CN117222640A - Heterocyclic compounds as FGFR inhibitors and uses thereof - Google Patents

Heterocyclic compounds as FGFR inhibitors and uses thereof Download PDF

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CN117222640A
CN117222640A CN202280024337.9A CN202280024337A CN117222640A CN 117222640 A CN117222640 A CN 117222640A CN 202280024337 A CN202280024337 A CN 202280024337A CN 117222640 A CN117222640 A CN 117222640A
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compound
alkyl
pharmaceutically acceptable
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stereoisomer
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祝伟
邹昊
麦万笋
汪涛
陈祥
李正涛
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Xiansheng Zaiming Pharmaceutical Co ltd
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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

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Abstract

Provides a heterocyclic compound serving as an FGFR inhibitor, in particular discloses a compound shown in a formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

Description

Heterocyclic compounds as FGFR inhibitors and uses thereof
cross Reference to Related Applications
The present application claims the benefit and priority of the following 2 chinese patent applications of application, the entire contents of which are hereby incorporated by reference in their entirety:
patent application No. 202110380922.X filed by the intellectual property office of China on day 03 of year 04 of 2021; and
patent application 202210224490.8 submitted to the China national intellectual property agency on the 2022, 03 and 07.
Technical Field
The application belongs to the technical field of medicines, and relates to a heterocyclic compound of an FGFR inhibitor, and a preparation method and application thereof.
Background
FGFR (Fibroblast Growth Factor Receptor ) is a transmembrane receptor type tyrosine kinase, and the family mainly comprises four members FGFR1, 2, 3 and 4. After FGFR binds to its ligand FGF (fibroblast growth factor ), receptor dimerization is caused to phosphorylate tyrosine residues in the kinase domain, so as to activate the receptor, and then the activated FGFR further activates downstream RAS/RAF, PI3K/AKT, JAK/STAT, plcγ and other signaling pathways, which participate in a plurality of processes of regulating cell proliferation, apoptosis, migration, repair of damaged tissues, neovascularization and the like. FGFR signaling pathways are tightly regulated under normal physiological conditions at weak activation levels. And after excessive activation, it often leads to the occurrence and development of tumors. The molecular mechanisms of abnormal activation of FGFR mainly include 1) gene amplification; 2) A gene mutation; 3) Gene fusion due to gene translocation, and the like. For example: FGFR2 gene amplification occurs in gastric cancer (5-10%), FGFR2 gene translocation occurs in intrahepatic cholangiocarcinoma (14%), and FGFR2 gene mutation occurs in endometrial cancer (12-14%). But the genetic abnormalities of FGFR3 are most commonly found in bladder cancer, including gene mutations (60-80% of non-muscle invasive bladder cancer and 15-20% of muscle invasive bladder cancer), gene translocations (3-6%) and gene amplifications (incidence not reported); second, myeloma, 15-20% of myeloma patients have FGFR3 gene translocation. Among the above genetic abnormalities of FGFR, some have been shown to be associated with poor prognosis for patients.
Given the importance of FGFR signaling pathways in tumor therapy, targeted therapies directed against FGFR signaling pathways have become a research hotspot in the field of tumor therapy in recent years. The application finds a heterocyclic compound which can selectively inhibit FGFR proteins, such as FGFR2, and has killing effect on related tumor cells.
Disclosure of Invention
The invention provides heterocyclic compounds of the formula, stereoisomers and pharmaceutically acceptable salts thereof. These compounds can inhibit FGFR activity, thereby affecting biological function.
In particular, the invention provides a compound shown in a formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof,
x, Z are each independently selected from CR 9 Or N;
w is selected from O or C (=o);
y is selected from C (=O), NHC (=O), C (=O) NH, N (CH) 3 ) Or a bond;
ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl;
ring B is selected from C 6 -C 10 Aryl, 5-to 10-membered heteroaryl or C 3 -C 10 Cyclic hydrocarbon groups;
e is selected from C 3 -C 10 Cyclic hydrocarbon radicals, C 6 -C 10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, said C 3 -C 10 Cyclic hydrocarbon radicals C 6 -C 10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R 1a Substitution;
R 1a independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, -S (=o) -C 1 -C 4 Alkyl, -S (=o) 2 -C 1 -C 4 Alkyl group,-S(＝O)(＝NR 8a )R 8b 、-N＝S(＝O)R 8a R 8b 、-NR 8a R 8b 、-C(＝O)NR 8a R 8b or-NR 7 C(＝O)R 8b The C is 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, -S (=o) -C 1 -C 4 Alkyl or-S (=o) 2 -C 1 -C 4 Alkyl groups optionally being independently selected from one or more of halogen, OH, C 1 -C 3 Substitution of an alkoxy group or a group of CN;
R 1 selected from-CN, - (CH) 2 ) q CN、-C≡CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-S(＝O)CR 6 ＝C(R 5 ) 2 、-S(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NHS(＝O)CR 6 ＝C(R 5 ) 2 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 ；
R 5 Independently selected from H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-12 membered heterocyclyl or C 6 -C 10 Aryl, said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-12 membered heterocyclyl or C 6 -C 10 Aryl is optionally substituted with one or more R 5a Substitution;
R 5a independently selected from halogen, CN, N (R) 5b ) 2 、OH、NO 2 、C 3 -C 8 Cycloalkyl or 3-12 membered heterocyclyl;
R 5b independently selected from H or C 1 -C 6 An alkyl group;
R 6 selected from H, CN, halogen or C 1 -C 6 An alkyl group;
R 7 selected from C 1 -C 6 Alkylene, C 3 -C 8 Cycloalkylene or 3-12 membered heterocyclylene;
R 2 selected from H, NH 2 、C 1 -C 6 Alkyl, OH or halogen;
R 3 independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 3 - 8 Cycloalkyl;
R 4 independently selected from halogen, CN, NH 2 、OH、NO 2 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, -C (=o) R 8a 、-C(＝O)OR 8a 、-NR 8a R 8b 、-C(＝O)NR 8a R 8b or-NR 7 C(＝O)R 8b The C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with one or more R 4a Substitution;
R 4a independently selected from halogen, CN, NH 2 OH or C 1 -C 6 An alkyl group;
R 8a 、R 8b each independently selected from H, halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkyl group;
R 9 selected from H, CN, OH, NH 2 、-NHR 10 、-NH-C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl, -NH-C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl optionally substituted with one or more R 10 Substitution;
R 10 independently selected from halogen, NH 2 、C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl, said NH 2 、C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 11 Substitution;
R 11 independently selected from C 1 -C 6 Alkyl, halogen, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl, said C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl optionally being C 1 -C 6 Alkyl, halogen, OH, -NH-C 1 -C 6 Alkyl, -N (C) 1 -C 6 Alkyl group 2 Substitution;
n, m are each independently selected from 0, 1, 2 or 3;
q is selected from 1, 2 or 3.
In some embodiments, ring a is selected from 5-10 membered heteroaryl.
In some embodiments, ring a is selected from 5-6 membered heteroaryl.
In some embodiments, ring A is selected from a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl.
In some embodiments, ring a is selected from pyrimidinyl, pyridinyl, or tetrahydropyrrolyl.
In some embodiments, ring a is selected from pyrimidinyl or tetrahydropyrrolyl.
In some embodiments, ring a is selected from pyridinyl or pyrimidinyl.
In some embodiments, ring a is selected from pyrimidinyl.
In some embodiments, ring B is selected from C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In some embodiments, ring B is selected from C 6 -C 10 Aryl or C 3 -C 10 Cyclic hydrocarbonsA base.
In some embodiments, ring B is selected from phenyl or cyclohexenyl.
In some embodiments, ring B is selected from phenyl.
In some embodiments, W is selected from O.
In some embodiments, Y is selected from C (=o), NHC (=o), C (=o) NH, or a bond.
In some embodiments, Y is selected from N (CH 3 ) Or a key.
In some embodiments, Z is selected from CR 9 。
In some embodiments, E is selected from C 3 -C 6 Cyclic hydrocarbon radicals, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3 -C 6 Cyclic hydrocarbon radicals, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 1a And (3) substitution.
In some embodiments, E is selected from C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 1a And (3) substitution.
In some embodiments, E is selected from C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-6 membered heteroaryl, said C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 1a And (3) substitution.
In some embodiments, E is selected from the group consisting of optionally R 1a The substituted following groups: phenyl, pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranylRadicals, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridonyl, 2-piperazinonyl, azetidinyl, 1, 4-diazacycloheptyl, bicyclo [ 1.1.1.1]Pentanyl, 2, 7-diazaspiro [4.4 ]]Nonylalkyl, 2, 8-diazaspiro [4.5 ]]Decyl, 2, 7-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.3 ]]Heptyl, 2, 6-diazaspiro [3.4 ]]Octyl, 2, 5-diazaspiro [3.4 ]]Octyl, 4, 7-diazaspiro [2.5 ]]Octyl, 2, 5-diazabicyclo [2.2.1]Heptyl, 5, 8-diazaspiro [3.5 ]]Nonylalkyl 3,8 diazabicyclo [3.2.1 ]Octyl or dihydropyrrole.
In some embodiments, E is selected from the group consisting of optionally R 1a The substituted following groups: phenyl, pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridonyl, 2-piperazinonyl, azetidinyl, 1, 4-diazacycloheptyl, bicyclo [1, 1)]Pentanyl, 2, 7-diazaspiro [4.4 ]]Nonylalkyl, 2, 8-diazaspiro [4.5 ]]Decyl, 2, 7-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.3 ]]Heptyl, 2, 6-diazaspiro [3.4 ]]Octyl or 2, 5-diazaspiro [3.4 ]]Octyl.
In some embodiments, E is selected from the group consisting of optionally R 1a The substituted following groups: phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piperazinonyl, 2-pyridonyl, 1, 4-diazepinyl, bicyclo [1,1 ]Pentanyl, 2, 7-diazaspiro [4.4 ]]Nonylalkyl, 2, 8-diazaspiro [4.5 ]]Decyl, 2, 7-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro-rings[3.3]Heptyl, 2, 6-diazaspiro [3.4 ]]Octyl, 2, 5-diazaspiro [3.4 ]]Octyl, 4, 7-diazaspiro [2.5 ]]Octyl, 2,5 diazabicyclo [ 2.2.1]Heptyl, 5, 8-diazaspiro [3.5 ]]Nonylalkyl 3,8 diazabicyclo [3,2,1]Octyl or dihydropyrrole.
In some embodiments, E is selected from the group consisting of optionally R 1a The substituted following groups: phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piperazinonyl, 2-pyridonyl, 1, 4-diazepinyl, bicyclo [1,1]Pentanyl, 2, 7-diazaspiro [4.4 ]]Nonylalkyl, 2, 8-diazaspiro [4.5 ]]Decyl, 2, 7-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.5 ]]Nonylalkyl, 2, 6-diazaspiro [3.3 ]]Heptyl, 2, 6-diazaspiro [3.4 ]]Octyl or 2, 5-diazaspiro [3.4 ]]Octyl.
In some embodiments, R 1a Independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, -S (=o) -C 1 -C 4 Alkyl, -S (=o) 2 -C 1 -C 4 Alkyl group,-S(＝O)(＝NR 8a )R 8b 、-N＝S(＝O)R 8a R 8b 、-NR 8a R 8b 、-C(＝O)NR 8a R 8b or-NR 7 C(＝O)R 8b The C is 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, -S (=o) -C 1 -C 4 Alkyl or-S (=o) 2 -C 1 -C 4 Alkyl groups optionally being independently selected from halogen, OH or C by one or more 1 -C 3 The groups of the alkoxy groups are substituted.
In some embodiments, R 1a Independently selected from halogen, CN, NH 2 、OH、-NR 8a R 8b 、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy group, the C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy groups optionally being independently selected from one or more of halogen, OH or C 1 -C 3 The groups of the alkoxy groups are substituted.
In some embodiments, R 1a Independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy group, the C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy groups optionally being independently selected from one or more of halogen, OH or C 1 -C 3 The groups of the alkoxy groups are substituted.
In some embodiments, R 1a Independently selected from halogen, -NR 8a R 8b 、C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy group, the C 1 -C 6 Alkyl groups optionally being independently selected from one or more of halogen, OH, CN or C 1 -C 3 The groups of the alkoxy groups are substituted.
In some embodiments, R 1a Independently selected from C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
In some embodiments, R 1a Independently selected from Cl, F, CH 3 、-OCH 3 、CF 3 、-N(CH 3 ) 2 Or CH (CH) 2 CN。
In some embodiments, R 1a Independently selected from CH 3 or-OCH 3 。
In some embodiments, R 1 Selected from-CN, - (CH) 2 ) q CN、-C≡CH、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-S(＝O)CR 6 ＝C(R 5 ) 2 、-S(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NHS(＝O)CR 6 ＝C(R 5 ) 2 or-NHS (=o) 2 CR 6 ＝C(R 5 ) 2 。
In some embodiments, R 1 Selected from-C.ident.CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、- S(＝O)CR 6 ＝C(R 5 ) 2 、-S(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NHS(＝O)CR 6 ＝C(R 5 ) 2 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 。
In some embodiments, R 1 Selected from-CN, - (CH) 2 ) q CN、-C≡CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 。
In some embodiments, R 1 Selected from- (CH) 2 ) q CN、-C≡CH、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 or-NHS (=o) 2 CR 6 ＝C(R 5 ) 2 。
In some embodiments, R 1 Selected from-C.ident.CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 。
In some embodiments, R 6 Selected from H, F, cl, CN or CH 3 。
In some embodiments, R 6 Selected from H, F, CN or CH 3 。
In some embodiments, R 5 Independently selected from H, C 1 -C 3 Alkyl or C 3 -C 6 Cycloalkyl group, the C 1 -C 3 Alkyl or C 3 -C 6 Cycloalkyl optionally substituted with one or more R 5a And (3) substitution.
In some embodiments, R 5 Independently selected from H or C 1 -C 3 Alkyl, said C 1 -C 3 Alkyl is optionally substituted with one or more R 5a And (3) substitution.
In some embodiments, R 5a Independently selected from halogen, CN, N (R) 5b ) 2 Or a 3-12 membered heterocyclic group.
In some embodiments, R 5a Independently selected from halogen, CN, N (R) 5b ) 2 Or a 3-6 membered heterocyclic group.
In some embodiments, R 5a Independently selected from N (R) 5b ) 2 Or a 3-6 membered heterocyclic group.
In some embodiments, R 5a Independently selected from halogen, CN, N (CH) 3 ) 2 Piperidinyl or morpholinyl.
In some embodiments, R 5a Independently selected from N (R) 5b ) 2 Piperidinyl or morpholinyl.
In some embodiments，R 5b Independently selected from C 1 -C 6 An alkyl group.
In some embodiments, R 5b Independently selected from CH 3 。
In some embodiments, R 7 Selected from C 1 -C 6 Alkylene, C 3 -C 6 Cycloalkylene or 3-6 membered heterocyclylene.
In some embodiments, R 7 Selected from the following groups: -CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -、
In some embodiments, R 7 Selected from the following groups: -CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -、
In some embodiments, R 1 Selected from the following groups:
in some embodiments, R 1 Selected from the following groups:
in some embodiments, R 2 Selected from H, NH 2 、CH 3 OH or halogen.
In some embodiments, R 2 Selected from H, NH 2 、CH 3 Or halogen.
In some embodiments, R 2 Selected from H, NH 2 Or halogen.
In some embodiments, R 2 Selected from H or NH 2 。
In some embodiments, R 3 Independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkyl group.
In some embodiments, R 3 Independently selected from halogen or C 1 -C 6 An alkoxy group.
In some embodiments, R 3 Selected from F and-OCH 3 。
In some embodiments, R 3 Selected from halogen.
In some embodiments, R 3 Selected from F.
In some embodiments, m is selected from 0 or 1.
In some embodiments, R 4 Independently selected from halogen, CN, NH 2 、OH、NO 2 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl optionally substituted with one or more R 4a And (3) substitution.
In some embodiments, R 4 Independently selected from CN, halogen、C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
In some embodiments, R 4 Independently selected from halogen, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
In some embodiments, R 4 Independently selected from CN or C 1 -C 6 An alkyl group.
In some embodiments, R 4 Independently selected from CN or CH 3 。
In some embodiments, R 4 Independently selected from C 1 -C 6 An alkyl group.
In some embodiments, R 4 Independently selected from CH 3 。
In some embodiments, n is selected from 0 or 1.
In some embodiments, R 9 Selected from H, NH 2 、-NHR 10 、-NH-C 1 -C 6 Alkyl or C 1 -C 6 Alkyl, said C 1 -C 6 Alkyl or-NH-C 1 -C 6 Alkyl is optionally substituted with one or more R 10 And (3) substitution.
In some embodiments, R 9 Selected from H, CN, OH, NH 2 、-NHR 10 or-NH-C 1 -C 6 Alkyl, said-NH-C 1 -C 6 Alkyl is optionally substituted with one or more R 10 And (3) substitution.
