 위하여 A2AR cAMP 기능 에세이를 수행하였다.In order to evaluate the A2A receptor antagonistic activity of the present compound, an A2AR cAMP function assay was performed.
상기 실시예들의 화합물을 DMSO에 용해시켜 10 mM 스톡 용액을 제조하였다. IC50을 측정하기 위해 화합물을 10개의 농도(최고 농도: 100 μM, 10배 연속 희석)에서 평가하였다.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 μM, 10-fold serial dilutions) to determine IC 50 .
96-웰 화이트 플레이트에 웰당 25,000개의 HEK293 세포(Life technologies, R705-07)를 2 x 106 개의 아데노신 수용체(A2AR)를 발현하는 배큘로바이러스 입자와 함께 접종하고 밤새 인큐베이션하였다. cAMP 기능 분석에 사용된 아데노신 수용체 작용제인 5-N-에틸카복스아미도아데노신(NECA)(Tocris, 1691)의 EC80을 측정하기 위하여 용량 반응 평가를 수행하였다. 다음 날, 배지를 제거하고 30 μL의 PBS로 교체하였다. 7.5 μL의 화합물을 첨가하고 30 분 동안 37℃/5% CO2에서 인큐베이션하였다. 이어서, 7.5 μL의 NECA를 EC80에 해당하는 최종 농도로 첨가하고, 37 ℃/5% CO2에서 60분 동안 인큐베이션한 후 생물학적 제제에 대한 Hithunter cAMP 분석(DiscoveRx; 90-0075 시리즈)에서 평가하였다. 발광 신호의 변화는 Perkin Elmer Envision에서 모니터링하였다. 화합물의 IC50을 하기 표 1에 나타낸 기준으로 평가하여 하기 표 2에 기재하였다.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. The next day, the medium was removed and replaced with 30 μL of PBS. 7.5 μL of compound was added and incubated for 30 min at 37° C./5% CO 2 . Then, 7.5 μL of NECA was added to a final concentration corresponding to EC 80 and incubated at 37° C./5% CO 2 for 60 minutes before evaluation in the Hithunter cAMP assay (DiscoveRx; 90-0075 series) for biologicals. . Changes in the luminescence signal were monitored by Perkin Elmer Envision. The IC 50 of the compound was evaluated according to the criteria shown in Table 1 below, and is shown in Table 2 below.
A2AR 길항 활성(IC50)A2AR antagonist activity (IC 50 ) <100nM <100nM 100nM~1uM100nM to 1uM >1uM>1uM
표시값display value ++++++ ++++ ++
A2AR 길항 활성(IC50, nM)A2AR antagonist activity (IC 50 , nM)
실시예 1(Ex-01)Example 1 (Ex-01) ++++++
실시예 2(Ex-02)Example 2 (Ex-02) ++++++
실시예 3(Ex-03)Example 3 (Ex-03) ++++++
실시예 4(Ex-04)Example 4 (Ex-04) ++++
실시예 5(Ex-05)Example 5 (Ex-05) ++++++
실시예 6(Ex-06)Example 6 (Ex-06) ++++
실시예 7(Ex-07)Example 7 (Ex-07) ++++
실시예 8(Ex-08)Example 8 (Ex-08) ++
실시예 9(Ex-09)Example 9 (Ex-09) ++
실시예 10(Ex-10)Example 10 (Ex-10) ++++
실시예 11(Ex-11)Example 11 (Ex-11) ++++++
실시예 12(Ex-12)Example 12 (Ex-12) ++++++
실시예 13(Ex-13)Example 13 (Ex-13) ++
실시예 14(Ex-14)Example 14 (Ex-14) ++++
실시예 15(Ex-15)Example 15 (Ex-15) ++
실시예 16(Ex-16)Example 16 (Ex-16) ++
실시예 17(Ex-17)Example 17 (Ex-17) ++
실시예 18(Ex-18)Example 18 (Ex-18) ++
실시예 19(Ex-19)Example 19 (Ex-19) ++++
실시예 20(Ex-20)Example 20 (Ex-20) ++
실시예 21(Ex-21)Example 21 (Ex-21) ++++
실시예 22(Ex-22)Example 22 (Ex-22) ++
실시예 23(Ex-23)Example 23 (Ex-23) ++
실시예 24(Ex-24)Example 24 (Ex-24) ++++
