CN113135924B - Pyrimidine derivatives and their use in medicine - Google Patents

Pyrimidine derivatives and their use in medicine Download PDF

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CN113135924B
CN113135924B CN202110069859.8A CN202110069859A CN113135924B CN 113135924 B CN113135924 B CN 113135924B CN 202110069859 A CN202110069859 A CN 202110069859A CN 113135924 B CN113135924 B CN 113135924B
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CN113135924A (en
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习宁
李敏雄
吴双
廖敏
张涛
李晓波
席云龙
杨芳
陈疏影
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Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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Abstract

The invention discloses pyrimidine derivatives and application thereof in medicines, and in particular relates to novel pyrimidine derivatives and a medicine composition containing the same. The invention also relates to a method for preparing the compound and a pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparing medicines for treating KRAS G12C mediated diseases and/or symptoms, in particular to application in preparing medicines for treating cancers.

Description

Pyrimidine derivatives and their use in medicine
Technical Field
The invention belongs to the field of medicines, and particularly relates to novel compounds serving as KRAS activity inhibitors, a method for preparing the novel compounds, a pharmaceutical composition containing the novel compounds and application of the novel compounds and the pharmaceutical composition thereof in treating various diseases. More specifically, the compounds of the present invention may act as inhibitors of KRAS G12C activity or function.
Background
KRAS is a murine sarcoma virus gene, and there are three genes related to human tumor in ras gene family-H-ras, K-ras and N-ras, which are located on chromosomes 11, 12 and 1, respectively. The K-ras gene encodes a 21kD ras protein, also known as the p21 gene. Among RAS genes, K-RAS has the greatest effect on human cancers, accounting for 86% of all RAS mutations, as if it were molecular switching: the path for regulating and controlling the cell growth can be controlled when normal; when an abnormality occurs, it causes the cells to continue to grow and prevent the cells from self-destroying. It is involved in intracellular signaling, and when the K-ras gene is mutated, the gene is permanently activated and cannot produce normal ras protein, so that intracellular signaling is disturbed, and cell proliferation is out of control and cancerous.
The G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine No. 12 to cysteine. KRAS G12C mutations are most common in lung cancer, and according to literature (Nat Rev Drug Discov 2014; 13:828-851) report data, KRAS G12C mutations account for about 10% of all lung cancer patients.
Currently, researchers have conducted some research in an effort to find therapeutic agents that are effective in inhibiting KRAS G12C muteins. PCT application WO2014152588、WO2015054572、WO2016049524、WO2016164675、WO2016168540、WO2017015562、WO2017058915、WO2017058807、WO2017058792、WO2017058902、WO2017087528、WO2017201161、WO2018064510、WO2018068017、WO2018119183、WO2018140600、WO2018140512、WO2018143315、WO2018206539、WO2018217651、WO2018218070、WO2019051291、WO2019099524、WO2019110751、WO2019137985 and WO2019141250 disclose a number of small molecule compounds that are useful as KRAS G12C mutein inhibitors for the prevention or treatment of cancer. However, there remains a need for more and better KRAS G12C mutein inhibitors in the clinic.