In some embodiments, R 10 Independently selected from halogen, NH 2 、C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl, said NH 2 、C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with one or more R 11 And (3) substitution.
In some embodiments, R 10 Independently selected from halogen, NH 2 、C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-6 membered heteroaryl, said NH 2 、C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-6 membered heteroaryl optionally substituted with one or more R 11 And (3) substitution.
In some embodiments, R 10 Independently selected from NH 2 、C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-6 membered heteroaryl, said NH 2 、C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 Aryl or 5-6 membered heteroaryl optionally substituted with one or more R 11 And (3) substitution.
In some embodiments, R 10 Independently selected from NH 2 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl, said NH 2 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 11 And (3) substitution.
In some embodiments, R 10 Independently selected from optionally one or more R 11 The substituted following groups: pyrazolyl, NH 2 Phenyl, pyridyl, pyrrolyl, tetrahydropyrrolyl or morpholinyl.
In some embodiments, R 11 Independently selected from C 1 -C 6 Alkyl, halogen, C 1 -C 3 Alkoxy, C 3 -C 6 Cycloalkyl or 5-6 membered heterocyclyl, said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 5-6 membered heterocyclyl optionally being C 1 -C 6 Alkyl groupHalogen, OH, -NH-C 1 -C 6 Alkyl or-N (C) 1 -C 6 Alkyl group 2 And (3) substitution.
In some embodiments, R 11 Independently selected from optionally covered by C 1 -C 6 Alkyl, halogen, OH, -NH-C 1 -C 6 Alkyl, or-N (C) 1 -C 6 Alkyl group 2 The substituted following groups: methyl, ethyl, tetrahydropyrrolyl, piperidinyl, -OCH 3 F, piperazinyl, cyclopropyl or isopropyl.
In some embodiments, R 11 Independently selected from optionally methyl, ethyl, OH, -N (CH) 3 ) 2 Or F-substituted: methyl, ethyl, tetrahydropyrrolyl, piperidinyl, -OCH 3 F, piperazinyl, cyclopropyl or isopropyl.
In some embodiments, R 11 Independently selected from C 1 -C 6 An alkyl group.
In some embodiments, R 9 Selected from the following groups: H. CN, OH, NH 2 、
In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein ring A,X、Y、Z、E、R 1 、R 2 、R 3 、R 4 N, m are as defined above. It will be appreciated that in claim 14 relating to formula (II), when claim 14 refers to the preceding claim x, the ring A, X, Y, Z, E, R in formula (II) 1 、R 2 、R 3 、R 4 N, m are as defined in claim x. For example, when claim 14 is appended to claim 1, the ring A, X, Y, Z, E, R in formula (II) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 1; when claim 14 is dependent on claim 2, the ring A, X, Y, Z, E, R in formula (II) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 2, and so on.
In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the ring B, X, Y, Z, E, R 1 、R 2 、R 3 、R 4 N, m are as defined above. It will be appreciated that in claim 15 relating to formula (III), when claim 15 refers to the preceding claim x, the ring B, X, Y, Z, E, R in formula (III) 1 、R 2 、R 3 、R 4 N, m are as defined in claim x. For example, when claim 15 is appended to claim 1, the ring B, X, Y, Z, E, R in formula (III) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 1; when claim 15 is dependent on claim 2, the ring B, X, Y, Z, E, R in formula (III) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 2, and so on.
In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (IV), or a stereoisomer or pharmaceutically acceptable salt thereof,
Therein, X, Y, Z, E, R 1 、R 2 、R 3 、R 4 N, m are as defined above.
It will be appreciated that in claim 16 relating to formula (IV), X, Y, Z, E, R in formula (IV) when claim 16 refers to the preceding claim x 1 、R 2 、R 3 、R 4 N, m are as defined in claim x. For example, when claim 16 is appended to claim 1, X, Y, Z, E, R in the formula (IV) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 1; when claim 16 is dependent on claim 2, X, Y, Z, E, R in said formula (IV) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 2, and so on.
In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (V), or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein, ring A, ring B, Y, W, E, R 1 、R 2 、R 3 、R 4 N, m are as defined above.
It will be appreciated that in claim 17 referring to formula (V), when claim 17 refers to the preceding claim x, the rings a, B, Y, W, E, R in formula (V) 1 、R 2 、R 3 、R 4 N, m are as defined in claim x. For example, when claim 17 is dependent on claim 1, ring A, ring B, Y, W, E, R in formula (V) 1 、R 2 、R 3 、R 4 N, m are as defined in claim 1; ring a, ring B, Y, W, E, R in the formula (V) when claim 17 is dependent on the preceding claim 2 1 、R 2 、R 3 、R 4 N, m are as defined in claim 2, and so on.
In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
further, the invention also provides a pharmaceutical composition, which comprises a compound shown in the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
Further, the present invention relates to the use of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with FGFR.
Further, the present invention relates to the use of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a disease associated with FGFR.
Further, the present invention relates to a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease associated with FGFR.
The invention also relates to a method of preventing or treating a disease associated with FGFR comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to the invention, or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a pharmaceutical formulation comprising a compound of formula (I) according to the invention, or a stereoisomer or a pharmaceutically acceptable salt thereof.
Further, the FGFR-associated disease is selected from cancer.
In some embodiments of the application, the cancer is, for example, a solid tumor, such as gastric cancer.
In another aspect, the present application provides the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a cancer disease.
In another aspect, the present application provides the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a cancer disease.
In another aspect, the present application provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a cancer disease.
In another aspect, the application provides a method of treating cancer disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description.
Herein, a method of manufacturing a semiconductor deviceRepresenting the ligation site.
Herein, double arrow in synthetic routeOr multiple arrowsRepresenting a multi-step reaction.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
The compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur,the description includes both the occurrence of the event or condition and the absence of the occurrence of the event or condition. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (e.g. CH 2 CH 2 F) Polysubstituted (e.g. CHFCH 2 F、CH 2 CHF 2 Etc.) or fully substituted (CF) 2 CF 3 ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, etc. The term "C 1 -C 3 Alkyl "is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3 carbon atoms.
The term "alkoxy" refers to a group generated by the loss of a hydrogen atom on a hydroxyl group of a straight or branched chain alcohol, and is understood to be "alkyloxy" or "alkyl-O-", where alkyl is as defined above. The term "C 1 -C 6 Alkoxy "is understood to mean" C 1 -C 6 Alkyloxy "or" C 1 -C 6 alkyl-O- ". The "C 1 -C 6 Alkoxy "may contain" C 1 -C 3 Alkoxy ", and the like.
The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1 -C 6 Haloalkyl "means C as defined above substituted with one or more halo groups 1 -C 6 Alkyl groups including, but not limited to, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.
The term "haloalkoxy" is intended to include monohaloalkoxy and polyhaloalkoxy groups in which the halogen is substituted on the alkyl portion of the alkoxy group. For example, the term "C 1 -C 6 Haloalkoxy "means C as defined above substituted by one or more halogens 1 -C 6 An alkoxy group.
The term "C 3 -C 10 Cycloalkyl "is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. It comprises C 3 -C 10 Cycloalkyl and C 3 -C 10 Partially saturated cyclic hydrocarbon groups (e.g., cycloalkenyl, cycloalkynyl, etc.), the term "C 3 -C 10 Cycloalkyl "means a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring. C (C) 3 -C 10 Partially saturated cyclic hydrocarbon means a partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl. According to the invention, the bicyclic hydrocarbon ring includes a bridged, spiro or fused ring structure. The term "C 3 -C 8 Cycloalkyl "is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms, which includes C 3 -C 8 Cycloalkyl and C 3 -C 8 Partially saturated cyclic hydrocarbon radicals, processThe word "C 3 -C 8 Cycloalkyl "means a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms. The term "C 3 -C 6 Cycloalkyl "is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms, which includes C 3 -C 6 Cycloalkyl and C 3 -C 6 Partially saturated cyclic hydrocarbon radicals, the term "C 3 -C 6 Cycloalkyl "means a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.
The term "C 6- C 10 Aryl "is understood to mean a monovalent aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular a ring having 6 carbon atoms (" C 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C " 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
The term "3-12 membered heterocyclyl" is understood to mean a saturated or partially unsaturated monovalent mono-or bicyclic ring having 3 to 12 ring atoms. The bicyclic ring includes bridged, spiro, fused rings. The "hetero" in the heterocyclic group includes, but is not limited to, those independently selected from N, O, S, C (=o), C (=s), S (=o), S (O) 2 The number of heteroatoms may be, for example, 1-6 (e.g., 1, 2, 3, 4, 5, or 6) atoms and/or groups of atoms. In particular, the heterocyclyl may be monocyclic, including but not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, 1-dioxothiomorpholinyl, piperazinyl, 2-piperazinonyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta [ c ] ]Pyrrole-2 (1H) -yl ring, or 56-membered bicyclic rings, e.g. hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl ring. The ring may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4]Thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4]Thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. The term "3-8 membered heterocyclyl" is understood to mean a saturated or partially unsaturated monovalent mono-or bicyclic ring having 3 to 8 ring atoms. The term "3-6 membered heterocyclyl" is understood to mean a saturated or partially unsaturated monovalent mono-or bicyclic ring having 3 to 6 ring atoms.
The term "5-to 12-membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, in particular 5 or 6 or 9 or 10 ring atoms, which in addition may be benzo-fused in each case. The "hetero" in the heteroaryl group means that the aromatic ring is selected from N, O, S, C (=o), C (=s), S (=o), S (O) independently, but not limited thereto 2 The number of heteroatoms may be, for example, 1-6 (e.g., 1,2, 3,4, 5, or 6) atoms and/or groups of atoms. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or phenoxazinyl Etc.
The term "treatment" means administration of a compound or formulation of the application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(ii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "therapeutically effective amount" means an amount of a compound of the application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.
The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal may be a human.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for use in the above formulations are: saccharides, starches, cellulose and derivatives thereof, and the like.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The words "comprise", "comprising" or "includes" and variations thereof such as include or comprise are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to".
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
Detailed Description
The following examples illustrate the technical aspects of the invention in detail, but the scope of the invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).
Abbreviations:
DMAP 4-dimethylaminopyridine; et3N or TEA: triethylamine; THF: tetrahydrofuran; meCN or ACN: cyanohydrin; 18-crown-6 or 18-crown-6:1,4,7,10,13, 16-hexaoxa Cyclooctadecane; pd (dppf) Cl 2 : [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride; dioxane: a dioxane; pd (PPh) 4 ) 3 Tetra (triphenylphosphine) palladium; DIEA or DIPEA: n, N-diisopropylethylamine; DMF: n, N-dimethylformamide; HATU:2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate; NMP: n-methylpyrrolidone; BOP-Cl: bis (2-oxo-3-oxazolidinyl) phosphinic chloride; pyridine: pyridine; pd (OAc) 2 : palladium acetate; s-phos: 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl; DCM: dichloromethane; BINAP:1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; TCHP: tricyclohexylphosphorus; TFA: trifluoroacetic acid; liHMDS, lithium hexamethyldisilazide; tsCl: p-toluenesulfonyl; meAC: acetic acid; TBAF, tetrabutylammonium fluoride; tsOH: p-toluene sulfonic acid; LAH: lithium aluminum hydride.
Example 1
N- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) acryloylamide (1)
First step N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acryloylamide (1B)
4, 5-tetramethyl-2- (4-aminophenyl) -1,3, 2-dioxaborolan (5.0 g,23mmol,1 eq), 4-dimethylaminopyridine (0.70 g,5.7mmol,0.25 eq) and triethylamine (4.6 g,46mmol,6.3mL,2 eq) were dissolved in tetrahydrofuran (50 mL) and a solution of acryloyl chloride (2.5 g,27mmol,2.2mL,1.2 eq) in tetrahydrofuran (5 mL) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 20 degrees celsius for 5 hours. The solvent was distilled off under reduced pressure, and water (100 mL) was added to the obtained residue. The resulting mixture was extracted with ethyl acetate (100 mL. Times.3). The organic phase was mixed, washed with saturated brine (100 ml×3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column (eluting phase was a petroleum ether mixed solvent containing 16 to 18% ethyl acetate) to give the title compound 1B (2.3 g,8.3mmol, yield: 36%) as a white solid.
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.24(s,1H),7.73-7.66(m,2H),7.65-7.59(m,2H),6.50-6.39(m,1H),6.31-6.22(m,1H),5.77(d,J＝10.8Hz,1H),1.28(s,12H).
Second step 2- (4-bromo-2-fluorophenoxy) -4-methylpyrimidine (1E)
4-bromo-2-fluorophenol (5.0 g,26mmol,1.0 eq) and 2-chloro-4-methylpyrimidine (3.7 g,29mmol,1.1 eq) were dissolved in acetonitrile (30 mL), and potassium carbonate (7.2 g,52mmol,2.0 eq) and 18-crown-6 (0.69 g,2.6mmol,0.10 eq) were added. The resulting mixture was stirred at 85 degrees celsius for 12 hours, cooled, added water (100 mL) and extracted with ethyl acetate (100 mL x 3 times). The organic phase was mixed, washed with saturated brine (100 mL. Times.3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by a silica gel column (eluted with 0-15% ethyl acetate in petroleum ether) to give the title compound 1E (7.2 g, yield: 97%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ＝8.35(d,J＝5.2Hz,1H),7.42-7.28(m,2H),7.22-7.10(m,1H),6.95(d,J＝5.2Hz,1H),2.50(s,3H).
Step three 2- (2-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) -4-methylpyrimidine (1G)
Compound 1E (4.7 g,17mmol,1.0 eq), 4', 5',5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (5.1 g,20mmol,1.2 eq), [1,1' -bis (diphenylphosphine) ferrocene ] Palladium dichloride (1.2 g,1.7mmol,0.1 eq) and potassium acetate (4.9 g,50mmol,3 eq) were mixed in dioxane (100 mL). The mixture was stirred under nitrogen at 80 degrees celsius for 3 hours. Acetonitrile (100 mL) was added to the mixture, stirred for 30 minutes, and then filtered. The filtrate was concentrated to give a black solid as the title compound 1G (10G, crude).
MS(ESI+)m/z＝331.0[M+H].
Fourth step 6-chloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-amine (1I)
6-chloro-5-iodo-4-aminopyrimidine (1.7G, 6.7mmol,1.0 eq), compound 1G (2.2G, 6.7mmol,1.0 eq), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (0.49G, 0.67mmol,0.10 eq) and potassium phosphate (2.8G, 13mmol,2.0 eq) were mixed in dioxane (40 mL) and water (4 mL). The resulting mixture was stirred under nitrogen at 85 degrees celsius for 2 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluting phase: petroleum ether mixed solvent containing 33 to 100% ethyl acetate) to give the title compound 1I (1.10 g, yield: 50%) as a pale yellow solid.
1H NMR(400MHz,DMSO-d 6 ):δ＝8.49(d,J＝5.2Hz,1H),8.23(s,1H),7.48(t,J＝8.4Hz,1H), 7.37(d,J＝11.2Hz,1H),7.21(d,J＝5.2Hz,1H),7.17(d,J＝8.0Hz,1H),2.45(s,3H).
Fifth step N- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) acryloylamide (1)
Compound 1I (0.24 g,0.72mmol,1.0 eq), compound 1B (0.19 g,0.72mmol,1.0 eq), tetrakis triphenylphosphine palladium (84 mg,0.073mmol,0.10 eq) and potassium carbonate (0.20 g,1.5mmol,2.0 eq) were mixed in dioxane (10 mL) and water (1 mL). The resulting mixture was stirred under nitrogen at 85 degrees celsius for 18 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction solution, and extracted with methylene chloride (30 mL. Times.3). The organic phase was mixed, washed with saturated brine (100 ml X3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative chromatography and lyophilized to give the title compound 1 (0.15 g, yield: 46%) as a white solid.
MS(ESI+)m/z＝443.1[M+H].
1 H NMR(400MHz,DMSO-d6):δ＝10.20(s,1H),8.50(d,J＝5.2Hz,1H),8.46(s,1H),7.55(d,J＝8.4Hz,2H),7.34(t,J＝8.4Hz,1H),7.29-7.14(m,4H),7.00(dd,J 1 ＝8.4Hz,J 2 ＝1.2Hz,1H),6.74-6.29(m,3H),6.29-6.19(m,1H),5.76(dd,J 1 ＝10.0Hz,J 2 ＝2.0Hz,1H),2.43(s,3H).