실시예 25(Ex-25)Example 25 (Ex-25) ++++
실시예 26(Ex-26)Example 26 (Ex-26) ++++
실시예 27(Ex-27)Example 27 (Ex-27) ++++
실시예 28(Ex-28)Example 28 (Ex-28) ++++++
실시예 29(Ex-29)Example 29 (Ex-29) ++
실시예 30(Ex-30)Example 30 (Ex-30) ++
실시예 31(Ex-31)Example 31 (Ex-31) ++++
실시예 32(Ex-32)Example 32 (Ex-32) ++
실시예 33(Ex-33)Example 33 (Ex-33) ++
실시예 34(Ex-34)Example 34 (Ex-34) ++
실시예 35(Ex-35)Example 35 (Ex-35) ++++
실시예 36(Ex-36)Example 36 (Ex-36) ++++
실시예 37(Ex-37)Example 37 (Ex-37) ++++
실시예 38(Ex-38)Example 38 (Ex-38) ++++
실시예 39(Ex-39)Example 39 (Ex-39) ++
실시예 40(Ex-40)Example 40 (Ex-40) ++
실시예 41(Ex-41)Example 41 (Ex-41) ++
실시예 42(Ex-42)Example 42 (Ex-42) ++
실시예 43(Ex-43)Example 43 (Ex-43) ++
실시예 44(Ex-44)Example 44 (Ex-44) ++++++
상기 표 2에서 알 수 있듯이, 본원 실시예 화합물들은 A2AR 수용체에 대하여 우수한 길항 활성을 나타내며, 특히 실시예 1, 2, 3, 5, 11, 12, 28 및 44의 화합물은 100 nM 이하의 IC50 값을 가짐으로써 A2AR 수용체에 대한 길항 활성이 특히 우수한 것을 확인하였다.As can be seen in Table 2 above, 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.

Claims (21)

  1. 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염:A compound represented by the following formula (1), a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022004084-appb-I000157
    Figure PCTKR2022004084-appb-I000157
    상기 화학식 1에서,In Formula 1,
    G1은 -(CH2)l-고리 A이고, G2는 H 또는 -(CH2)m-피리딘일이고;G 1 is —(CH 2 ) 1 -ring A, G 2 is H or —(CH 2 ) m -pyridinyl;
    상기 고리 A는 C6-12 아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; N, O 및 S로부터 선택되는 1~3개의 헤테로원자를 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택되고;wherein 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;
    상기 고리 A는 할로겐, -CN, -OH, C1-6 알킬, 할로겐으로 치환된 C1-6 알킬, C1-6 알콕시, 할로겐으로 치환된 C1-6 알콕시, 및 NRARB로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 치환 또는 비치환될 수 있고;wherein ring A is selected from halogen, -CN, -OH, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, and NR A R B may be unsubstituted or substituted with one or more substituents selected from the group consisting of;
    RA 및 RB은 각각 독립적으로 H 또는 C1-6 알킬이고;R A and R B are each independently H or C 1-6 alkyl;
    X1 및 X2는 각각 독립적으로 C 또는 N이고, X3는 CR' 또는 N이고, X4는 CH, N 또는 NH이되, X1, X2, X3 및 X4 중 1~3개가 N 또는 NH이고;X 1 and X 2 are each independently C or N, X 3 is CR' or N, X 4 is CH, N or NH, wherein 1-3 of X 1 , X 2 , X 3 and X 4 are N or NH;
    R'은 H 또는 -(CH2)n-피리딘일이고;R' is H or -(CH 2 ) n -pyridinyl;
    R은 -OH, -O-(CH2)o-R1, -(CH2)p-O-R2, -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5이고;R is -OH, -O-(CH 2 ) o -R 1 , -(CH 2 ) p -OR 2 , -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r -O- CO-R 4 or -CO-R 5 ;