Disclosure of Invention
The present invention provides a compound, or pharmaceutical composition thereof, that is useful as an inhibitor of KRAS. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or disorders by inhibiting KRAS activity by said compounds. The invention further describes a synthesis method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
Specifically:
In one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Wherein:
X is-L-X 1 -, wherein L is a bond or-NH-, and X 1 is a 4-12 membered saturated or partially unsaturated monocyclic, fused, spiro or bridged ring containing a nitrogen atom, which monocyclic, fused, spiro and bridged rings may independently be optionally substituted with m R x;
Y is
R 1 is -C(＝O)-CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rc or-S (=o) 2-C≡C-Rc;
R a and R b are each independently hydrogen, deuterium, a halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkoxy and 3-6 membered heterocyclyl;
W is a bond, -O- (CR mRn)p-、-S-(CRmRn)p -or-NR d-(CRmRn)p -;
R d is hydrogen, deuterium, C 1-3 alkyl or C 1-3 haloalkyl, wherein said C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1,2,3,4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
R 2 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 6-12 aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or-CR eRf-NRgRh, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 6-12 aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkoxy;
R m、Rn、Re and R f are each independently hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
r g and R h are each independently hydrogen, deuterium, C 1-3 alkyl or C 1-3 haloalkyl, wherein said C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy; or (b)
R f、Rg and the atoms to which they are attached together form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring may independently be optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
R 3 is C 6-12 aryl or 5-12 membered heteroaryl, wherein said C 6-12 aryl and 5-12 membered heteroaryl may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkoxy;
Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
Each R y is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl may independently be optionally substituted with 1, 2,3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
R i and R j are each independently hydrogen, deuterium, C 1-3 alkyl or C 1-3 haloalkyl, wherein said C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1,2, 3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy;
m is 0,1, 2,3, 4, 5, 6, 7 or 8;
n is 0,1, 2,3, 4, 5, 6, 7 or 8;
p is 0, 1, 2, 3, 4, 5 or 6.
In some embodiments, X is Wherein m and R x have the meanings as described in the present invention.
In some embodiments, R a and R b are each independently hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy groups are independently optionally substituted with 1, 2, 3,4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R c is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl groups may be independently optionally substituted with 1,2, 3, 4 or 5 groups selected from halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2OH、-OCH2CH2 OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and morpholinyl groups.
In some embodiments, R d is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl or difluoromethyl may independently be optionally substituted with 1,2, 3,4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R 2 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or-CR eRf-NRgRh, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy; wherein R e、Rf、Rg and R h have the meaning described in the present invention.
In some embodiments, R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CR eRf-NRgRh, wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl groups may be independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH; wherein R e、Rf、Rg and R h have the meaning described in the present invention.
In some embodiments, R m、Rn、Re and R f are each independently hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy groups are independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH;
R g and R h are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl may independently be optionally substituted with 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH; or alternatively
R f、Rg and the atoms to which they are attached together form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein the azetidine, pyrrolidine, piperidine ring, piperazine ring, and morpholine ring may independently be optionally substituted with 1,2, 3, 4, or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl and 5-10 membered heteroaryl may independently be optionally substituted with 1,2, 3,4, or 5 groups selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1-4 hydroxyalkoxy.
In some embodiments, R 3 is Wherein said/> May be independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In some embodiments, each R x is independently deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, each R y is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In some embodiments, each R y is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R i and R j are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups are independently optionally substituted with 1, 2, 3,4 or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In one aspect, the present invention relates to a pharmaceutical composition comprising a compound according to formula (I) of the present invention, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.
In one aspect, the invention relates to the use of a compound as described above or a pharmaceutical composition thereof for the manufacture of a medicament for preventing, treating or alleviating KRAS G12C-mediated diseases in a patient.
In some embodiments, the KRAS G12C-mediated disease of the present invention is cancer.
In some embodiments, the cancer of the invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, cholangiocarcinoma, breast cancer, colon cancer, leukemia, and melanoma.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds comprised by formula (I).
The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, and "March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"Stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
"Chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
"Enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
"Diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007).
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and other instances where it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
The term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with …," i.e., the structure is unsubstituted or substituted with one or more substituents described herein; when the number of the substituents is greater than 1, the substituents may be the same or different from each other. For example, "optionally substituted with 1, 2,3,4, or 5 groups selected from … …" as described herein, the substituents may be the same or different when the number of substituents is greater than 1.
An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, hydrogen, deuterium, oxo, halogen, cyano, nitro, hydroxy, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkynyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkanoyl, aryl acyl, heteroaryl acyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylacyloxy, carboxy, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, and the like.