Example 2
N- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) methacryl amide (2)
First step N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methacryloylamide (2B)
4, 5-tetramethyl-2- (4-aminophenyl) -1,3, 2-dioxaborolane (0.20 g,0.91mmol,1 eq), methacrylic acid (0.16 g,1.8mmol,2.0 eq), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.69 g,1.8mmol,2 eq) and N, N-diisopropylethylamine (0.24 g,0.18mmol,2.0 eq) were dissolved in acetonitrile (50 mL) and the resulting mixture was stirred under nitrogen at 25℃for 2 hours. The solvent was distilled off under reduced pressure, and water (30 mL) was added to the obtained residue. The resulting mixture was extracted with ethyl acetate (30 mL. Times.3). The organic phase was mixed, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column (eluted with 0-50% ethyl acetate in petroleum ether) to give the title compound 2B (0.20 g, yield: 76%) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 ):δ＝7.79(d,J＝8.4Hz,2H),7.59(d,J＝8.4Hz,2H),5.80(s,1H),5.48(d,J＝1.2Hz,1H),2.07(s,3H),1.35(s,12H)
Second step N- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) methacryl amide (2)
Compound 1I (0.030 g,0.090mmol,1.0 eq), compound 2B (0.029 g,0.099mmol,1.0 eq), tetrakis triphenylphosphine palladium (0.010mg, 9.4. Mu. Mol,0.10 eq) and potassium carbonate (0.025 g,0.18mmol,2.0 eq) were mixed in dioxane (5 mL) and water (0.5 mL). The resulting mixture was stirred under nitrogen at 80 degrees celsius for 2 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction solution, and extracted with methylene chloride (30 mL. Times.3). The organic phase was mixed, washed with saturated brine (20 mL. Times.3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative chromatography and lyophilized to give the title compound 2 (3.9 mg, yield: 9.2%) as a white solid.
MS(ESI+)m/z＝457.2[M+1].
1 H NMR(400MHz,MeOD-d 4 ):δ＝9.50-9.40(m,2H),8.61-8.56(m,2H),8.37-8.30(m,3H),8.19-8.14(m,2H),8.12-8.08(m,1H),6.79(s,1H),6.52(s,1H),3.51(s,3H),3.02(s,3H)
Example 3
6- (6-ethynyl-4-methylpyridin-3-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-amine (3)
First step 5-bromo-4-methyl-2- ((triisopropylsilyl) ethynyl) pyridine (3C)
Compound 3A (10 g,40mmol,1.0 eq), compound 3B (7.3 g,40mmol,9.0mL,1.0 eq), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (2.9 g,4.0mmol,0.10 eq), cuprous iodide (0.76 g,4.0mmol,0.10 eq) and triethylamine (8.1 g,80mmol,11mL,2.0 eq) were mixed in N, N-dimethylformamide (50 mL). The resulting mixture was stirred under nitrogen at 85 degrees celsius for 2 hours. A saturated ammonium chloride solution (100 mL) was added to the reaction solution, and extracted with methylene chloride (100 mL. Times.3). The organic phase was mixed, washed with saturated brine (50 mL. Times.3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column (eluted with 5-12% ethyl acetate in petroleum ether) to give the title compound 3C (8.5 g, yield: 61%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ＝8.56-8.47(m,1H),7.26(s,1H),2.30(s,3H),1.08-1.06(m,21H)
Second step 4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- ((triisopropylsilyl) ethynyl) pyridine (3D)
Compound 3C (4.0 g,11mmol,1.0 eq), compound 1F (5.8 g,23mmol,2.0 eq), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.83 g,1.1mmol,0.10 eq), potassium acetate (2.2 g,23mmol,2.0 eq) were mixed in 1, 4-dioxane (40 mL). The resulting mixture was stirred under nitrogen at 80 degrees celsius for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by a C18 reverse phase silica gel column (eluent phase was an aqueous solution containing 20 to 100% of acetonitrile) and lyophilized to give the title compound 3D (0.80 g, yield: 16%) as a white solid
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.61(s,1H),7.38(s,1H),2.45(s,3H),1.31(s,12H),1.18-1.04(m,21H)
Third step 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6- (4-methyl-6- ((triisopropylsilyl) ethynyl) pyridin-3-yl) pyrimidin-4-amine (3E)
Compound 1I (0.060 g,0.18mmol,1.0 eq), compound 3D (0.073 g,0.18mmol,1.0 eq), tetrakis triphenylphosphine palladium (0.021 mg, 18. Mu. Mol,0.10 eq) and potassium carbonate (0.075 g,0.54mmol,3.0 eq) were mixed in dioxane (3 mL) and water (0.3 mL). The resulting mixture was stirred under nitrogen at 85 degrees celsius for 12 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by preparative chromatography and lyophilized to give the title compound 3E (75 mg, yield: 73%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ＝8.59(s,1H),8.26(d,J＝5.2Hz,1H),8.13(s,1H),7.19-7.14(m,2H),6.92-6.82(m,3H),5.29-5.07(m,2H),2.40(s,3H),2.13(s,3H),1.10-1.03(m,21H)
Fourth step 6- (6-ethynyl-4-methylpyridin-3-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-amine (3)
Compound 3E (70 mg,0.12mmol,1.0 eq) was dissolved in 2mL tetrahydrofuran, and triethylamine trihydrofluoride (0.20 g,1.2mmol,0.20mL,10 eq) was added. The resulting mixture was stirred under nitrogen at 40 degrees celsius for 3 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by preparative chromatography and lyophilized to give the title compound 3 (24 mg, yield: 47%) as a white solid.
MS(ESI+)m/z＝413.1[M+H].
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.45(d,J＝5.2Hz,1H),8.48(s,1H),8.16(s,1H),7.40(s,1H),7.28-7.21(m,2H),7.16(d,J＝5.2Hz,1H),7.04-6.45(m,3H),4.29(s,1H),2.38(s,3H),2.14(s,3H)
Example 4
N- (1- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) piperidin-4-yl) acryloylamide (4)
First step 1-tert-butyloxycarbonyl 4-acryloylaminopiperidine (4C)
1-tert-Butyloxycarbonyl 4-aminopiperidine (3.0 g,15mmol,1.0 eq) and N, N-diisopropylethylamine (3.9 g,30mmol,6.3mL,2.0 eq) were dissolved in dichloromethane (40 mL) and a solution of acryloyl chloride (2.0 g,22mmol,1.8mL,1.5 eq) in dichloromethane (5 mL) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 20 degrees celsius for 3 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluting phase was a petroleum ether mixed solvent containing 0 to 50% ethyl acetate) to give the title compound 4C (2.5 g, yield: 66%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ＝6.29(dd,J＝1.3,16.0Hz,1H),6.12-6.03(m,1H),5.65(dd,J＝1.3,10.4Hz,1H),5.57(br d,J＝8.0Hz,1H),4.15-3.91(m,3H),2.87(t,J＝12.0Hz,2H),2.00-1.87(m,2H),1.46(s,9H),1.39-1.30(m,2H).
Second step 4-Acylaminopiperidine hydrochloride (4D)
Compound 4C (2.0 g,7.9mmol,1.0 eq) was dissolved in dichloromethane (15 mL) and 4M dioxane hydrochloride solution (7.86 mL,4.0 eq) was slowly added dropwise at 0deg.C. The resulting mixture was stirred at 20 degrees celsius for 2 hours. The reaction solution was distilled off under reduced pressure to remove the solvent, whereby the title compound 4D (2.5 g, crude product) was obtained as a solid.
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.30(d,J＝7.2Hz,1H),6.28-6.19(m,1H),6.14-6.06(m,1H),5.60(dd,J＝2.3,10.0Hz,1H),3.30-3.19(m,2H),3.03-2.86(m,2H),1.92(dd,J＝3.0,
13.6Hz,2H),1.72-1.56(m,2H).
Third step N- (1- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) piperidin-4-yl) acryloylamide (4)
Compound 4D (0.50 g,3.2mmol,1 eq), compound 1I (0.11 mg,0.32mmol,0.1 eq) and N, N-diisopropylethylamine (0.84 g,6.5mmol,1.1mL,2.0 eq) were dissolved in N-methylpyrrolidone (3 mL). The resulting mixture was stirred under microwave heating at 120 degrees celsius for 1 hour in a nitrogen atmosphere. The resulting reaction solution was purified by preparative chromatography (Waters Xbridge C18,20-70% acetonitrile in water (0.01% aqueous ammonia)), and lyophilized to give the title compound 4 (1.6 mg, yield: 1.0%) as a white solid.
MS(ESI+)m/z＝450.1[M+H].
1 H NMR(400MHz,MEOD-d 4 ):δ＝8.43(d,J＝5.2Hz,1H),8.25(s,1H),7.53(t,J＝8.2Hz,1H),7.38(dd,J＝1.8,10.8Hz,1H),7.30(d,J＝7.6Hz,1H),7.18(d,J＝5.2Hz,1H),6.20(d,J＝6.4Hz,2H),5.64(t,J＝6.0Hz,1H),4.07(br d,J＝13.6Hz,2H),3.98-3.89(m,1H),3.31(s,10H),3.04(t,J＝11.6Hz,2H),2.48(s,3H),1.83(d,J＝10.8Hz,2H),1.46-1.36(m,2H)
Example 5
1- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-2-en-1-one (5)
First step 4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (5B)
Compound 1I (1.1 g,3.32mmol,1.0 eq), compound 5A (1.1 g,3.5mmol,1.1 eq), tetrakis triphenylphosphine palladium (0.24 g,0.33mmol,0.10 eq) and potassium carbonate (1.4 g,10mmol,3.0 eq) were mixed in dioxane (30 mL) and water (3 mL). The resulting mixture was stirred under nitrogen at 85 degrees celsius for 12 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting phase was a methylene chloride mixed solvent containing 0-10% methanol) to give the title compound 5B (0.70 g, yield: 44%) as a brown solid.
1 H NMR(400MHz,CDCl 3 ):δ＝8.56(s,1H),8.38(d,J＝5.2Hz,1H),7.37(t,J＝8.0Hz,1H),7.17-7.06(m,2H),6.96(d,J＝5.2Hz,1H),5.84(s,1H),5.31(s,1H),5.00(s,2H),3.90(s,2H),3.49-3.33(m,2H),2.51(s,3H),1.45(s,9H)
Second step 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-4-amine hydrochloride (5C)
Compound 5B (0.20 g,0.42mmol,1.0 eq) was dissolved in dichloromethane (5 mL) and 4M dioxane hydrochloride solution (1.04 mL,10 eq) was slowly added dropwise at 0deg.C. The resulting mixture was stirred at 25 degrees celsius for 1 hour. The reaction solution was distilled under reduced pressure to remove the solvent, whereby the title compound 5C (0.18 g, crude product) was obtained as a solid.
MS(ESI+)m/z＝378.9[M+H].
Third step 1- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-2-en-1-one (5)
Compound 5C (0.16 g,0.39mmol,1.0 eq) and triethylamine (0.12 g,1.2mmol,0.16mL,3.0 eq) were dissolved in dichloromethane (5 mL) and methacryloyl chloride (42 mg,0.40mmol,1.0 eq) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 25 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the resulting residue was purified by preparative chromatography (Waters Xbridge C18,20-70% aqueous acetonitrile (containing 0.01% aqueous ammonia)) to give the title compound 5 (0.070 g, yield: 39%) as a white solid.
MS(ESI+)m/z＝447.2[M+H].
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.46(d,J＝4.8Hz,1H),8.37(s,1H),7.38(t,J＝8.2Hz,1H),7.24(dd,J 1 ＝11.2Hz,J 2 ＝2.0Hz,1H),7.17(d,J＝5.2Hz,1H),7.10(td,J＝8.4,0.8Hz,1H),6.17(s,2H),5.61(s,1H),5.20-5.03(m,1H),4.90(s,1H),3.89(q,J＝2.8Hz,2H),3.49(t,J＝5.6Hz,2H),2.43(s,3H),2.22(d,J＝2.0Hz,2H),1.79(s,3H).
Example 6
1- (2-methacryloyl) - (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) piperidine (6)
First step 4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (6A)
Compound 5B (0.40 g,0.84mmol,1.0 eq) was dissolved in methanol (20 mL) and 10% palladium on carbon (0.050 g) was added. The resulting mixture was stirred under a hydrogen atmosphere at 30 degrees celsius for 12 hours. The reaction solution was filtered to remove palladium on carbon, the solvent was removed by distillation under the reduced pressure, and the obtained residue was slurried with a petroleum ether solution containing 10% ethyl acetate and filtered to give the title compound 6A (0.34 g, yield: 85%) as a solid.
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.51(d,J＝5.2Hz,1H),8.40-8.31(m,1H),7.52-7.43(m,1H),7.31(dd,J＝11.2Hz,1.2Hz,1H),7.22(d,J＝5.2Hz,1H),7.12(d,J＝8.0Hz,1H),6.24(s,2H),4.18-3.81(m,4H),3.17(s,1H),2.44(s,3H),1.70-1.59(m,2H),1.53(d,J＝12.8Hz,2H),1.40(s,9H)
Second step 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6- (piperidin-4-yl) pyrimidin-4-amine hydrochloride (6B)
Compound 6A (0.30 g,0.62mmol,1.0 eq) was dissolved in dichloromethane (5 mL) and 4M dioxane hydrochloride solution (1 mL) was slowly added dropwise at 0deg.C. The resulting mixture was stirred at 25 degrees celsius for 1 hour. The reaction solution was distilled off under reduced pressure to remove the solvent, whereby the title compound 6B (0.39 g, crude product) was obtained as a solid.
MS(ESI+)m/z＝381.2[M+H].
Third step 1- (2-methacryloyl) - (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) piperidine (6)
Compound 6B (0.39 g,0.94mmol,1.0 eq) and triethylamine (0.28 g,1.2mmol,0.16mL,3.0 eq) were dissolved in dichloromethane (5 mL) and methacryloyl chloride (98 mg,0.94mmol,1.0 eq) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 25 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the resulting residue was purified by preparative chromatography (Waters Xbridge C18,20-70% aqueous acetonitrile (containing 0.01% aqueous ammonia)) to give the title compound 6 (0.075 g, yield: 18%) as a white solid.
MS(ESI+)m/z＝449.2[M+H].
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.51(d,J＝5.2Hz,1H),8.37(s,1H),7.49(t,J＝8.4Hz,1H),7.38-7.27(m,1H),7.22(d,J＝5.2Hz,1H),7.13(d,J＝8.0Hz,1H),6.28(s,2H),5.14(s,1H),4.93(s,1H),4.37(s,1H),3.87(s,1H),2.99-2.74(m,1H),2.64-2.55(m,1H),2.45(s,3H),1.85(s,3H),1.76-1.54(m,5H)
Example 7
6- (4-propynylamidophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4-aminopyrimidine (7)
First step 6- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4-aminopyrimidine (7A)
Compound 1I (6.0 g,18.1 mmol), compound 1A (4.0 g,18.1 mmol), tetrakis triphenylphosphine palladium (2.1 g,1.81 mmol) and potassium carbonate (5.0 g,36.2 mmol) were mixed in dioxane (80 mL) and water (8 mL). The resulting mixture was stirred under nitrogen at 100 degrees celsius for 2 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting phase was a methylene chloride mixed solvent containing 0-10% methanol) to give the title compound 7A (6.0 g, yield: 85%) as a brown solid. MS (esi+) m/z=389.2 [ m+h ].
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.56-8.46(m,1H),8.38(s,1H),7.69-7.49(m,1H),7.35(t,J＝8.4Hz,1H),7.22-7.15(m,2H),7.01(d,J＝8.4Hz,2H),6.37(d,J＝8.4Hz,2H),5.33(s,2H),2.44(s,3H)
Second step 6- (4-propynylamidophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4-aminopyrimidine (7)
Compound 7B (54 mg,0.77 mmol) was dissolved in dichloromethane (5 mL) and bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride (0.26 g,1.0 mmol), compound 7A (0.20 g,0.51 mmol) and N, N-diisopropylethylamine (0.26 g,2.0 mmol) were slowly added dropwise at 0deg.C. The resulting mixture was stirred at 0 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the crude product was purified by preparative chromatography (Waters Xbridge C18,20-70% aqueous acetonitrile (0.01% aqueous ammonia)), to give the title compound 7 (23 mg, yield: 10%).
MS(ESI+)m/z＝441.1[M+H].
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.85(s,1H),8.49(d,J＝5.2Hz,1H),8.45(s,1H),7.47(d,J＝8.8Hz,2H),7.33(t,J＝8.4Hz,1H),7.27-7.14(m,4H),6.98(dd,J＝8.4,1.6Hz,1H),6.52(s,2H),4.43(s,1H),2.42(s,3H).
Example 8
By following a similar synthetic route and procedure as in example 7, the following compounds 8-14 can be synthesized in the second step by substituting starting material A for starting material 7B in the table below.
Example 9
By following a similar synthetic route and procedure as in example 7, substituting starting material 1A with starting material B in the table below in the first step and substituting starting material C for propiolic acid 7B in the second step, the corresponding compounds 15-26 may be synthesized.
Wherein the synthetic route of compound 23A is as follows:
compound 23A can be synthesized using a similar synthetic procedure as the second step compound 3D of example 3. MS (esi+) m/z=263.2 [ m+h ].
Example 10
By following a similar synthetic route and procedure as in example 5, substituting in the first step 5A with a different starting material D in the table below and in the third step methacryloyl chloride with acryloyl chloride, the corresponding compounds 27-29 in the table below can be synthesized.