    R1 및 R2는 각각 독립적으로 C4-6 사이클로알킬; 1~3개의 N 또는 O를 함유하는 5-6원 헤테로아릴; 1~2개의 N을 함유하는 5-6원 헤테로사이클릴; 및 C6-12 아릴로 이루어진 군으로부터 선택되고,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,
    상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; 아미노; 니트로; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, 아미노, 니트로, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 임의로 1~2개의 O에 의해 중단된 C1-6 알킬; 할로겐, 시아노, OH, 아미노, 니트로, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알콕시; R''으로 임의로 치환된 C6-12 아릴; 및 R'''으로 임의로 치환된 1-2개의 N, O 또는 S를 함유하는 5-6원 헤테로사이클릴로 이루어진 군으로부터 선택되는 치환기에 의해 임의로 치환될 수 있고,wherein 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''';
    R'' 및 R'''은 각각 독립적으로 할로겐, 시아노, OH, 아미노, 니트로, COOH, COO-(C1-6 알킬), C1-6 알킬, 및 C1-6 알콕시로 이루어진 군으로부터 선택되고;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. is selected from;
    R3, R4 및 R5는 각각 독립적으로 -NH-C6-12 아릴; -NH-(1~2개의 N, O 또는 S를 포함하는 5-6원 헤테로아릴); 및 -NRaRb로 이루어진 군으로부터 선택되고, 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 ,
    Ra 및 Rb는 이들이 결합한 N과 함께 임의로 1개의 N을 더 포함하는 5-6원 헤테로사이클릴을 형성하되, 상기 5-6원 헤테로사이클릴은 임의로 -(CH2)s-C6-12 아릴로 치환되거나 C6-12 아릴과 융합될 수 있고, R a and R b together with the N to which they are attached form a 5-6 membered heterocyclyl optionally further comprising 1 N, wherein said 5-6 membered heterocyclyl is optionally -(CH 2 ) s -C 6- 12 aryl or fused with C 6-12 aryl;
    상기 R3, R4 및 R5는 각각 독립적으로 할로겐, 시아노, OH, 아미노, 니트로, COOH, COO-(C1-6 알킬), C1-6 알킬, 및 C1-6 알콕시로 이루어진 군으로부터 선택된 치환기로 임의로 치환될 수 있고;wherein R 3 , R 4 and R 5 are each independently halogen, cyano, OH, amino, nitro, COOH, COO-(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 alkoxy may be optionally substituted with a substituent selected from the group;
    l, m 및 n은 0 내지 3의 정수이고, o 및 p는 0 내지 5의 정수이고, q, r 및 s는 각각 0 내지 3의 정수이다.l, m and n are integers from 0 to 3, o and p are integers from 0 to 5, and q, r and s are each integer from 0 to 3.
  2. 제1항에 있어서,According to claim 1,
    Figure PCTKR2022004084-appb-I000158
    은 벤조트리아졸일, [1,2,4]트리아졸로[4,3-a]피리딘일, [1,2,3]트리아졸로[1,5-a]피리딘일, [1,2,4]트리아졸로[1,5-a]피리딘일, 인다졸릴, 벤즈이미다졸릴, 인돌릴 및 이소인돌릴로 이루어진 군으로부터 선택되는, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용 가능한 염.
    Figure PCTKR2022004084-appb-I000158
    Silver benzotriazolyl, [1,2,4] triazolo [4,3-a] pyridinyl, [1,2,3] triazolo [1,5-a] pyridinyl, [1,2,4] A compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof, selected from the group consisting of triazolo[1,5-a]pyridinyl, indazolyl, benzimidazolyl, indolyl and isoindolyl.