In addition, unless explicitly indicated otherwise, the description used in this disclosure of the manner in which "each … is independently" and "… is independently" and "… is independently" are to be understood in a broad sense as meaning that the particular choices expressed between the same symbols in different groups do not affect each other, or that the particular choices expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in some embodiments, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), n-propyl (n-Pr, -CH 2CH2CH3), isopropyl (i-Pr, -CH (CH 3)2), n-butyl (n-Bu, -CH 2CH2CH2CH3), isobutyl (i-Bu, -CH 2CH(CH3)2), sec-butyl (s-Bu, -CH (CH 3)CH2CH3), tert-butyl (t-Bu, -C (CH 3)3), n-pentyl (-CH 2CH2CH2CH2CH3), 2-pentyl (-CH (CH 3)CH2CH2CH3), 3-pentyl (-CH (CH 2CH3)2), 2-methyl-2-butyl (-C (CH 3)2CH2CH3), 3-methyl-2-butyl (-CH (CH 3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH 2CH(CH3)CH2CH3), n-hexyl (-CH 2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH 3)CH2CH2CH2CH3), 3-hexyl (-CH (CH 2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH 3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH 3)CH(CH3)CH2CH3), 3-methyl-2-butyl (-CH 3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C (CH 3)(CH2CH3)2), 2-methyl-3-pentyl (-CH (CH 2CH3)CH(CH3)2), 2, 3-dimethyl-2-butyl (-C (CH 3)2CH(CH3)2)), 3-dimethyl-2-butyl (-CH (CH 3)C(CH3)3), n-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents as described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group comprises 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch 2), allyl (-CH 2CH＝CH2), 1-propenyl (propenyl, -ch=ch-CH 3), and the like.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2 to 8 carbon atoms; in other embodiments, alkynyl groups contain 2 to 6 carbon atoms; in still other embodiments, alkynyl groups contain 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), 1-propynyl ((propynyl, -C≡C-CH 3), and the like.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3), ethoxy (EtO, -OCH 2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH 2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3)2), 1-butoxy (n-BuO, n-butoxy, -OCH 2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH (CH 3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH 3)3), 1-pentoxy (n-pentoxy, -OCH 2CH2CH2CH2CH3), 2-pentoxy (-OCH (CH 3)CH2CH2CH3), 3-pentoxy (-OCH (CH 2CH3)2), 2-methyl-2-butoxy (-OC (CH 3)2CH2CH3), 3-methyl-2-butoxy (-OCH (CH 3)CH(CH3)2), 3-methyl-l-butoxy (-OCH 2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH 2CH(CH3)CH2CH3), and the like.
The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "hydroxyalkoxy" means that the alkoxy group is substituted with one or more hydroxyl groups, examples of which include, but are not limited to, -OCH 2OH、-OCH2CH2 OH, and the like.
The term "carbocyclyl" or "carbocycle" means a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclo groups include spirocarbobicyclo groups, fused carbobicyclo groups, and bridged carbobicyclo groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups comprise 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups comprise 3 to 8 carbon atoms; in still other embodiments, cycloalkyl groups contain 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.
The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms in which one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a monocyclic ring of 3-8 membered rings (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2,PO,PO2), or a bicyclic ring of 7-12 membered rings (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2,PO,PO2). In other embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a monocyclic ring of 3-6 membered rings (2-4 carbon atoms and 1-3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2,PO,PO2). The heterocyclyl group is optionally substituted with one or more substituents described herein.
The heterocyclic group may be a carbon group or a heteroatom group; wherein the-CH 2 -group of the ring may optionally be replaced by-C (=o) -and the sulphur atom of the ring may optionally be oxidised to S-oxide and the nitrogen atom of the ring may optionally be oxidised to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazalkyl, homopiperazinyl, homopiperidinyl, oxacycloheptyl, thietanyl, oxazanyl, and the likeRadical, diazaRadical, thiaza/>A radical, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, and the like. Examples of the substitution of the-CH 2 -group in the heterocyclyl by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl, and the like. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, sulfolane, thiomorpholino 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.
The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring of 3 to 7 atoms, and wherein one or more attachment points are attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
The term "heteroaryl" or "heteroaromatic ring" means a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. Heteroaryl groups are typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group consisting of 5 to 10 ring atoms comprises 1,2, 3, or 4 heteroatoms independently selected from O, S and N; in other embodiments, the heteroaryl group consisting of 5 to 6 ring atoms is a monocyclic ring system and comprises 1,2, 3, or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-dithiotriazinyl, 1, 3-dithio, 3-triazolyl, 1, 3-triazolyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.