Example 11
N- (4- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) vinylsulfonamide (30)
Compound 7A (150 mg,0.39 mmol) and pyridine (122 mg,1.54 mmol) were dissolved in dichloromethane (5 mL) and chloroethylsulfonyl chloride 30A (69 mg,0.42 mmol) was slowly added dropwise at 0deg.C. The resulting mixture was stirred at 0 degrees celsius for 3 hours. The solvent was removed by distillation under the reduced pressure, and the crude product was purified by preparative chromatography (Phenomenex Luna C) 18 100.30 mm.5 um,5-35% acetonitrile in water mobile phase) to afford the title compound 30 (13 mg, yield: 7.3%).
MS(ESI+)m/z＝479.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),8.49(d,J＝5.2Hz,1H),8.43(s,1H),7.32(t,J＝8.4Hz,1H),7.23-7.17(m,4H),7.01-6.94(m,3H),6.74(dd,J＝16.4,9.6Hz,1H),6.50(s,2H),6.06(d,J＝16.4Hz,1H),5.97(d,J＝9.6Hz,1H),2.43(s,3H).
Example 12
1- (2- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) prop-2-en-1-one (31)
First step tert-butyl 2- (6-amino-5-iodopyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (31C)
Compound 31A (0.50 g,2.2 mmol), compound 31B (1.1 g,2.3 mmol) and potassium carbonate (0.61 g,4.4 mmol) were mixed in dioxane (30 mL). The resulting mixture was stirred under nitrogen at 80 degrees celsius for 4 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting phase was a petroleum ether mixed solvent containing 25-50% ethyl acetate) to give the title compound 31C (1.04 g, yield: 97%) as a pale yellow solid.
MS(ESI+)m/z＝446.3[M+H].
Second step 2- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (31D)
Compound 31C (0.50G, 0.92 mmol), compound 1G (0.36G, 1.1 mmol), palladium acetate (10 mg, 46. Mu. Mol), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (38 mg, 92. Mu. Mol) and potassium carbonate (0.25G, 1.84 mmol) were mixed in dioxane (7.5 mL) and water (0.75 mL). The resulting mixture was stirred under nitrogen at 85 degrees celsius for 12 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting phase was a methylene chloride mixed solvent containing 0-10% methanol) to give the title compound 31D (60 mg, yield: 12%) as a brown solid.
MS(ESI+)m/z＝522.1[M+H].
Third step 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6- (2, 7-diazaspiro [3.5] nonan-2-yl) -4-aminopyrimidine (31E)
Compound 31D (60 mg,0.11 mmol) was dissolved in dichloromethane (2 mL) and 4M dioxane solution (1.0 mL) of hydrochloric acid was slowly added dropwise at 0deg.C. The resulting mixture was stirred at 25 degrees celsius for 1 hour. The solvent was distilled off under reduced pressure to leave the hydrochloride salt of the title compound 31E (80 mg, crude product) as a solid.
MS(ESI+)m/z＝422.1[M+H].
Fourth step 1- (2- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) prop-2-en-1-one (31)
Compound 31E (32 mg, 75. Mu. Mol) and triethylamine (32 mg,0.32 mmol) were dissolved in dichloromethane (5 mL) and a solution of acryloyl chloride 4B in dichloromethane (5.8 mg, 64. Mu. Mol, 64. Mu.L, 1.0 mol/L) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 25 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the residue was purified by preparative chromatography (Phenomenex Luna C 18 150 x 25mm x 10um, eluting phase 3% -33% acetonitrile-water (0.1%TFA)) to give the title compound 31 (11 mg, yield: 30%) as a white solid.
MS(ESI+)m/z＝476.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ8.47(d,J＝5.2Hz,1H),7.98(s,1H),7.40(t,J＝8.4Hz,1H),7.27(dd,J＝11.2,1.6Hz,1H),7.18(d,J＝5.2Hz,1H),7.12(dd,J＝8.4,1.2Hz,1H),6.76(dd,J＝16.4,10.4Hz,1H),6.05(dd,J＝16.4,2.4Hz,1H),5.79(br s,2H),5.65-5.60(m,1H),3.41-3.34(m,8H),2.37(s,3H),1.55(br s,4H).
Example 13
By following a similar synthetic route and procedure as in example 12, substituting 31A with a different starting material E in the following table in the first step, the corresponding compounds 32-43 in the table below can be synthesized.
Example 14
N- (1- (6-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) azetidin-3-yl) vinylsulfonamide (44)
Compound 44 was synthesized via a similar synthetic route and procedure as example 12, substituting 34A for 31A in the first step and substituting 2-chloroethylsulfonyl chloride 30A for acryloyl chloride 4B in the fourth step.
MS(ESI+)m/z＝458.1[M+H].
1 HNMR(400MHz,DMSO-d 6 )δ8.48(d,J＝5.2Hz,1H),8.24-7.72(m,2H),7.41(t,J＝8.4Hz,1H),7.33-7.16(m,2H),7.09(d,J＝8.8Hz,1H),6.67(dd,J＝16.8,9.6Hz,1H),5.99(d,J＝16.4 Hz,1H),5.91(d,J＝9.6Hz,1H),5.85(s,2H),3.89(d,J＝4.8Hz,1H),3.71(t,J＝8.0Hz,2H),3.56-3.45(m,2H),2.41(s,3H).
Example 15
The compound 34E was used as a starting material, and 7B was substituted for the starting material C in the following table by the synthesis method of the second step of example 7 to synthesize the corresponding compounds 45 to 48.
Example 16
From the similar synthetic method and procedure as in example 1, substituting 1H in the fourth step with starting material F in the following table, the corresponding compounds 49-55 were synthesized.
Wherein starting material 54B of compound 54 is synthesized from 54A by the following procedure.
54A (500 mg,3.3 mmol) was dissolved in 10mL of dichloromethane and iodine chloride (1.6 g,10 mmol) was slowly added dropwise under nitrogen at 0 ℃. After the resulting reaction solution was reacted at room temperature for 1 hour, it was quenched by adding 5mL of a saturated solution of sodium sulfite, and extracted by adding 25mL of methylene chloride. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained crude product was purified by a silica gel column (eluent 0-100% ethyl acetate in petroleum ether) to give compound 54B (410 mg, yield: 45%).
Example 17
N- (4- (6-amino-5- (4- ((S) -2-cyanopyrrolidine-1-carbonyl) cyclohex-1-en-1-yl) pyrimidin-4-yl) phenyl) -2-butynamide (55)
First step 4- (4-amino-6-chloropyrimidin-5-yl) cyclohex-3-ene-1-carboxylic acid ethyl ester (55B)
4-amino-6-chloro-5-iodopyrimidine 1H (2.0 g,7.8 mmol), compound 55A (2.6 g,9.4 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.57 g,0.78 mmol) and potassium carbonate (2.2 g,16 mmol) were dissolved in dioxane (20 mL) and water (2 mL), and after three nitrogen substitutions were placed at 100℃and stirred for 2 hours. After the reaction solution was cooled, 20mL of a saturated ammonium chloride solution was added and extracted with 40mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by column chromatography (eluting phase was petroleum ether containing 50% ethyl acetate) to give solid compound 55B (1.1 g, yield: 50%).
1 H NMR(400MHz,DMSO-d 6 )δ8.09(s,1H),7.56-6.28(m,2H),5.67(s,1H),4.16-4.03(m,2H),2.99-2.57(m,1H),2.41-1.87(m,6H),1.20(t,J＝7.2Hz,3H)
Second step 4- (4-amino-6- (4-nitrophenyl) pyrimidin-5-yl) cyclohex-3-ene-1-carboxylic acid ethyl ester (55D)
Compound 55B (1.1 g,3.9 mmol), 4-nitrobenzeneboronic acid 55C (0.78 g,4.7 mmol), tetrakis (triphenylphosphine) palladium (0.45 g,0.39 mmol) and potassium carbonate (1.1 g,7.8 mmol) were dissolved in dioxane (15 mL) and water (1.5 mL), and after three nitrogen substitutions, the mixture was stirred at 100deg.C for 2 hours. After the reaction solution was cooled, 20mL of a saturated ammonium chloride solution was added and extracted with 40mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (eluting phase was petroleum ether containing 50% ethyl acetate) to give compound 55D (0.39 g, yield: 27%).
MS(ESI+)m/z＝368.2[M+H].
Third step 4- (4-amino-6- (4-aminophenyl) pyrimidin-5-yl) cyclohex-3-en-1-carboxylic acid ethyl ester (55E)
Compound 55D (0.36 g,1.0 mmol) was dissolved in 10mL of methanol, and iron powder (0.56 g,10 mmol) and 2mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was filtered through celite and the filter cake was washed with 40mL ethyl acetate. To the resulting filtrate was added 20mL of saturated sodium chloride solution, and an additional 20mL of ethyl acetate was added for extraction. The organic phase obtained was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (eluting with petroleum ether containing 50% -100% ethyl acetate) to give solid 55E (0.21 g, yield: 62%).
MS(ESI+)m/z＝339.2[M+H].
Fourth step 4- (4-amino-6- (4- (-2-butynylamido) phenyl) pyrimidin-5-yl) cyclohex-3-ene-1-carboxylic acid ethyl ester (55G)
Compound 55E (0.21 g,0.58 mmol) and N, N-diisopropylethylamine (0.23 g,1.8 mmol) were dissolved in 3mL of dichloromethane and 2-butynoyl chloride 55F (55 mg,0.55 mmol) was added at 0deg.C. The resulting mixture was stirred at 0 degrees celsius for 1 hour. Concentrating the obtained reaction solution under reduced pressure, and subjecting the obtained crude product to C 18 Purification by reverse phase chromatography (eluting phase was an aqueous solution containing 5 to 80% acetonitrile) and lyophilization removed the solvent gave compound 55G (0.19G, yield: 81%).
MS(ESI+)m/z＝405.2[M+H].
Fifth step 4- (4-amino-6- (4- (-2-butynylamido) phenyl) pyrimidin-5-yl) cyclohex-3-ene-1-carboxylic acid (55H)
Compound 55G (0.19G, 0.47 mmol) and lithium hydroxide (23 mg,0.95 mmol) were mixed in tetrahydrofuran (2 mL) and water (0.5 mL). After the obtained mixture was stirred at room temperature for 1 hour, dry ice (5 g) was added to the reaction solution. The resulting mixture was concentrated under reduced pressure to give crude compound 55H (0.24 g).
MS(ESI+)m/z＝377.2[M+H].
Sixth step N- (4- (6-amino-5- (4- ((S) -2-cyanopyrrolidine-1-carbonyl) cyclohex-1-en-1-yl) pyrimidin-4-yl) phenyl) -2-butynamide (55)
2- (7-Azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (57 mg,0.15 mmol) was added to a solution of crude 55H (48 mg, about 0.1 mmol) in N, N-dimethylformamide (1 mL), followed by N, N-diisopropylethylamine (39 mg,0.3 mmol) and (S) -2-cyanopyrrolidine 55I (20 mg,0.21 mmol). The resulting solution was stirred at room temperature for 2 hours. The mixture was filtered and purified by preparative high performance liquid phase (Waters Xbridge C18,20-60% acetonitrile in water (0.01% aqueous ammonia)), to give the title compound 55 (3.6 mg, yield: 7.9%).
MS(ESI+)m/z＝455.2[M+H].
1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.31(s,1H),7.62(d,J＝8.6Hz,4H),6.63(s,2H),5.76(s,1H),4.72(dt,J＝7.6,3.9Hz,1H),3.69(s,4H),2.34-2.10(m,4H),2.06(m,4H),1.71(m,2H),1.24(m,2H),0.96(m,2H).
Example 18-1
By following a similar route and procedure as in example 17, substituting a different starting material G in the table below for compound 55A in the first step, substituting acryloyl chloride 4B for 2-butynyl chloride 55F in the fourth step, substituting starting material H in the table below for 55I in the sixth step, the corresponding compounds 56-59 in the table were synthesized.
Example 18-2
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (60)
First step 2, 4-dichloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidine (60B)
2, 4-dichloro-5-iodopyrimidine 60A (5.0G, 18 mmol), compound 1G (6.0G, 18 mmol), potassium carbonate (5.0G, 36 mmol) and (diphenylphosphino ferrocene) palladium dichloride (0.70G, 0.91 mmol) were added to a mixed solvent of dioxane (50 mL) and water (5 mL), and after three nitrogen substitutions, the reaction was stirred at 100℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 100mL of ethyl acetate was added thereto, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to give compound 60B (2.9 g, yield: 45%).
MS(ESI+)m/z＝351.0[M+H].
Second step 2-chloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- (3-nitrophenyl) pyrimidine (60D)
Compound 60B (2.1 g,6.0 mmol), 3-nitrobenzoic acid 60C (1.0 g,6.0 mmol), potassium carbonate (1.7 g,12.0 mmol) and tetrakis triphenylphosphine palladium (0.35 g,0.30 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL), and after three nitrogen substitutions, the mixture was stirred at 100℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 50mL of ethyl acetate was added thereto for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-1/1) to give compound 60D (1.0 g, yield: 38%).
MS(ESI+)m/z＝438.1[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.05(s,1H),8.52(d,J＝5.2Hz,1H),8.39-8.31(m,2H),7.87(d,J＝8.0Hz,1H),7.79-7.71(m,1H),7.53-7.43(m,2H),7.30-7.20(m,2H),2.48-2.44(m,3H).
Third step 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) -4- (3-nitrophenyl) pyrimidin-2-amine (60F)
Compound 60D (0.40 g,0.91 mmol), 1-methyl-1H-pyrazol-4-amine 60E (0.17 g,1.8 mmol), cesium carbonate (0.88 g,2.7 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (57 mg,0.091 mmol) and palladium acetate (20 mg,0.091 mmol) were added to dioxane (20 mL), and after three nitrogen substitutions, the mixture was stirred at 100℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 50mL of ethyl acetate was added thereto for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to give compound 60F (0.20 g, yield: 44%)
MS(ESI+)m/z＝499.1[M+H].
Fourth step 4- (3-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (60G)
Compound 60F (0.18 g,0.36 mmol) was dissolved in 5mL of methanol and iron powder (0.2 g,3.6 mmol) and 1mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was filtered through celite and the filter cake was washed with 20mL ethyl acetate. To the resulting filtrate was added 10mL of saturated sodium chloride solution, and an additional 20mL of ethyl acetate was added for extraction. The organic phase obtained was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product is passed through C 18 Purification by reverse phase column (mobile phase 5-80% acetonitrile in water) and lyophilization removed the solvent gave solid 60G (80 mg, yield: 47%). MS (esi+) m/z=469.2 [ m+h ]].
Fifth step N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (60)
Compound 60G (70 mg,0.15 mmol) and triethylamine (45 mg,0.45 mmol) were dissolved in dichloromethane (5 mL) and a solution of acryloyl chloride 4B in dichloromethane (13 mg,0.15mmol,150uL,1.0 mol/L) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 0 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the residue was purified by preparative chromatography (Phenomenex Luna C, 150×25mm×10um, eluting with 3% -55% acetonitrile-water) to give the title compound 60 (20 mg, yield: 26%) as a white solid.
MS(ESI+)m/z＝523.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.27(s,1H),9.75(s,1H),8.53(s,1H),8.46(d,J＝4.8Hz,1H),8.43-7.80(m,2H),7.60(s,1H),7.53(s,1H),7.33-7.20(m,3H),7.18(d,J＝5.2Hz,1H),7.03(d,J＝8.0Hz,1H),6.91(d,J＝7.6Hz,1H),6.53-6.39(m,1H),6.35-6.19(m,1H),5.77(d,J＝11.2Hz,1H),3.84(s,3H),2.41(s,3H).
Example 19
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) methacryl amide (61)
Compound 61 was synthesized using a similar synthesis as the fifth step of example 18-2, starting from compound 60G, substituting 61A for acryloyl chloride 4B.
MS(ESI+)m/z＝537.1[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.94(s,1H),9.76(s,1H),8.52(s,1H),8.46(d,J＝5.2Hz,1H),8.0(s,2H),7.60(s,1H),7.51(s,1H),7.32-7.16(m,4H),7.03(d,J＝8.0Hz,1H),6.86(d,J＝6.8Hz,1H),5.82(s,1H),5.54(s,1H),3.85(s,3H),2.41(s,3H),1.96(s,3H).
Example 20
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) propionylamide (62)
Compound 62 was synthesized using compound 60G as a starting material and using a similar synthesis method as the fifth step in example 18-2, substituting 62A for acryloyl chloride 4B.
MS(ESI+)m/z＝525.1[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),9.73(s,1H),8.52(s,1H),8.47(d,J＝5.2Hz,1H),8.09(s,2H),7.52-7.51(m,1H),7.52(s,1H),7.36-7.13(m,4H),7.02(d,J＝8.0Hz,1H),6.84(d,J＝7.2Hz,1H),3.84(s,3H),2.42(s,3H),2.38-2.29(m,2H),1.19-1.04(m,3H).