  3. 제1항에 있어서,According to claim 1,
    Figure PCTKR2022004084-appb-I000159
    는 하기 군으로부터 선택되는 것인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염:
    Figure PCTKR2022004084-appb-I000159
    is selected from the group consisting of: a compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof:
    Figure PCTKR2022004084-appb-I000160
    ,
    Figure PCTKR2022004084-appb-I000161
    ,
    Figure PCTKR2022004084-appb-I000162
    ,
    Figure PCTKR2022004084-appb-I000163
    및
    Figure PCTKR2022004084-appb-I000164
    .
    Figure PCTKR2022004084-appb-I000160
    ,
    Figure PCTKR2022004084-appb-I000161
    ,
    Figure PCTKR2022004084-appb-I000162
    ,
    Figure PCTKR2022004084-appb-I000163
    and
    Figure PCTKR2022004084-appb-I000164
    .
  4. 제1항에 있어서,According to claim 1,
    R은 X1 내지 X4를 포함하는 5원환에 인접하지 않은 탄소 원자에 결합하는, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.R is bonded to a carbon atom not adjacent to a 5-membered ring comprising X 1 to X 4 , a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  5. 제1항 내지 제4항 중 어느 한 항에 있어서,5. The method according to any one of claims 1 to 4,
    R은 -OH, -O-(CH2)o-R1, -(CH2)p-O-R2, -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5이고;R is -OH, -O-(CH 2 ) o -R 1 , -(CH 2 ) p -OR 2 , -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r -O- CO-R 4 or -CO-R 5 ;
    R1 및 R2는 각각 독립적으로 C4-6 사이클로알킬; 1~2개의 N 및 임의로 1개의 O를 함유하는 5-6원 헤테로아릴; 1개의 N을 포함하는 5-6원 헤테로사이클릴; 및 페닐로 이루어진 군으로부터 선택되고;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;
    상기 R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 임의로 1~2개의 O에 의해 중단된 C1-6 알킬; C1-6 알콕시; R''로 임의로 치환된 페닐; 및 R'''로 임의로 치환된 1-2개의 N을 함유하는 5-6원 헤테로사이클릴로 이루어진 군으로부터 선택되는 치환기에 의해 임의로 치환될 수 있고;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); 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 N optionally substituted with R''';
    R'' 및 R'''은 각각 독립적으로 할로겐, 시아노, OH, COOH, COO-(C1-6 알킬), C1-6 알킬 및 C1-6 알콕시로 이루어진 군으로부터 선택되고; R'' and R''' are each independently selected from the group consisting of halogen, cyano, OH, COOH, COO-(C 1-6 alkyl), C 1-6 alkyl and C 1-6 alkoxy;
    R3, R4 및 R5는 각각 독립적으로 -NH-페닐; -NH-(1개의 N, O 또는 S를 포함하는 5-6원 헤테로아릴); 및 NRaRb로 이루어진 군으로부터 선택되고, Ra 및 Rb는 이들이 결합한 N과 함께 피페라진일 또는 피페리딘일을 형성하되, 상기 피페라진일 또는 피페리딘일은 임의로 -(CH2)s-페닐로 치환되거나 페닐과 융합될 수 있고;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 - may be substituted with or fused with phenyl;
    o 및 p는 각각 0 내지 3의 정수이고, q, r 및 s는 각각 0 또는 1인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.o and p are each an integer from 0 to 3, and q, r and s are each 0 or 1. A compound, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof.
  6. 제5항에 있어서,6. The method of claim 5,
    R은 -OH, -O-(CH2)o-R1 또는 -(CH2)p-O-R2이고;R is —OH, —O—(CH 2 ) o —R 1 or —(CH 2 ) p —OR 2 ;
    R1 및 R2는 각각 독립적으로 사이클로펜틸, 피리딘일, 피라졸릴, 옥사디아졸릴, 이미다졸릴, 피페리딘일 및 페닐로 이루어진 군으로부터 선택되고; R 1 and R 2 are each independently selected from the group consisting of cyclopentyl, pyridinyl, pyrazolyl, oxadiazolyl, imidazolyl, piperidinyl and phenyl;
    R1 및 R2는 각각 독립적으로 할로겐; 시아노; OH; COOH; COO-(C1-6 알킬); 할로겐, 시아노, OH, COOH 또는 COO-(C1-6 알킬)로 임의로 치환된 C1-6 알킬; 임의로 1~2개의 O에 의해 중단된 C1-6 알킬; C1-6 알콕시; R''로 임의로 치환된 페닐; 및 R'''로 임의로 치환된 피롤리딘일로 이루어진 군으로부터 선택되는 치환기에 의해 임의로 치환될 수 있고;R 1 and R 2 are each independently halogen; cyano; OH; COOH; COO-(C 1-6 alkyl); C 1-6 alkyl optionally substituted with halogen, cyano, OH, COOH or COO—(C 1-6 alkyl); C 1-6 alkyl optionally interrupted by 1-2 O; C 1-6 alkoxy; phenyl optionally substituted with R''; and pyrrolidinyl optionally substituted with R''';
    R'' 및 R'''은 각각 독립적으로 할로겐, 시아노, OH, COOH, COO-(C1-6 알킬), C1-6 알킬 및 C1-6 알콕시로 이루어진 군으로부터 선택되고;R'' and R''' are each independently selected from the group consisting of halogen, cyano, OH, COOH, COO-(C 1-6 alkyl), C 1-6 alkyl and C 1-6 alkoxy;
    o 및 p는 각각 0 내지 3의 정수인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.o and p are each an integer from 0 to 3; a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  7. 제5항에 있어서,6. The method of claim 5,
    R은 -O-(CH2)q-CO-R3, -(CH2)r-O-CO-R4 또는 -CO-R5이고;R is -O-(CH 2 ) q -CO-R 3 , -(CH 2 ) r -O-CO-R 4 or -CO-R 5 ;
    R3은 -NH-페닐, 또는 페닐 또는 -(CH2)-페닐로 임의로 치환된 피페라진일이고;R 3 is —NH-phenyl, or piperazinyl optionally substituted with phenyl or —(CH 2 )-phenyl;
    R4는 -NH-티오페닐 또는 테트라히드로이소퀴놀리닐이고;R 4 is —NH-thiophenyl or tetrahydroisoquinolinyl;
    R5는 -(CH2)-페닐 또는 페닐로 임의로 치환된 피페라진일이고;R 5 is -(CH 2 )-phenyl or piperazinyl optionally substituted with phenyl;
    q 및 r은 0 또는 1인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.q and r are 0 or 1; a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  8. 제1항 내지 제7항 중 어느 한 항에 있어서, 8. The method according to any one of claims 1 to 7,
    G1은 -(CH2)l-고리 A이고, G2는 H 또는 -(CH2)m-피리딘일이고;G 1 is —(CH 2 ) 1 -ring A, G 2 is H or —(CH 2 ) m -pyridinyl;
    고리 A는 C6-10 아릴; N, O 및 S로부터 선택되는 1~2개의 헤테로원자를 포함하는 5원 또는 6원 헤테로아릴; 1개의 N을 포함하는 4원 내지 6원 헤테로사이클릴; 및 4원 내지 6원 사이클로알킬로 이루어진 군으로부터 선택되고,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,
    상기 고리 A는 할로겐, -CN, -OH, C1-4 알킬, 할로겐으로 치환된 C1-4 알킬, C1-4 알콕시, 할로겐으로 치환된 C1-4 알콕시 및 -NRARB로 이루어진 군에서 선택되는 1개 또는 2개의 치환기로 치환 또는 비치환되고, wherein 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 Unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of,
    RA 및 RB는 각각 독립적으로 H 또는 C1-4 알킬이고,R A and R B are each independently H or C 1-4 alkyl,