Example 21
2-fluoro-N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (63)
Compound 63 was synthesized using a similar synthetic method as the second step in example 7, using compound 60G as starting material, substituting 63A for 7B and 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate for bis (2-oxo-3-oxazolidinyl) phosphinic chloride, and reacting at room temperature for 1 hour.
MS(ESI+)m/z＝541.1[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.44(d,J＝4.4Hz,1H),9.77(s,1H),8.53(s,1H),8.46(d,J＝5.2Hz,1H),8.13(s,2H),7.66(d,J＝7.2Hz,1H),7.53(s,1H),7.34-7.15(m,4H),7.09-6.90(m,2H),5.83-5.63(m,1H),5.45(dd,J＝3.6,15.5Hz,1H),3.84(s,3H),2.41(s,3H).
Example 22
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) 2-methylphenyl) acryloylamide (64)
Compound 64 was synthesized using a similar synthetic procedure and method after the second step in example 18-2, substituting 64A for 60C.
MS(ESI+)m/z＝537.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.76(s,1H),9.52(s,1H),8.59(s,1H),8.44(d,J＝5.2Hz,1H),8.02-7.70(m,1H),7.64-7.43(m,2H),7.28-7.19(m,2H),7.16(d,J＝5.2Hz,1H),7.14-7.05(m,2H),6.94(d,J＝8.0Hz,1H),6.52(dd,J＝10.4,16.6Hz,1H),6.23(d,J＝17.2Hz,1H),5.73(d,J＝10.4Hz,1H),3.80(s,3H),2.39(s,3H),1.92(s,3H).
Example 23
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) 2-methoxyphenyl) acryloylamide (65)
Compound 65 was synthesized using a similar synthetic procedure and method after the second step in example 18-2, substituting 65A for 60C.
MS(ESI+)m/z＝553.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.79(s,1H),9.57(s,1H),8.59(s,1H),8.44(d,J＝5.2Hz,1H),8.18(d,J＝6.3Hz,1H),7.88(s,1H),7.53(s,1H),7.24-7.14(m,5H),6.97(dd,J＝1.6,8.4Hz,1H),6.75(dd,J＝10.0,17.0Hz,1H),6.25(dd,J＝1.8,16.8Hz,1H),5.75-5.68(m,1H),3.81(s,3H),3.44(s,3H),2.38(s,3H).
Example 24
N- (3- (2- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) acryloylamide (66)
Compound 66 was synthesized using a similar synthetic procedure and method following the third step of example 18-2, substituting 66A for 60E.
MS(ESI+)m/z＝580.3[M+H].
Example 25
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (67)
Compound 67 was synthesized using a similar synthetic procedure and method as the third step and thereafter in example 18-2, substituting 67A for 60E.
MS(ESI+)m/z＝592.3[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.27(t,J＝5.2Hz,1H),9.77(s,1H),8.55(s,1H),8.47(d,J＝5.2Hz,1H),8.22(s,1H),7.67-7.59(m,1H),7.57(s,1H),7.32-7.21(m,3H),7.19(d,J＝4.8Hz,1H),7.03(d,J＝6.8Hz,1H),6.94(d,J＝8.0Hz,1H),6.52-6.40(m,1H),6.33-6.24(m,1H),5.78(d,J＝11.6Hz,1H),4.91(s,1H),2.87-2.80(m,4H),2.41(s,3H),2.26(s,5H),2.05(d,J＝6.4Hz,1H).
Example 26
N- (3- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (68)
Compound 68 was synthesized using a similar synthetic procedure and method as the third step and thereafter in example 18-2, substituting 68A for 60E.
MS(ESI+)m/z＝605.3[M+H].
Example 27
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (69)
First step 2, 5-dichloro-4- (4-nitrophenyl) pyrimidine (69B)
2,4, 5-trichloropyrimidine 69A (1.8 g,10 mmol), p-nitrophenylboronic acid 55C (1.7 g,10 mmol), potassium carbonate (2.8 g,20 mmol) and (diphenylphosphino ferrocene) palladium dichloride (0.35 g,0.46 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL), and after three nitrogen substitutions, the reaction was stirred at 70℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 100mL of ethyl acetate was added thereto, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to give compound 69B (1.7 g, yield: 63%).
MS(ESI+)m/z＝270.0[M+H].
Second step 5-chloro-N- (1-methyl-1H-pyrazol-4-yl) -4- (4-nitrophenyl) pyrimidin-2-amine (69C)
Compound 69B (0.24 g,0.91 mmol), 1-methyl-1H-pyrazol-4-amine 60E (0.17 g,1.8 mmol), cesium carbonate (0.88 g,2.7 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (57 mg,0.091 mmol) and palladium acetate (20 mg,0.091 mmol) were added to dioxane (20 mL), and after three nitrogen substitutions, the mixture was stirred at 100℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 50mL of ethyl acetate was added thereto for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to give compound 69C (0.20 g, yield: 67%)
MS(ESI+)m/z＝331.0[M+H].
Third step 5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) -4- (4-nitrophenyl) pyrimidin-2-amine (69D)
Compound 69C (0.20G, 0.61 mmol), compound 1G (0.20G, 0.61 mmol), potassium carbonate (170 mg,1.2 mmol), palladium acetate (13 mg,0.06 mmol) and tricyclohexylphosphorus (34 mg,0.12 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL), and after three times of nitrogen substitution, the mixture was allowed to stand at 100℃for 2 hours with stirring. The reaction mixture was quenched with 20mL of ammonium chloride, 50mL of ethyl acetate was added thereto for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to give compound 69D (0.13 g, yield: 41%).
MS(ESI+)m/z＝499.1[M+H].
Fourth step 4- (4-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (69E)
Compound 69D (0.13 g,0.26 mmol) was dissolved in 5mL of methanol, and iron powder (0.2 g,3.6 mmol) and 1mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was filtered through celite and the filter cake was washed with 20mL ethyl acetate. To the resulting filtrate was added 10mL of saturated sodium chloride solution, and an additional 20mL of ethyl acetate was added for extraction. The organic phase obtained was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by a C18 reverse phase column (mobile phase 5-80% acetonitrile in water) and lyophilized to remove the solvent to give 69E (42 mg, yield: 34%). MS (esi+) m/z=469.2 [ m+h ].
Fifth step N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (69)
Compound 69E (42 mg,0.09 mmol) and triethylamine (18 mg,0.18 mmol) were dissolved in dichloromethane (5 mL) and a solution of acryloyl chloride 4B in dichloromethane (7.6 mg,0.085mmol,85uL,1.0 mol/L) was slowly added dropwise at 0 ℃. The resulting mixture was stirred at 0 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the residue was purified by preparative chromatography (Phenomenex Luna C, 150×25mm×10um, eluting with 3% -55% acetonitrile-water) to give the title compound 69 (18 mg, yield: 38%) as a white solid.
MS(ESI+)m/z＝523.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),9.72(s,1H),8.49(s,1H),8.48(d,J＝5.0Hz,1H),7.92(s,1H),7.67(d,J＝8.4Hz,2H),7.49(d,J＝60.8Hz,3H),7.31(t,J＝8.4Hz,1H),7.26-7.21(m,1H),7.19(d,J＝5.1Hz,1H),7.05-6.98(m,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.27(dd,J＝16.9,2.0Hz,1H),5.78(dd,J＝10.0,2.1Hz,1H),3.82(s,3H),2.43(s,3H).
Example 28
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (70)
Compound 70 was synthesized using similar synthetic procedures and methods as the third step and beyond in example 27, substituting 70A for 69A.
MS(ESI+)m/z＝537.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),9.54(s,1H),8.43(d,J＝5.0Hz,1H),7.57-7.50(m,2H),7.48(s,1H),7.24(t,J＝8.3Hz,1H),7.18(dd,J＝11.4,2.0Hz,1H),7.13(d,J＝5.1Hz,1H),6.95(d,J＝8.1Hz,1H),6.35(dd,J＝16.8,10.1Hz,1H),6.19(dd,J＝17.0,2.0Hz,1H),5.70(dd,J＝10.1,2.1Hz,1H),3.74(s,3H),2.35(s,3H),2.22(s,3H).
Example 29
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6-amino-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (71)
Compound 71 was synthesized using a similar synthetic procedure and method as the third step and thereafter in example 27, substituting 71A for 69A.
MS(ESI+)m/z＝538.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.50-8.48(m,1H),8.19-8.08(m,1H),7.74-7.51(m,4H),7.33-7.25(m,3H),7.20-7.19(m,2H),6.98-6.96(m,1H),6.69-6.66(m,2H),6.45-6.38(m,1H),6.28-6.23(m,1H),5.57-5.76(m,1H),3.80(s,3H),2.42(s,3H).
Example 30
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) but-2-ynamide (72)
Compound 72 was synthesized using compound 69E as a starting material and using a method similar to the fifth step of example 27, in which acryloyl chloride 4B was replaced with 2-butynyl chloride 55F.
MS(ESI+)m/z＝535.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),9.65(s,1H),8.41(d,J＝5.0Hz,2H),7.85(s,1H),7.57-7.44(m,3H),7.32(s,2H),7.23(t,J＝8.4Hz,1H),7.19-7.08(m,2H),6.97-6.89(m,1H),3.75(s,3H),2.36(s,3H),1.98(s,3H).
Example 31
2-fluoro-N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (73)
Compound 73 was synthesized using a similar synthetic method as the second step in example 7, starting with compound 69E, substituting 63A for 7B and substituting 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate for bis (2-oxo-3-oxazolidinyl) phosphinic chloride.
MS(ESI+)m/z＝541.1[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.43(s,1H),9.74(s,1H),8.51(s,1H),8.48(d,J＝5.0Hz,1H),7.92(s,1H),7.74(d,J＝8.4Hz,2H),7.57(s,1H),7.43(s,2H),7.31(t,J＝8.4Hz,1H),7.26-7.21(m,1H),7.19(d,J＝5.1Hz,1H),7.01(dd,J＝8.1,1.8Hz,1H),5.73(dd,J＝47.6,3.7Hz,1H),5.46(dd,J＝15.6,3.7Hz,1H),3.82(s,3H),2.43(s,3H).
Example 32
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (74)
Compound 74B was synthesized using a similar route and procedure as in example 27, substituting 74A for 60E in the second step.
Compound 74B (27 mg,0.039 mmol) was dissolved in 2mL of dichloromethane and 1mL of trifluoroacetic acid was added at 0deg.C. The resulting mixed solution was stirred at 0 degrees celsius for 1 hour. Concentrating under reduced pressure to remove solvent and trifluoroacetic acid, and purifying the crude product by preparative chromatography (Phenomenex Luna C) 18 150.25 mm.10 um, eluting with 3% -55% acetonitrile-water) to give compound 74 (8.7 mg, yield: 37%).
MS(ESI+)m/z＝592.3[M+H].
Example 33
2-fluoro-N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (75)
Compound 75B can be synthesized using a similar route and procedure as in example 27, substituting 74A for 60E in the second step. Compound 75 can be synthesized from compound 75B through a further two-step reaction.
First step 4- (4- ((5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -4- (4- (2-fluoroacryloylamino) phenyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (75C)
Compound 75B (56 mg,0.088 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (38 mg,0.10 mmol) and 2-fluoroacrylic acid (18 mg,0.20 mmol) were mixed in dichloromethane solution, followed by addition of N, N-diisopropylethylamine (39 mg,0.30 mmol). The resulting solution was stirred at 0 degrees celsius for 1 hour. The mixture was filtered and then subjected to C 18 Purification by reverse phase chromatography (elution phase 20-80% acetonitrile in water) afforded compound 75C (26 mg, yield: 42%).
MS(ESI+)m/z＝710.3[M+H].
Second step 2-fluoro-N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (75)
Compound 75C (26 mg,0.037 mmol) was dissolved in 2mL of dichloromethane and 1mL of trifluoroacetic acid was added at 0deg.C. The resulting mixed solution was stirred at 0 degrees celsius for 1 hour. Concentrating under reduced pressure to remove solvent and trifluoroacetic acid, and purifying the crude product by preparative chromatography (Phenomenex Luna C) 18 150.25 mm.10 um, eluting with 3% -55% acetonitrile-water) to give compound 75 (6.1 mg, yield: 27%).
MS(ESI+)m/z＝610.2[M+H].
Example 34
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -3-methylphenyl) acryloylamide (76)
Referring to the synthetic route and method of example 27, compound 76 was synthesized using 76A instead of 55C.
MS(ESI+)m/z＝537.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.73(s,1H),8.58(s,1H),8.46(d,J＝5.0Hz,1H),7.70(m,1H),7.49(m,3H),7.23(t,J＝8.4Hz,1H),7.15(m,2H),7.12(dd,J＝11.7,1.8Hz,1H),6.89(m,1H),6.43(dd,J＝17.0,10.1Hz,1H),6.26(d,J＝18.8Hz,1H),5.76(d,J＝12.0Hz,1H),3.80(s,3H),2.40(s,3H),2.03(s,3H).
Example 35
N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -3-fluorophenyl) acryloylamide (77)
Referring to the synthetic route and method of example 27, compound 77 was synthesized using 77A instead of 55C.
MS(ESI+)m/z＝541.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ12.40(s,1H),9.20(s,1H),9.07(d,J＝6.6Hz,1H),8.49(d,J＝5.0Hz,1H),7.92(s,1H),7.83–7.55(m,2H),7.39(t,J＝8.4Hz,1H),7.32(dd,J＝11.5,2.1Hz,1H),7.24–7.13(m,2H),5.58(d,J＝3.5Hz,0.5H),5.46(d,J＝3.5Hz,0.5H),5.27(dd,J＝15.6,3.5Hz,1H),4.58–4.51(m,1H),4.12–4.00(m,2H),3.86–3.74(m,2H),2.42(s,3H).
Example 36
2-fluoro-N- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -3-methylphenyl) acryloylamide (78)
Referring to the synthetic route and method of example 27, compound 78 was synthesized using 76A instead of 55C, while using 2-fluoroacryloyl chloride instead of acryloyl chloride 4B.
MS(ESI+)m/z＝555.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.75(s,1H),8.59(s,1H),8.47-8.45(m,1H),7.61-7.9(m,2H),7.52(s,1H),7.25-7.11(m,5H),6.94-6.92(m,1H),5.78-5.77(m,0.5H),5.66-5.65(m,0.5H),5.47-5.42(m,1H),3.80(s,3H),2.40(s,3H).
Example 37
N- (4- (5- (4- ((S) -2-cyanopyrrolidine-1-carbonyl) cyclohex-1-en-1-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (79)
Referring to the synthetic route and procedure of example 27, compound 79A was synthesized using 55A instead of 1G. Compound 79 was synthesized by the fifth and sixth synthetic steps and methods of example 17, replacing 55G of example 17 with compound 79A.
MS(ESI+)m/z＝523.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.36(d,J＝3.5Hz,1H),9.49(s,1H),8.20(s,1H),7.88(d,J＝4.7Hz,1H),7.84-7.70(m,4H),7.52(s,1H),6.54-6.38(m,1H),6.35-6.20(m,1H),5.86-5.73(m,2H),4.73(ddd,J＝7.4,5.2,3.6Hz,1H),3.80(s,3H),3.74-3.61(m,1H),3.51(dt,J＝16.3,7.6Hz,1H),2.68(d,J＝9.1Hz,1H),2.41-1.63(m,10H).
Example 38
N- (3- (5- (4- ((S) -2-cyanopyrrolidine-1-carbonyl) cyclohex-1-en-1-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acryloylamide (80)
Referring to the synthetic route and method of example 18-2, compound 80A can be synthesized by substituting 55A for 1G. Compound 80 was synthesized by the fifth and sixth synthetic steps and methods of example 17, replacing 55G of example 17 with compound 80A.
MS(ESI+)m/z＝523.2[M+H].
Example 39
N- (1- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) azetidin-3-yl) acryloylamide (81)
First step (1- (2-chloro-5-bromopyrimidin-4-yl) azetidin-3-yl) carbamic acid tert-butyl ester (81C)
2, 4-dichloro-5-bromopyrimidine 81A (2.3 g,10 mmol), 3-t-butoxycarbonyl-aminoazetidine 81B (1.7 g,10 mmol) and N, N-diisopropylethylamine (2.6 g,20 mmol) were mixed in 25mL dioxane. The resulting mixture was stirred at 80℃for 1 hour and then concentrated under reduced pressure, and the resulting crude 81C (6.6 g, about 10 mmol) was used directly in the next step.
MS(ESI+)m/z＝363.1,365.1[M+H].
Second step (tert-butyl 1- (2-chloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) azetidin-3-yl) carbamate (81D)
Compound 81C (3.3G, crude product, about 5.0 mmol), compound 1G (2.0G, 6.0 mmol), potassium carbonate (2.8G, 20 mmol) and (diphenylphosphino ferrocene) palladium dichloride (0.38G, 0.5 mmol) were added to a mixed solvent of dioxane (30 mL) and water (3 mL), and after three nitrogen substitutions, the reaction was stirred at 100℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 100mL of ethyl acetate was added thereto, and the organic phase obtained by separation was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to give compound 81D (1.7 g, yield: 71%).