    l 및 m은 각각 0 또는 1의 정수인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용 가능한 염.l and m are each an integer of 0 or 1, a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  9. 제8항에 있어서,9. The method of claim 8,
    고리 A는 페닐, 퓨란일, 티아졸일, 피리미딘일, 아제티딘일 및 사이클로부틸 로 이루어진 군으로부터 선택되고, Ring A is selected from the group consisting of phenyl, furanyl, thiazolyl, pyrimidinyl, azetidinyl and cyclobutyl;
    상기 고리 A는 할로겐, -CN, -OH, -NH2 및 C1-4 알킬로 이루어진 군에서 선택되는 1개 또는 2개의 치환기로 치환 또는 비치환되는 것인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용 가능한 염.The ring A is halogen, -CN, -OH, -NH 2 and C 1-4 will be unsubstituted or substituted with one or two substituents selected from the group consisting of alkyl, a compound, a stereoisomer, a solvate thereof or a pharmaceutically acceptable salt.
  10. 제1항 내지 제8항 중 어느 한 항에 있어서,9. The method according to any one of claims 1 to 8,
    상기 G2는 피리미딘 고리의 5번 위치에 결합되고, 상기 G1은 피리미딘 고리의 나머지 치환 가능한 탄소 원자에 결합되는, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용 가능한 염.wherein G 2 is bonded to the 5th position of the pyrimidine ring, and G 1 is bonded to the remaining substitutable carbon atoms of the pyrimidine ring, a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  11. 제1항에 있어서,The method of claim 1,
    G1은 -(CH2)l-고리 A이고, G2는 H 또는 -(CH2)m-피리딘일이고,G 1 is -(CH 2 ) l -ring A, G 2 is H or -(CH 2 ) m -pyridinyl,
    Figure PCTKR2022004084-appb-I000165
    은
    Figure PCTKR2022004084-appb-I000166
    이고, l 및 m은 0 또는 1인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.
    Figure PCTKR2022004084-appb-I000165
    silver
    Figure PCTKR2022004084-appb-I000166
    and l and m are 0 or 1, a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  12. 제1항에 있어서,The method of claim 1,
    G1은 고리 A이고, G2는 H이고,G 1 is ring A, G 2 is H;
    Figure PCTKR2022004084-appb-I000167
    은
    Figure PCTKR2022004084-appb-I000168
    ,
    Figure PCTKR2022004084-appb-I000169
    ,
    Figure PCTKR2022004084-appb-I000170
    또는
    Figure PCTKR2022004084-appb-I000171
    이고, R'은 H, 피리딘일 또는 -(CH2)-피리딘일인, 화합물, 이의 입체이성질체, 용매화물 또는 이의 약학적으로 허용가능한 염.
    Figure PCTKR2022004084-appb-I000167
    silver
    Figure PCTKR2022004084-appb-I000168
    ,
    Figure PCTKR2022004084-appb-I000169
    ,
    Figure PCTKR2022004084-appb-I000170
    or
    Figure PCTKR2022004084-appb-I000171
    and R' is H, pyridinyl or -(CH 2 )-pyridinyl; a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  13. 제12항에 있어서,13. The method of claim 12,
    G1은 고리 A이고, G2는 H이고,G 1 is ring A, G 2 is H;
    Figure PCTKR2022004084-appb-I000172
    은
    Figure PCTKR2022004084-appb-I000173
    이고, R'은 피리딘일 또는 -(CH2)피리딘일인, 화합물, 이의 입체이성질체, 용매화물 또는 이의 약학적으로 허용가능한 염.
    Figure PCTKR2022004084-appb-I000172
    silver
    Figure PCTKR2022004084-appb-I000173
    and R' is pyridinyl or -(CH 2 )pyridinyl, a compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  14. 제1항에 있어서, The method of claim 1,
    하기 군으로부터 선택되는 것인 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염:A compound selected from the group consisting of: a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
    Figure PCTKR2022004084-appb-I000174
    ;
    Figure PCTKR2022004084-appb-I000175
    ;
    Figure PCTKR2022004084-appb-I000174
    ;
    Figure PCTKR2022004084-appb-I000175
    ;
    Figure PCTKR2022004084-appb-I000176
    ;
    Figure PCTKR2022004084-appb-I000177
    ;
    Figure PCTKR2022004084-appb-I000176
    ;
    Figure PCTKR2022004084-appb-I000177
    ;
    Figure PCTKR2022004084-appb-I000178
    ;
    Figure PCTKR2022004084-appb-I000179
    ;
    Figure PCTKR2022004084-appb-I000178
    ;
    Figure PCTKR2022004084-appb-I000179
    ;
    Figure PCTKR2022004084-appb-I000180
    ;
    Figure PCTKR2022004084-appb-I000181
    ;
    Figure PCTKR2022004084-appb-I000180
    ;
    Figure PCTKR2022004084-appb-I000181
    ;
    Figure PCTKR2022004084-appb-I000182
    ;
    Figure PCTKR2022004084-appb-I000183
    ;
    Figure PCTKR2022004084-appb-I000182
    ;
    Figure PCTKR2022004084-appb-I000183
    ;
    Figure PCTKR2022004084-appb-I000184
    ;
    Figure PCTKR2022004084-appb-I000185
    ;
    Figure PCTKR2022004084-appb-I000184
    ;
    Figure PCTKR2022004084-appb-I000185
    ;
    Figure PCTKR2022004084-appb-I000186
    ;
    Figure PCTKR2022004084-appb-I000187
    ;
    Figure PCTKR2022004084-appb-I000186
    ;
    Figure PCTKR2022004084-appb-I000187
    ;
    Figure PCTKR2022004084-appb-I000188
    ;
    Figure PCTKR2022004084-appb-I000189
    ;
    Figure PCTKR2022004084-appb-I000188
    ;
    Figure PCTKR2022004084-appb-I000189
    ;
    Figure PCTKR2022004084-appb-I000190
    ;
    Figure PCTKR2022004084-appb-I000191
    ;
    Figure PCTKR2022004084-appb-I000190
    ;
    Figure PCTKR2022004084-appb-I000191
    ;
    Figure PCTKR2022004084-appb-I000192
    ;
    Figure PCTKR2022004084-appb-I000193
    ;
    Figure PCTKR2022004084-appb-I000192
    ;
    Figure PCTKR2022004084-appb-I000193
    ;
    Figure PCTKR2022004084-appb-I000194
    ;
    Figure PCTKR2022004084-appb-I000195
    ;
    Figure PCTKR2022004084-appb-I000194
    ;
    Figure PCTKR2022004084-appb-I000195
    ;
    Figure PCTKR2022004084-appb-I000196
    ;
    Figure PCTKR2022004084-appb-I000197
    ;
    Figure PCTKR2022004084-appb-I000196
    ;
    Figure PCTKR2022004084-appb-I000197
    ;
    Figure PCTKR2022004084-appb-I000198
    ;
    Figure PCTKR2022004084-appb-I000199
    ;
    Figure PCTKR2022004084-appb-I000198
    ;
    Figure PCTKR2022004084-appb-I000199
    ;
    Figure PCTKR2022004084-appb-I000200
    ;
    Figure PCTKR2022004084-appb-I000201
    ;
    Figure PCTKR2022004084-appb-I000200
    ;
    Figure PCTKR2022004084-appb-I000201
    ;
    Figure PCTKR2022004084-appb-I000202
    ;
    Figure PCTKR2022004084-appb-I000203
    ;
    Figure PCTKR2022004084-appb-I000202
    ;
    Figure PCTKR2022004084-appb-I000203
    ;
    Figure PCTKR2022004084-appb-I000204
    ;
    Figure PCTKR2022004084-appb-I000205
    ;
    Figure PCTKR2022004084-appb-I000204
    ;
    Figure PCTKR2022004084-appb-I000205