MS(ESI+)m/z＝487.1[M+H].
Third step (tert-butyl 1- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) azetidin-3-yl) carbamate (81E)
Compound 81D (0.49 g,1.0 mmol), 1-methyl-1H-pyrazol-4-amine 60E (0.17 g,1.8 mmol), cesium carbonate (0.88 g,2.7 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (62 mg,0.10 mmol) and palladium acetate (22 mg,0.10 mmol) were added to dioxane (20 mL), and after three nitrogen substitutions, the mixture was stirred at 100℃for 2 hours. The reaction mixture was quenched with 20mL of ammonium chloride, 50mL of ethyl acetate was added thereto for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to give compound 81E (0.37 g, yield: 67%).
MS(ESI+)m/z＝548.2[M+H].
Fourth step 4- (3-Aminoazetidin-1-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (81F)
Compound 81E (0.37 g,0.67 mmol) was dissolved in 5mL of dichloromethane and 1mL of trifluoroacetic acid was slowly added at 0deg.C. The obtained solution is stirred and reacted for 1 hour at the temperature of 0 ℃ and then concentrated under reduced pressure to obtain a crude product. The crude product is reversed phase C 18 Chromatographic column (eluent phase 5-75% acetonitrile water solution (containing 8mmol/L NH) 3 ) Purification gave compound 81F (0.26 g, yield: 87%). MS (esi+) m/z=448.2 [ m+h ]].
Fifth step N- (1- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) azetidin-3-yl) acryloylamide (81)
Compound 81F (45 mg,0.10 mmol) and triethylamine (20 mg,0.20 mmol) were dissolved in dichloromethane (2 mL) and a solution of acryloyl chloride 4B in dichloromethane (9.0 mg,0.1mmol,100uL,1.0 mol/L) was slowly added dropwise at 0deg.C. The resulting mixture was stirred at 0 degrees celsius for 1 hour. The solvent was removed by distillation under the reduced pressure, and the residue was purified by preparative chromatography (Phenomenex Luna C 18 150 x 25mm x 10um, eluting with 5% -75% acetonitrile-water) to afford the title compound 81 as a white solid (26 mg, yield: 52%).
MS(ESI+)m/z＝502.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.21(s,1H),8.72(d,J＝6.8Hz,1H),8.49(d,J＝5.0Hz,1H),7.92(s,1H),7.83(s,1H),7.49(s,1H),7.39(t,J＝8.3Hz,1H),7.32(dd,J＝11.4,2.0Hz,1H),7.24-7.13(m,2H),6.23-6.01(m,2H),5.61(dd,J＝9.6,2.6Hz,1H),4.51(d,J＝7.4Hz,1H),4.08(s,2H),3.80(s,3H),3.66(s,2H),2.42(s,3H).
Example 40
N- (1- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) azetidin-3-yl) -2-butynamide (82)
Compound 82 was synthesized using compound 81F as a starting material and using a method similar to the fifth step of example 27, in which acryloyl chloride 4B was replaced with 2-butynyl chloride 55F.
MS(ESI+)m/z＝514.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.13(s,1H),9.05(d,J＝6.7Hz,1H),8.42(d,J＝5.0Hz,1H),7.84(s,1H),7.75(s,1H),7.42(s,1H),7.31(t,J＝8.4Hz,1H),7.24(dd,J＝11.5,2.1Hz,1H),7.14-7.06(m,2H),4.37(s,1H),4.07-3.82(m,2H),3.73(s,3H),3.67-3.44(m,2H),2.35(s,3H),1.88(s,3H).
Example 41
2-fluoro-N- (1- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) azetidin-3-yl) acryloylamide (83)
Compound 81F (40 mg,0.088 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (38 mg,0.10 mmol) and 2-fluoroacrylic acid 63A (18 mg,0.20 mmol) were mixed in dichloromethane, followed by N, N-diisopropylethylamine (39 mg,0.30 mmol). The resulting solution was stirred at 0 degrees celsius for 1 hour. The mixture was filtered and then subjected to C 18 Purification by reverse phase chromatography (elution phase: 20-70% acetonitrile in water) afforded compound 83 (21 mg, yield: 46%). MS (esi+) m/z=520.2 [ m+h ]].
1 H NMR(400MHz,DMSO-d 6 )δ9.20(s,1H),9.07(d,J＝6.9Hz,1H),8.48(d,J＝5.0Hz,1H),7.92(s,1H),7.83(s,1H),7.49(s,1H),7.39(t,J＝8.4Hz,1H),7.31(dd,J＝11.4,2.0Hz,1H),7.23-7.13(m,2H),5.52(dd,J＝47.9,3.5Hz,1H),5.27(dd,J＝15.6,3.5Hz,1H),4.58(d,J＝7.4Hz,1H),4.06(s,2H),3.94-3.46(m,5H),2.42(s,3H).
Example 42
By following a similar route and procedure as in example 39, substituting compound 81B in the first step with starting material I in the following table, the corresponding compounds 84-117 in the table can be synthesized. By the similar route and procedure as in example 39, when the corresponding compounds 118 to 119 in the synthesis table of compound 81B in the first step were replaced with 118A and 119A in the raw material I, it was necessary to raise the concentration of trifluoroacetic acid in the reaction liquid to 50% in the fourth step.
117a,118a in feedstock I can be synthesized by the following steps:
first step 1- (tert-butyl) 3-methyl 3- ((S) -1- (((R) -tert-butylsulfinyl) amino) ethyl) azetidine-1, 3-dicarboxylic acid ester (117D)
Compound 117B (4.4 g,20 mmol) and 117C (1.5 g,10 mmol) were dissolved in 50mL anhydrous tetrahydrofuran and the resulting solution cooled to-78 ℃. Lithium hexamethyldisilazide solution (1.0M tetrahydrofuran solution, 20ml,20 mmol) was slowly added dropwise with stirring, and stirring was continued at-78 ℃ for 3 hours. After the reaction mixture was quenched by adding 10mL of a saturated aqueous ammonia chloride solution, the temperature was slowly raised to room temperature. To the resulting mixture, 100mL of ethyl acetate and 50mL of a saturated aqueous ammonia solution were added, and the obtained organic phase was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-1/1) to give compound 117D (2.1 g, yield: 58%). MS (esi+) m/z=363.2 [ m+h ].
Second step 3- ((S) -1- (((R) -tert-butylsulfinyl) amino) ethyl) -3- (hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester (117E)
Compound 117D (2.1 g,5.8 mmol) was dissolved in 40mL anhydrous tetrahydrofuran and the resulting solution cooled to 0 ℃. Lithium aluminum hydride (0.38 g,10 mmol) was slowly added to the reaction solution, and the reaction was stirred at 0℃for 2 hours. To the resulting reaction solution, 10g of sodium sulfate decahydrate was added, and the reaction was stirred at 0℃for 1 hour, slowly warmed to room temperature, and stirred for 16 hours. The resulting mixture was filtered under reduced pressure, the filter cake was washed with 50mL of ethyl acetate, and the resulting filtrate was concentrated to give a crude product which was purified by column chromatography on silica gel (eluting with 3% methanol in methylene chloride) to give the major product 117E (1.2 g, yield 62%).
MS(ESI+)m/z＝335.2[M+H].
Third step (S) -6- ((R) -tert-butylsulfinyl) -5-methyl-2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (117F)
Crude compound 117E (1.2 g,3.6 mmol) and p-toluenesulfonyl chloride (1.03 g,5.4 mmol) were dissolved in 20mL anhydrous tetrahydrofuran and sodium hydride (0.7 g,60%,17.4 mmol) was added slowly at 0deg.C. After the resulting mixture was stirred at 0℃for 2 hours, it was quenched by slowly adding 20mL of water. The resulting reaction solution was extracted 3 times with 30mL of ethyl acetate, and the obtained organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-1/1) to give compound 117F (1.0 g, yield: 88%).
MS(ESI+)m/z＝317.2[M+H].
Fourth step (R) -5-methyl-2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (117A) and (R) -2- ((S) -tert-butylsulfinyl) -1-methyl-2, 6-diazaspiro [3.3] heptane (118A)
Compound 117F (0.63 g,2.0 mmol) was dissolved in 5mL of dichloromethane and 0.5mL of trifluoroacetic acid was added at 0deg.C. The resulting reaction solution was stirred at 0 degrees celsius for 1 hour. Concentrating the reaction solution under reduced pressure at 0deg.C to obtain crude product, and subjecting to C 18 Purification by reverse phase column (mobile phase 0-60% acetonitrile in water) gave compound 117A (63 mg, yield: 15%) and 118A (122 mg, yield: 28%).
Compound 117 ams (esi+) m/z=213.2 [ m+h ].
Compound 118A MS (esi+) m/z=217.2 [ m+h ].
119A was synthesized via a similar synthetic method and procedure for compound 118A, using 119C instead of 117C.
MS(ESI+)m/z＝217.2[M+H].
Example 43
By a similar procedure and procedure as in the first to fourth steps of example 39, substituting compound 81B in the first step with starting material I in the table below, and using a similar procedure and procedure as in example 41 in the fifth step, the corresponding compounds 120-125 in the table can be synthesized.
Example 44
The corresponding compounds 126-154 in the following table can be synthesized by a similar method and procedure as in example 39, substituting starting material I in the following table for compound 81B in the first step and starting material J in the following table for 60E in the third step.
Example 45
By a similar procedure and procedure as in example 39, compound 81B in the first step was replaced with starting material I in the table below and 1G in the second step was replaced with starting material K in the table below, the corresponding compounds 156-159 in the table below were synthesized.
Wherein the synthetic route of compound 158A is as follows
Using a similar synthetic procedure for compound 1G of example 1, compound 158B was substituted for compound 1C, compound 158C was substituted for 1D, the reaction solvent was substituted for N, N-dimethylformamide, and the reaction temperature was increased to 130 degrees celsius for 12 hours, and then a similar procedure was followed to synthesize compound 158A. MS (esi+) m/z=342.0 [ m+h ].
1 H NMR(400MHz,DMSO-d 6 )δ＝7.66(t,J＝7.6Hz,1H),7.36-7.24(m,2H),7.09(d,J＝8.0Hz,1H),6.92(d,J＝7.2Hz,1H),6.69(d,J＝8.0Hz,1H),3.70(s,3H),2.26(s,3H),1.31(s,12H).
Wherein the synthetic route of compound 159A is as follows
Compound 159A can be synthesized using a similar synthetic procedure as compound 1G of example 1, substituting compound 159B for compound 1D in step one. MS (esi+) m/z=234.9 [ m+h ].
1 H NMR(400MHz,DMSO-d 6 )δ＝8.66(d,J＝4.8Hz,2H),7.55(d,J＝8.0Hz,1H),7.51(d,J＝11.2Hz,1H),7.41(t,J＝7.2Hz,1H),7.32(t,J＝4.8Hz,1H),1.31(s,12H).
Example 46
(2S) -1- (4- (4- ((2S, 5R) -4-propenoyl-2, 5-dimethylpiperazin-1-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) cyclohex-3-ene-1-carbonyl) pyrrolidine-2-carbonitrile (162)
Referring to the synthetic route and method of example 39, compound 162F was synthesized using 162A instead of 81B and 55A instead of 1G.
Compound 162 was synthesized by the fifth and sixth synthetic steps and methods of example 17, substituting compound 162F for 55G of example 17.
MS(ESI+)m/z＝544.3[M+H].
1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.74-7.72(m,2H),7.44-7.43(m,1H),6.89-6.76(m,1H),6.18-6.13(m,1H),5.76-5.68(m,2H),4.77-4.72(m,1H),4.60-4.41(m,3H),4.16-4.12(m,1H),3.91-3.87(m,1H),3.79(s,3H),3.74-3.70(m,2H),3.62-3.55(m,2H),2.77-2.58(m,2H),2.32-2.26(m,3H),2.21-2.15(m,2H),2.05-1.91(m,5H),1.16-1.09(m,3H),1.04-0.96(m,3H).
Example 47
(R) -4-propenoyl-1- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -5-methylpiperazin-2-one (163)
First step (R) -4- (5-bromo-2-chloropyrimidin-4-yl) -2-methyl-5-carbonylpiperazine-1-carboxylic acid tert-butyl ester (163B)
Compound 163A (84 mg,0.4 mmol) was dissolved in 3mL dioxane and sodium hydride (32 mg,60%,0.8 mmol) was added with stirring at 0deg.C. After stirring the resulting mixture at 0℃for 30 minutes, 2, 4-dichloro-5-bromopyrimidine 81A (123 mg,0.5 mmol) was added and stirring was continued at 0℃for 1 hour. After the reaction solution was quenched with 1mL of saturated ammonium chloride solution, 20mL of saturated sodium chloride solution was added, and extracted 3 times with 20mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-1/2) to give compound 163B (89 mg, yield: 55%).
MS(ESI+)m/z＝405.0,407.0[M+H].
Compound 163 was synthesized using similar experimental procedures and procedures as the second to fifth steps of example 39, substituting compound 163B for 81C.
MS(ESI+)m/z＝544.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.83(s,1H),8.54–8.45(m,2H),7.87(s,1H),7.54(s,1H),7.35(d,J＝11.6Hz,1H),7.28(s,1H),7.19(d,J＝5.0Hz,2H),6.72(d,J＝64.7Hz,1H),5.65(s,1H),4.73(d,J＝57.0Hz,1H),4.20(d,J＝84.4Hz,3H),3.86–3.78(m,3H),3.70(t,J＝20.6Hz,1H),2.42(s,3H),1.22(s,4H).
Example 48
1- (4- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -3, 6-dihydropyridin-1 (2H) -yl) prop-2-en-1-one (164)
First step 4- (2-chloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (164B)
Compound 60B (0.35 g,1.0 mmol), compound 164A (0.40 g,1.3 mmol), potassium carbonate (0.34 g,2.4 mmol) and (diphenylphosphino ferrocene) palladium dichloride (70 mg,0.10 mmol) were added to a mixed solvent of dioxane (5 mL) and water (0.5 mL), and after three nitrogen substitutions, the mixture was stirred at 100℃for 2 hours. The reaction mixture was quenched with 10mL of ammonium chloride, extracted with 20mL of ethyl acetate, and the organic phase was separated and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-1/1) to give compound 164B (270 mg, yield: 54%).
MS(ESI+)m/z＝498.2[M+H].
Compound 164 can be synthesized using similar experimental procedures and procedures as the third through fifth steps of example 39, substituting compound 164B for 81D.
MS(ESI+)m/z＝513.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.65(s,1H),8.49(d,J＝5.0Hz,1H),8.42(s,1H),7.88(s,1H),7.53(s,1H),7.39(t,J＝8.3Hz,2H),7.30–7.14(m,2H),6.86(dd,J＝16.6,10.4Hz,1H),6.12(dd,J＝16.6,2.4Hz,1H),5.86(s,1H),5.68(d,J＝10.4Hz,1H),4.16–3.97(m,2H),3.82(s,3H),3.66(s,2H),2.48–2.29(m,5H).
Example 49
By a similar procedure and step in the synthesis of compound 164, starting material L in the table below was substituted for 164A in the first step, and the corresponding compounds 165-166 in the table below were synthesized.
Example 50
N- (3- (2-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) acryloylamide (167)
The first step: 3- (2-chloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) aniline (167B)
Compound 60B (3.0 g,8.5 mmol), compound 167A (1.9 g,8.5 mmol) and (diphenylphosphino ferrocene) palladium dichloride (0.38 g,0.51 mmol), potassium carbonate (2.4 g,17 mmol) were dissolved in dioxane (35 mL) and water (3.5 mL). The obtained mixture is reacted for 2 hours in a nitrogen environment at 100 ℃ and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to give compound 167B (0.40 g,0.98mmol, yield: 11%).
MS(ESI+)m/z＝407.9[M+H].
And a second step of: 4- (3-aminophenyl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-2-amine (167C)
Compound 167B (0.4 g,0.98 mmol) was placed in a pressure-resistant reaction tube, and a methanol solution of ammonia (7 mol/L,6 mL) was added. The resulting solution was stirred at 60 degrees celsius for 16 hours with closed stirring. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=3/1-1/2) to give compound 167C (0.11 g,0.28mmol, yield: 29%).
MS(ESI+)m/z＝389.2[M+H].
And a third step of: n- (3- (2-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) acryloylamide (167)
Compound 167C (0.10 g,0.26 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (78 mg,0.77 mmol) was added. Acryloyl chloride (19 mg,0.21 mmol) was added at 0deg.C. The reaction was stirred at 0℃for 1 hour. The reaction solution was concentrated, and the crude product was purified by preparative high performance liquid chromatography (mobile phase: 25% -55% acetonitrile aqueous solution (containing 0.1% formic acid)) to give 167 (17 mg, yield: 15%) as a solid.