    ;
    Figure PCTKR2022004084-appb-I000206
    ;
    Figure PCTKR2022004084-appb-I000207
    ;
    Figure PCTKR2022004084-appb-I000206
    ;
    Figure PCTKR2022004084-appb-I000207
    ;
    Figure PCTKR2022004084-appb-I000208
    ;
    Figure PCTKR2022004084-appb-I000209
    ;
    Figure PCTKR2022004084-appb-I000208
    ;
    Figure PCTKR2022004084-appb-I000209
    ;
    Figure PCTKR2022004084-appb-I000210
    ;
    Figure PCTKR2022004084-appb-I000211
    ;
    Figure PCTKR2022004084-appb-I000210
    ;
    Figure PCTKR2022004084-appb-I000211
    ;
    Figure PCTKR2022004084-appb-I000212
    ;
    Figure PCTKR2022004084-appb-I000213
    ;
    Figure PCTKR2022004084-appb-I000212
    ;
    Figure PCTKR2022004084-appb-I000213
    ;
    Figure PCTKR2022004084-appb-I000214
    ;
    Figure PCTKR2022004084-appb-I000215
    ;
    Figure PCTKR2022004084-appb-I000214
    ;
    Figure PCTKR2022004084-appb-I000215
    ;
    Figure PCTKR2022004084-appb-I000216
    ; 및
    Figure PCTKR2022004084-appb-I000217
    .
    Figure PCTKR2022004084-appb-I000216
    ; and
    Figure PCTKR2022004084-appb-I000217
    .
  15. 제1항 내지 제14항 중 어느 한 항의 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 포함하는, 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하기 위한 약학적 조성물.A pharmaceutical composition for preventing or treating a disease associated with adenosine A2A receptors, comprising the compound of any one of claims 1 to 14, a stereoisomer, a solvate or a pharmaceutically acceptable salt thereof.
  16. 제15항에 있어서, 상기 아데노신 A2A 수용체와 관련된 질병은 암인 것인 약학적 조성물.The pharmaceutical composition according to claim 15, wherein the disease associated with the adenosine A2A receptor is cancer.
  17. 제16항에 있어서, 상기 약학적 조성물은 항암제를 더 포함하는 것인 약학적 조성물.The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition further comprises an anticancer agent.
  18. 제17항에 있어서, 상기 항암제는 면역항암제인 것인 약학적 조성물.The pharmaceutical composition according to claim 17, wherein the anti-cancer agent is an immuno-cancer agent.
  19. 제1항 내지 제14항 중 어느 한 항의 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염을 개체에게 투여하는 단계를 포함하는 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하는 방법.15. A method for preventing or treating a disease associated with an adenosine A2A receptor comprising administering to a subject a compound of any one of claims 1 to 14, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.
  20. 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료에 사용하기 위한 제1항 내지 제14항 중 어느 한 항에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도.15. Use of a compound according to any one of claims 1 to 14, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of a disease associated with adenosine A2A receptors.
  21. 아데노신 A2A 수용체와 관련된 질병을 예방 또는 치료하기 위한 의약을 제조하기 위한 제1항 내지 제14항 중 어느 한 항에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도.15. Use of a compound according to any one of claims 1 to 14, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating a disease associated with adenosine A2A receptors.
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Citations (4)

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US20130231519A1 (en) * 2010-11-05 2013-09-05 Merck Patent Gmbh 1H-Pyrrolo[2,3 b]pyridine derivatives
KR20150138383A (en) * 2013-04-04 2015-12-09 오리온 코포레이션 Protein kinase inhibitors
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