MS(ESI+)m/z＝443.0[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),8.45(d,J＝5.2Hz,1H),8.36(s,1H),7.83(s,1H),7.72-7.66(m,1H),7.23(dt,J＝8.2,6.4Hz,2H),7.19-7.11(m,2H),6.98-6.85(m,4H),6.47-6.38(m,1H),6.29-6.20(m,1H),5.78-5.72(m,1H),2.40(s,3H).
Example 51
N- (3- (2-amino-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) -2-methylphenyl) acryloylamide (168)
Compound 168 was synthesized using a similar synthetic method and procedure as example 50, substituting compound 168A for compound 167A.
MS(ESI+)m/z＝457.0[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),8.46(d,J＝5.2Hz,1H),8.33(s,1H),7.72(s,1H),7.26(t,J＝8.4Hz,1H),7.21-7.09(m,3H),6.96(d,J＝8.2Hz,1H),6.92(d,J＝8.0Hz,1H),6.87(s,2H),6.52(dd,J＝17.6,10.4Hz,1H),6.23(dd,J＝16.8,1.6Hz,1H),5.74(d,J＝9.6Hz,1H),2.41(s,3H),2.20(s,3H).
Example 52
N- (3- (2-hydroxy-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) phenyl) acryloylamide (169)
Compound 169 was synthesized using a similar synthetic method and procedure as the second and third steps of example 50, substituting 7mol/L ammonia in methanol with 1.0mol/L sodium hydroxide in dioxane/water (1/1, v/v).
MS(ESI+)m/z＝444.1[M+H].
Example 53
The corresponding compounds 170-174 in the tables can be synthesized by a similar method and procedure as the first to fourth steps in example 39, substituting the compound 81B in the first step with the starting material I in the table below, and then substituting the compound 63A therein with the starting material M in the table below in the fifth step by a similar method and procedure as in example 41.
Example 54
2-fluoro-N- (5- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) pyri-din-3-yl) acryloylamide (181)
First step 5- (2-chloro-5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) pyrimidin-4-yl) pyridin-3-amine (181B)
Compound 60B (1.5 g,4.3 mmol), compound 181A (0.94 g,4.3 mmol), potassium carbonate (2.2 g,17 mmol) and (diphenylphosphino ferrocene) palladium dichloride (0.62 g,0.85 mmol) were mixed in 1, 4-dioxane (20 mL) and water (2 mL). The resulting mixture was stirred at 100 degrees celsius for 2 hours under nitrogen atmosphere. Cooled to room temperature, water (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was subjected to preparative high performance liquid chromatograph (Waters Xbridge C18,20-60% acetonitrile in water (0.01% aqueous ammonia)), to give compound 181B (0.67 g, yield: 38%).
MS(ESI+)m/z＝409.1[M+H]
Second step 4- (5-Aminopyridin-3-yl) -5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (181C)
Compound 118B (0.52 g,1.3 mmol), compound 60E (0.24 g,2.5 mmol), and p-toluenesulfonic acid (0.22 g,1.3 mmol) were dissolved in N-methylpyrrolidone (4 mL). The resulting mixture was placed under microwave 140 degrees celsius with stirring to react for 1 hour. Cooled to room temperature, water (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative high performance liquid chromatography (Waters Xbridge C18,20-60% acetonitrile in water (0.01% aqueous ammonia)), to give compound 181C (67 mg, 11% yield).
MS(ESI+)m/z＝470.3[M+1].
Third step 2-fluoro-N- (5- (5- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) pyridin-3-yl) acryloylamide (181)
Compound 181C (10 mg,0.021 mmol) was dissolved in dichloromethane (2 mL) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (16 mg,0.042 mmol), compound 63A (1.9 mg,0.021 mmol) and N, N-diisopropylethylamine (8.1 mg,0.063 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under the reduced pressure, and the crude product was purified by preparative high performance liquid chromatograph (Waters Xbridge C18,20-60% aqueous acetonitrile (containing 0.01% aqueous ammonia)) to give compound 181 (2.4 mg, yield: 21%).
MS(ESI+)m/z＝542.2[M+H].
1 H NMR(400MHz,DMSO-d 6 )δ10.70(s,1H),9.86(s,1H),8.82(s,1H),8.80-8.61(m,1H),8.58(s,1H),8.46(d,J＝5.2Hz,1H),8.15(s,1H),8.06(s,1H),7.54(s,1H),7.38-7.26(m,2H),7.19(d,J＝5.2Hz,1H),7.06(d,J＝6.4Hz,1H),5.85-5.68(m,1H),5.51(dd,J＝15.2,3.6Hz,1H),3.84(s,3H),2.42(s,3H).
Biological evaluation
The following further description explains the application in connection with test examples, which are not meant to limit the scope of the application.
Test example 1 FGFR enzyme inhibition test of the Compound of the present application
Control positive compound BGJ398 used in the experiment was purchased from Selleck cat No. S2183. Test compound samples were dissolved in DMSO to make 10mM stock solutions and stored at-30 ℃.
The enzyme reaction was carried out using an enzyme reaction Kit (FGFR 1 Kit accession number V2991, FGFR2 Kit accession number V4060, FGFR3 Kit accession number VA7459, reaction substrate Poly E4Y 1) produced by Promega company according to the method recommended by the manufacturer. As a reaction product, ADP detection kit (ADP-Glo) manufactured by Promega corporation was used TM Kinase Assay, cat# V9101).
The reaction system contained 0.4 ng/. Mu.L in 5. Mu.LLGFR 1 kinase (or 1.4 ng/. Mu.L FGFR2 (WT (wild-type) or V564F mutant) kinase, or 1 ng/. Mu.L FGFR3 kinase), 0.2. Mu.g/. Mu.L Poly E4Y1, 5. Mu.M ATP, and gradient diluted test compound. The final concentration of DMSO in the reaction system was 1%. Reactions were performed in 384 well plates (Perkinelmer, cat.6007290), all assays were double multiplexed. In the above system, ATP is finally added to start the reaction. The 384-well reaction plate was allowed to react at 25℃for 60 minutes, then 5. Mu.L of ADP-Glo was added thereto, and the reaction was carried out at 25℃for 40 minutes, and then 10. Mu.L of detection buffer (buffer) was added thereto, and the reaction was carried out at 25℃for 30 minutes. After completion of the reaction, a Luminescence value was measured by Perkinelmer Envision. The Luminescence value represents the amount of ADP produced, the inhibition rate of kinase activity was calculated by high signal (Luminescence value without enzyme addition), low signal (low signal) (Luminescence value without enzyme addition), sample signal (sample signal) (Luminescence value with enzyme addition), and half Inhibition Concentration (IC) was calculated by XLfit2.0 software (ID Business Solutions Ltd) 50 )。
The inhibition ratio = (high signal-sample signal)/(high signal-low signal) ×100%.
The in vitro activity of the compound of the embodiment of the invention on the wild FGFR2 enzyme is measured by the test, and the measured IC 50 The values are shown in Table 1.
TABLE 1
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
1 62.6 79 63.9 134 32.3
8 69.3 80 5.1 135 8.3
12 85.5 81 9.5 136 59.6
18 92.6 82 124.0 137 130.6
20 124.7 83 164.1 138 27.4
45 175.4 84 8.1 139 80.1
47 94.8 89 80.2 140 44.4
50 179.5 90 40.4 141 154.8
57 194.8 93 88.7 142 63.3
60 27.5 96 135.9 143 47.3
64 9.9 97 137.2 145 17.7
65 13.2 98 26.1 146 12.6
66 30.2 99 152.0 147 8.6
67 16.6 105 123.5 148 42.7
68 18.0 109 8.7 149 48.9
69 23.2 114 69.8 150 179.7
70 175.2 115 104.1 156 72.9
71 37.8 118 140.4 159 52.5
72 25.8 119 94.6 164 8.7
74 43.1 120 127.1 167 178.3
75 189.6 130 17.2 170 120.7
76 11.5 132 34.4 174 56.6
77 11.5 133 151.8 181 149.0
The in vitro activity of the compound of the embodiment of the invention on the V564F mutant FGFR2 enzyme is measured by the test, and the IC is measured 50 The values are shown in Table 2.
TABLE 2
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
1 104.2 8 105.2 43 200.4
50 125.9 60 11.6 65 13.4
67 15.6 69 22 71 55.7
72 12.5 76 14.6 77 14.8
78 22 79 105.2 80 11.9
81 19.8 84 43.8 89 151.6
90 19.6 93 61.3 96 131.6
98 23 99 35.2 105 21.1
109 11.1 114 41.4 115 43.6
118 142.1 119 62.2 130 15.8
132 25 133 82.4 134 22.8
135 9.1 136 35.9 138 16.6
139 75.4 140 37.4 141 161.5
142 146.2 143 101 144 136.4
145 11.9 146 16.7 147 16.3
148 24 149 28.1 154 29.4
156 47.5 159 34 162 181.2
163 201.2 163 56.1 164 16.6
170 125 174 20.4 BGJ398 >1000
Test example 2 cell proliferation assay of the Compounds of the invention
Test compound samples were dissolved in DMSO to make 10mM stock solutions and stored at-30 ℃. At the time of assay, the compounds were diluted to 10 times the assay concentration in serum-free medium containing 5% dmso.
In the experiment cell SNU-16 was purchased from ATCC (American Type Culture Collection, USA, cat#)CRL-5974), RT-112 from cobioer (Nanjac Bai Biotech Co., ltd., product No. CBP 60316), KG-1 from ATCC (product No. CCL-246), JMSU-1 from DSMZ (product No. ACC 505). Medium IMDM was purchased from Gibco (accession number 12440-061), medium 1640 was purchased from Gibco (accession number 12634-010), and serum was purchased from Gibco (accession number 10099-141C). Cell-counting kit-8 (CK 04) was purchased from Tonic chemical Co.Luminescent Cell Viability Assay from Promega (cat# G7570).
Cells in the logarithmic growth phase were inoculated into 96-well cell culture plates in a volume of 100. Mu.L. Incubated overnight at 37℃in an incubator containing 5% carbon dioxide. The next day, add 10. Mu.L/well gradient dilutionTest compound, control group was added with 10 μl/well of serum-free medium containing 5% DMSO instead of drug dilution, the final concentration of DMSO was 0.5%. The cells were incubated in an incubator for 72 hours. mu.L/well of Cell-counting kit-8 reagent (or 50. Mu.L/well CTG) was added. Incubation was performed in a carbon dioxide incubator at 37℃for 40 minutes, and the absorbance at 450nm was read on Perkinelmer Envision (CTG read Lumineancece). The inhibition rate of the compound on cell growth was calculated according to the following formula, and the half proliferation inhibition concentration (GI) of the drug was calculated using xlfit2.0 software 50 )。
Inhibition (%) = [1- ([ OD ] 450 ] Compounds of formula (I) -[OD 450 ] Background )/([OD 450 ] Cells -[OD 450 ] Background )]×100％
Wherein:
[OD 450 ] compounds of formula (I) Representing the optical density value of the compound-treated wells;
[OD 450 ] cells Representative of the optical density values on day 3 of the cell well with DMSO instead of compound;
[OD 450 ] background Optical density values representing day 0 of the cell well with DMSO instead of compound;
the compound of the present invention was measured in the cell proliferation assay by the above assay, and the GI was measured 50 The values are shown in Table 3.
TABLE 3 Table 3
"-" means not tested
Test example 3 blood stability test of the Compound of the present invention
The stability of the compounds of the invention in whole blood was assessed by measuring the residual percentage of the tested compounds in SD rat or human blood (containing EDTA-K2 anticoagulant) at various time points by liquid chromatography tandem mass spectrometry (LC/MS/MS).
398 μl of blood was added to the wells of the culture plate and pre-treated at 37 degrees celsius for 15 minutes. mu.L of the test compound (1 mmol/L DMSO solution) or the positive compound (1 mmol/L DMSO solution) was added to 398. Mu.L of blood after pretreatment and mixed so that the final concentration of the test compound (or positive compound) was 5. Mu.M and the final concentration of the organic solvent was 0.5%. Two tests were performed for each test compound or positive compound. The resulting mixture samples were incubated at 37 degrees celsius. At 0, 15, 30, 60, 120, 240 minutes of reaction, 50uL of each sample was taken, and the reaction was terminated by adding 50uL of ultrapure water and 400 uL of cold acetonitrile containing an internal standard compound (0.5 uM tolbutamide). All samples were vortexed for 10 minutes and centrifuged at 3220g for 30 minutes to pellet the protein. 200. Mu.L of the supernatant was subjected to LC-MS/MS analysis.
All calculations were performed using Microsoft Excel. The peak area ratio is determined from the extracted ion chromatogram. The percentage of remaining compounds at each time point was calculated from the following formula:
Residual percentage t min (%) =peak area ratio t min Peak area ratio 0 min x 100％
Wherein the peak area ratio t min Peak area ratio for test compound (or positive compound) and internal standard compound at t min time point;
peak area ratio 0 min Peak area ratio of the test compound (or positive compound) and the internal standard compound at the 0 minute time point.
The slope value k is determined by natural log linear regression of the residual percentage of the compound tested versus the incubation time curve.
In vitro half-life (in vitro t) 1/2 ) Determined by the slope value k:
in vitro t 1/2 ＝-(0.693/k)
the half-lives measured in SD rat or human blood of the compounds of the present invention are shown in Table 4.
TABLE 4 stability of the compounds of the invention in SD rat and human blood
"-" means not tested
Test example 4 CYP enzyme inhibition test of the Compounds of the invention
Representative substrate metabolic reactions of the human major 5 CYP subtypes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6, CYP3 A4) were assessed using 150 donor mixed human liver microsomes (available from Corning under accession number 452117). The effect of different concentrations of the compound to be tested on the metabolic reactions of phenacetin (CYP 1A 2), diclofenac sodium (CYP 2C 9), S-mefenacet (CYP 2C 19), bufuralol hydrochloride (CYP 2D 6) and midazolam (CYP 3A 4) is measured by liquid chromatography tandem mass spectrometry (LC/MS/MS).
mu.M of phenacetin, 10. Mu.M of diclofenac sodium, 35. Mu. M S-mefenacet, 5. Mu.M of bufuralol hydrochloride, 3. Mu.M of midazolam, 1mM of reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH), test compounds (concentrations of 0.1, 0.3, 1, 3, 10, 30. Mu. Mol/L, respectively) or positive compounds or blank were incubated with 200. Mu.L (100 mmol/L phosphate buffer, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, 0.1% methanol, respectively) of a reaction system mixing human liver microsomes (0.2 mg/mL) at 37℃for 5 minutes. 200. Mu.L of acetonitrile containing 3% formic acid and 40nM of internal standard verapamil was then added and centrifuged at 4000rpm for 50 minutes. Cooling on ice for 20 min, and centrifuging at 4000rpm for 20 min to precipitate protein. 200. Mu.L of the supernatant was subjected to LC-MS/MS analysis.
Peak areas were calculated from chromatograms. The residual activity ratio (%) was calculated using the following formula:
peak area ratio = metabolite peak area/internal standard peak area
Residual activity ratio (%) =peak area ratio of test compound group/peak area ratio of blank group
CYP half-maximal Inhibitory Concentration (IC) 50 ) Calculated by Excel XLfit 5.3.1.3.
Measurement of the CYP half Inhibition Concentration (IC) of the Compound of the invention 50 ) The values are shown in Table 5.
TABLE 5 half inhibition concentration of CYP by the compounds of the invention (IC 50 )
Test example 5, caco-2 permeability experiment
Determination of apparent permeability coefficient (P) of analytical drugs by Caco-2 cell model using liquid chromatography tandem mass spectrometry (LC-MS/MS) app )。
In this test example, caco-2 cells were purchased from American Type Culture Collection (ATCC), HEPES was purchased from Beijing Soilebao technologies Co., ltd., hank's Balanced Salt Solution (HBSS) and nonessential amino acids (NEAA) were purchased from Semer Feishmania technologies Co., penicillin, streptomycin and trypsin/EDTA were purchased from Soilebao, fetal Bovine Serum (FBS) and DMEM medium were purchased from Corning Co., HTS-96 well Transwell plates and other sterile consumables were purchased from Corning Co., millicell resistance measurement systems were purchased from Millipore,purchased from Nexcelom Bioscience, infinite 200 PRO microplate reader from Tecan, MTS2/4 orbital shaker from IKA Labortechnik.
First step cell culture and seed plate
Caco-2 was cultured in cell culture flasks. The incubator was set at 37℃with 5% CO 2 Ensuring the relative humidity to be 95 percent. The cell confluence reaches 70-90% and can be used for inoculation of Transwell. Before cell seeding, 50. Mu.L of cell culture medium was added to each well of the Transwell upper chamber, and 25mL of cell culture medium was added to the lower plate. The plates were placed at 37℃with 5% CO 2 After incubation in the incubator for 1 hour, it can be used to inoculate cells. After cell digestion, the aspirated cell suspension was transferred to a round bottom centrifuge tube 120g for 5 minutes. Cells were resuspended using medium at a final concentration of 6.86×10 5 cells/mL (individual cells/mL). The cell suspension was added to the upper chamber of a 96-well Transwell plate at 50. Mu.L per well and the final seeding density was 2.4X10 5 cells/cm 2 . The medium was changed at intervals of one day after the culture for 14-18 days after the inoculation for 24 hours. The medium exchange procedure was as follows, the Transwell cells were separated from the receiving plate, medium was discarded from the receiving plate and then from the Transwell cells, and finally 75. Mu.L fresh medium was added to each cell and 25mL fresh medium was added to the receiving plate.
Evaluation of the integrity of the cell monolayer in the second step
Caco-2 reached confluence and completed differentiation after approximately 14 days of culture. At this time, it can be applied to a penetration test. The single layer film resistance was measured with a resistance meter (Millipore, USA) and the resistance per well was recorded. After the measurement, the Transwell plates were returned to the incubator. Calculating the resistance value: measurement of resistance value (ohms). Times.membrane area (cm) 2 ) TEER value (ohm cm) 2 ) If TEER value<230ohms·cm 2 The well cannot be used for penetration testing.
Third step of solution preparation
2.38g HEPES,0.35g sodium bicarbonate was weighed separately, dissolved by adding 900mL of pure water, then stirred well by adding 100mL of 10XHBSS, adjusted to pH 7.4, and finally filtered to give 1L of transport buffer (HBSS, 10mM HEPES,pH 7.4).
1mM stock solution of the test compound in DMSO was diluted with transport buffer to give a 5. Mu.M test solution. The control compound digoxin or minoxidil was diluted to 2mM with DMSO and the transport buffer described above was used to 10. Mu.M to give a control compound test solution. In addition, DMSO was also diluted with the transport buffer to a receiver solution containing 0.5% DMSO.
Fourth step drug penetration test
The Transwell plates were removed from the incubator. The cell monolayer was rinsed twice with transport buffer (10mM HEPES,pH 7.4) buffer and incubated at 37℃for 30 min.
The transport rate of the compound from the apical to basal end was determined. 125 μl of test solution was added to each well of the upper chamber (tip) and immediately transferred from the tip to 200 μl of acetonitrile (0.1 μl M toluene sulfobutylurea) containing internal standard as the initial sample from tip to base. The lower chamber (substrate end) was charged with 235 μl of receiver solution per well.
The rate of transport of the compound from the substrate end to the top end was determined. 285 μl of receiver solution was added to each well of the upper chamber (top) and immediately transferred from the top to 200 μl of acetonitrile containing internal standard (0.1 μl toluene sulfobutylurea) as a substrate to top initial sample. The lower chamber (substrate end) was charged with 75 μl of test solution per well.
After combining the upper and lower transfer devices, incubation was performed at 37℃for 2 hours.
After incubation was completed, 50 μl samples were taken from each well of the Transwell plate upper and lower chambers, respectively, and added to new sample tubes. 200. Mu.L of acetonitrile containing an internal standard (0.1. Mu.M tolbutamide) was added to the sample tube, vortexed for 10 minutes and centrifuged at 3220g for 40 minutes. The supernatant was aspirated at 150. Mu.L and diluted with 150. Mu.L water before LC-MS/MS analysis. All samples were prepared in triplicate.
The integrity of the cell monolayer after 2 hours incubation was assessed by leakage of the fluorescein, and the fluorescein stock was diluted to a final concentration of 100 μm using transport buffer (10mM HEPES,pH 7.4). 100. Mu.L of fluorescent yellow solution was added to each well of the upper Transwell plate, and 300. Mu.L of transport buffer solution (10mM HEPES,pH 7.4) was added to each well of the lower receiving plate. After incubation at 37 ℃ for 30 minutes, 80 μl of solution was aspirated from each well upper and lower layer into a new 96-well plate. Fluorescence measurement was performed using an enzyme-labeled instrument at excitation wavelength 485nm and emission wavelength 530 nm.
Fifth step data analysis all calculations were performed using microsoft Excel. The peak area was determined by using the extracted ion chromatogram.
Apparent permeability coefficient (P) app Units: cm/s.times.10 -6 ) Calculated by the following formula：
In the formula: v (V) A To the volume of the receiving side solution (Ap. Fwdarw.Bl is 0.3mL, bl. Fwdarw.Ap is 0.1 mL), the Area (membrane Area) was the Transwell-96 well plate membrane Area (0.143 cm) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the time (time) is incubation time (unit: s); [ drug ]] receiver ([ medicine ]] Receiving terminal ) Drug concentration at the receiving end; [ drug ]] initial，donor ([ medicine ]] Initially, donor ) Initial drug concentration at the drug administration end.
The Efflux rate (Efflux ratio) is calculated using the following formula:
in the formula: p (P) app(B-A) Is the apparent permeability coefficient from the base end to the top end;
P app(A-B) is the apparent permeability coefficient from the top end to the bottom end of the substrate.
Recovery ("Percentage recovery" (%) was calculated using the following equation:
in the formula: v (V) A The volume of solution at the receiving end (unit: mL); v (V) D To give the end of the solution volume (unit: mL) [ drug ]] donor ([ medicine ]] Donor(s) ) Is the drug concentration at the administration end.
The leak rate (Percentage leakage (%) or LY (%)) is calculated using the following formula:
in the formula: i receiver (I Receiving terminal ) Refers to the fluorescence density of the receiving well (0.3 mL), I donor (I Donor(s) ) Refers to the fluorescence density of the drug-loaded wells (0.1 mL). LY (LY)<1.5% indicates that the monolayer cell membrane is intact. For individual LY>1.5% in case of P app Values and other parallel approaches, based on scientific judgment, final data can be adopted.
Caco2 permeability data obtained from testing the compounds of the present invention are shown in Table 6 below.
TABLE 6 Caco2 permeability data for the compounds of the invention
Numbering of compounds Papp (A-B) (10 -6 ,cm/s) Papp (B-A) (10 -6 ,cm/s) Efflux Ratio
8 0.90 15.4 17.2
34 0.50 27.1 54.7
78 0.71 5.0 7.0
83 1.45 19.5 13.5
84 0.59 32.0 54.4
89 0.53 30.6 58.3
90 0.85 14.6 17.3
93 1.20 20.2 16.9
98 3.10 12.4 4.0
99 3.75 19.9 5.4
105 1.47 23.7 16.1
109 0.89 17.8 20.2
114 1.27 6.5 5.1
115 1.76 21.2 12.1
118 0.55 24.1 44.2
119 1.62 23.9 14.9
120 1.75 18.8 10.8
142 0.39 23.6 60.2
143 0.40 28.7 71.2
144 0.70 13.0 18.8
154 2.08 6.2 3.0
164 1.99 18.0 9.2
Test example 6 in vivo pharmacokinetic testing of Compounds of the invention in rats
The concentration of the drug in plasma was determined by LC/MS using SD rats as the test animals at various times after intravenous injection and intragastric administration of the compounds of the present invention. The pharmacokinetic behavior of the compound of the invention in rats was studied and its pharmacokinetic profile was evaluated.
3 male SD rats were healthy for 6-8 weeks in each group.
Intravenous administration: weighing a certain amount of medicine, adding 10% of N, N-dimethylacetamide, 33% of triethylene glycol and 57% of physiological saline to prepare colorless clear transparent liquid of 1 mg/mL;
gastric lavage administration: a certain amount of the medicine is weighed, and 0.5% of hydroxypropyl methylcellulose, 0.1% of Tween 80 and 99.6% of physiological saline are added to prepare a white suspension of 1 mg/mL.
SD rats were administered intravenously or intragastrically after overnight fast.
Rats were given the compounds of the invention by intravenous injection, 0.2mL of blood was collected from the jugular vein 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration, and the plasma was isolated by centrifugation at 4000 rpm for 5 minutes at 4℃in a tube containing EDTA-K2 and stored at-75 ℃.
Or the compound of the invention is administrated by lavage of rats, 0.2mL of the compound is collected from jugular vein 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, and the compound is placed in a test tube containing EDTA-K2, centrifuged at 3500 revolutions per minute for 10 minutes at 4 ℃ to separate plasma, and the plasma is preserved at-75 ℃.
Determination of the content of the test compound in rat plasma after intravenous injection or drug gavage administration at different concentrations: rat plasma was taken at 30. Mu.L at each time after dosing, 200. Mu.L (50 ng/mL) of acetonitrile solution of the internal standard dexamethasone was added, vortexed for 30 seconds, centrifuged at 4℃at 4700 rpm for 15 minutes, and the plasma sample was taken as a supernatant diluted three times with water and 2.0. Mu.L was taken for LC-MS/MS analysis.
The in vivo pharmacokinetic parameters of the compounds of the invention in rats are shown in table 7 below:
TABLE 7 in vivo pharmacokinetic results of SD rats of the compounds of the invention
IV represents intravenous administration; PO represents intragastric administration.

Claims (21)

  1. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof,
    x, Z are each independentGround is selected from CR 9 Or N;
    w is selected from O or C (=o);
    y is selected from C (=O), NHC (=O), C (=O) NH, N (CH) 3 ) Or a bond;
    ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl;
    ring B is selected from C 6 -C 10 Aryl, 5-to 10-membered heteroaryl or C 3 -C 10 Cyclic hydrocarbon groups;
    e is selected from C 3 -C 10 Cyclic hydrocarbon radicals, C 6 -C 10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, said C 3 -C 10 Cyclic hydrocarbon radicals C 6 -C 10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R 1a Substitution;
    R 1a independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, -S (=o) -C 1 -C 4 Alkyl, -S (=o) 2 -C 1 -C 4 Alkyl group,-S(＝O)(＝NR 8a )R 8b 、-N＝S(＝O)R 8a R 8b 、-NR 8a R 8b 、-C(＝O)NR 8a R 8b or-NR 7 C(＝O)R 8b The C is 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, -S (=o) -C 1 -C 4 Alkyl or-S (=o) 2 -C 1 -C 4 Alkyl groups optionally being independently selected from one or more of halogen, OH, C 1 -C 3 Substitution of an alkoxy group or a group of CN;
    R 1 selected from-CN, - (CH) 2 ) q CN、-C≡CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-S(＝O)CR 6 ＝C(R 5 ) 2 、-S(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NHS(＝O)CR 6 ＝C(R 5 ) 2 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 ；
    R 5 Independently selected from H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-12 membered heterocyclyl or C 6 -C 10 Aryl, said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-12 membered heterocyclyl or C 6 -C 10 Aryl is optionally substituted with one or more R 5a Substitution;
    R 5a independently selected from halogen, CN, N (R) 5b ) 2 、OH、NO 2 、C 3 -C 8 Cycloalkyl or 3-12 membered heterocyclyl;
    R 5b independently selected from H or C 1 -C 6 An alkyl group;
    R 6 selected from H, CN, halogen or C 1 -C 6 An alkyl group;
    R 7 selected from C 1 -C 6 Alkylene, C 3 -C 8 Cycloalkylene or 3-12 membered heterocyclylene;
    R 2 selected from H, NH 2 、C 1 -C 6 Alkyl, OH or halogen;
    R 3 independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 3 - 8 Cycloalkyl;
    R 4 independently selected from halogen, CN, NH 2 、OH、NO 2 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, -C (=o) R 8a 、-C(＝O)O R 8a 、-NR 8a R 8b 、-C(＝O)N R 8a R 8b or-NR 7 C(＝O)R 8b The C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with one or more R 4a Substitution;
    R 4a independently selected from halogen, CN, NH 2 OH or C 1 -C 6 An alkyl group;
    R 8a 、R 8b each independently selected from H, halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkyl group;
    R 9 selected from H, CN, OH, NH 2 、-NHR 10 、-NH-C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl group, the C 1 -C 6 Alkyl, -NH-C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl optionally substituted with one or more R 10 Substitution;
    R 10 independently selected from halogen, NH 2 、C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl, said NH 2 、C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more R 11 Substitution;
    R 11 independently selected from C 1 -C 6 Alkyl, halogen, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl, said C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl or 3-10 membered heterocyclyl optionally being C 1 -C 6 Alkyl, halogen, OH, -NH-C 1 -C 6 Alkyl, -N (C) 1 -C 6 Alkyl group 2 Substitution;
    n, m are each independently selected from 0, 1, 2 or 3;
    q is selected from 1, 2 or 3.
  2. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1, wherein: ring A is selected from 5-6 membered heteroaryl or 5-6 membered heterocyclyl; or alternatively
    Ring a is selected from 5-6 membered heteroaryl; or alternatively
    Ring a is selected from pyrimidinyl, pyridinyl or tetrahydropyrrolyl.
  3. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 or 2, wherein: ring B is selected from C 6 -C 10 Aryl or C 3 -C 10 Cyclic hydrocarbon groups; or alternatively
    Ring B is selected from phenyl or cyclohexenyl; or alternatively
    Ring B is selected from phenyl.
  4. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein: e is selected from C 3 -C 6 Cyclic hydrocarbon radicals, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3 -C 6 Cyclic hydrocarbon radicals, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 1a And (3) substitution.
  5. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein: r is R 1a Independently selected from halogen, CN, NH 2 、OH、-NR 8a R 8b 、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy group, the C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy groups optionally being independently selected from one or more of halogen, OH or C 1 -C 3 Substitution of the alkoxy group; or alternatively
    R 1a Independently selected from halogen, CN, NH 2 、OH、C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy group, the C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy groups optionally being independently selected from one or more of halogen, OH or C 1 -C 3 Substitution of the alkoxy group; or alternatively
    R 1a Independently selected from halogen, -NR 8a R 8b 、C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy group, the C 1 -C 6 Alkyl groups optionally being independently selected from one or more of halogen, OH, CN or C 1 -C 3 The groups of the alkoxy groups are substituted.
  6. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein: r is R 1 Selected from-C.ident.CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-S(＝O)CR 6 ＝C(R 5 ) 2 、-S(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NHS(＝O)CR 6 ＝C(R 5 ) 2 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively
    R 1 Selected from-CN, - (CH) 2 ) q CN、-C≡CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively
    R 1 Selected from-C.ident.CR 5 、-C(＝O)C≡CR 5 、-C(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 C(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)CR 6 ＝C(R 5 ) 2 、-R 7 NHC(＝O)CH＝C(R 5 ) 2 、-NHC(＝O)C≡CR 5 、-NHS(＝O) 2 CR 6 ＝C(R 5 ) 2 、-NR 6 C(＝O)CR 6 ＝C(R 5 ) 2 Or NHC (=o) R 5 。
  7. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 6, wherein: r is R 1 Selected from the following groups:
  8. a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein: r is R 2 Selected from H, NH 2 、CH 3 OH or halogen; or R is 2 Selected from H, NH 2 、CH 3 Or halogen.
  9. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein: r is R 3 Independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 A haloalkyl group; or R is 3 Independently selected from halogen or C 1 -C 6 An alkoxy group; or R is 3 Selected from halogen.
  10. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein: m is selected from 0 or 1.
  11. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, wherein: r is R 4 Independently selected from halogen, CN, NH 2 、OH、NO 2 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl, said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocyclyl optionally substituted with one or more R 4a Substitution; or alternatively
    R 4 Independently selected from CN, halogen, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; or alternatively
    R 4 Independently selected from CN or C 1 -C 6 An alkyl group.
  12. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein: n is selected from 0 or 1.
  13. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, wherein: r is R 9 Selected from H, CN, OH, NH 2 、-NHR 10 or-NH-C 1 -C 6 Alkyl, said-NH-C 1 -C 6 Alkyl is optionally substituted with one or more R 10 Substitution; or alternatively
    R 9 Selected from H, NH 2 、-NHR 10 、-NH-C 1 -C 6 Alkyl or C 1 -C 6 Alkyl, said C 1 -C 6 Alkyl or-NH-C 1 -C 6 Alkyl is optionally substituted with one or more R 10 And (3) substitution.
  14. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1-2 or 4-13, wherein: the compound shown in the formula (I) or the stereoisomer or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (II) or the stereoisomer or the pharmaceutically acceptable salt thereof,
  15. a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 or 3 to 13, wherein: the compound shown in the formula (I) or the stereoisomer or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (III) or the stereoisomer or the pharmaceutically acceptable salt thereof,
  16. a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 14 or 15, wherein: the compound shown in the formula (I) or the stereoisomer or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (IV) or the stereoisomer or the pharmaceutically acceptable salt thereof,
  17. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, wherein: the compound shown in the formula (I) or stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (V) or stereoisomer or pharmaceutically acceptable salt thereof,
  18. a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1, wherein: the compound shown in the formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds or the stereoisomer or the pharmaceutically acceptable salt thereof,
  19. a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18, and a pharmaceutically acceptable adjuvant.
  20. Use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 18, or a pharmaceutical composition as defined in claim 19, for the manufacture of a medicament for the prophylaxis or treatment of a disease associated with FGFR.
  21. Use according to claim 20, characterized in that: the FGFR-associated disease is selected from cancer.
CN202280024337.9A 2021-04-03 2022-04-01 Heterocyclic compounds as FGFR inhibitors and uses thereof Pending CN117222640A (en)

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