The term "nitrogen atom-containing monocyclic ring" refers to a monocyclic ring of 4-8 ring atoms containing a nitrogen atom, which may be fully saturated or contain one or more degrees of saturation, but no aromaticity. Examples of the nitrogen atom-containing monocyclic ring include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like. The nitrogen atom containing monocyclic ring is optionally substituted with one or more substituents described herein.
The terms "fused bicyclic", "fused ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated bicyclic ring system comprising 4 to 12 ring atoms, said bicyclic ring system being a non-aromatic bicyclic ring system. Such systems may comprise independent or conjugated unsaturated systems, but the core structure does not comprise an aromatic or heteroaromatic ring (but an aromatic group may act as a substituent thereon). The term "condensed ring containing nitrogen atoms" refers to a condensed ring containing 1 or 2 nitrogen atoms, examples of condensed rings containing nitrogen atoms include, but are not limited to, octahydropyrrolo [3,4-c ] pyrrole, and the like. The fused rings are optionally substituted with one or more substituents described herein.
The terms "spirocyclic", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated ring system containing 5 to 12 ring atoms, one of which originates from a specific ring carbon atom on the other ring. As shown in formula (a), ring A and ring B share one carbon atom in two saturated ring systems, referred to as "spiro" or "spirobicyclo", and ring B' are referred to as "fused bicyclo". Each ring in the spirobicyclic group may be a carbocyclyl or a heterocyclyl. The term "nitrogen atom-containing spiro ring" refers to spiro rings containing 1 or 2 nitrogen atoms, examples of which include, but are not limited to, 2, 7-diazaspiro [3.5] nonane, 2, 6-diazaspiro [3.3] heptane, and the like.
The spiro ring is optionally substituted with one or more substituents described herein.
The term "bridged ring" or "bridged ring radical" means a saturated or partially unsaturated bridged ring system, and refers to a non-aromatic bicyclic ring system, such as that shown in formula (b), i.e., ring A1 shares an alkyl or heteroalkyl chain with ring A2, wherein each X 3 is independently optionally a carbon atom or heteroatom, and j is 1,2,3, or 4. Such systems contain 5-12 ring atoms and may contain independent or conjugated unsaturation, but the core structure does not contain an aromatic ring or rings (although aromatic groups may be substituted thereon). Wherein each ring, such as A1 or A2, contains 4-7 atoms, the term "bridged ring containing a nitrogen atom" refers to bridged rings containing 1 or 2 nitrogen atoms, examples of which include, but are not limited to, (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane, and the like. The bridged ring is optionally substituted with one or more substituents described herein.
The term "k atoms" or "k-membered", where k is an integer, typically describes the number of atoms making up a ring in a molecule where the number of atoms making up the ring is k. For example, a piperidinyl group is a 6-atom-composed heterocycle or a 6-membered heterocycle, and a pyridinyl group is a 6-atom-composed heteroaryl or a 6-membered heteroaryl.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R is a substituent according to the invention).
The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. Some of these examples are alkylamino groups in which one or two C 1-6 alkyl groups are attached to a nitrogen atom. Still other embodiments are where the alkylamino group is an amino group substituted with one or two C 1-3 alkyl groups. Suitable alkylamino groups may be mono-or dialkylamino, such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N, N-dimethylamino (dimethylamino), N, N-diethylamino (diethylamino), and the like.
The term "aminoalkyl" includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups. Some of these embodiments are C 1-6 aminoalkyl groups substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
The ring system formed by the attachment of substituents (R) f to the central ring by a bond, as described herein, represents that f substituents R may be substituted at any substitutable position or at any reasonable position on the ring. For example, formula d represents that the G ring may be substituted with f R, and when f is greater than 1, each R may be independently selected from the same or different substituents.
The attachment point may be attached to the remainder of the molecule at any attachable position on the ring, as described herein. For example, formula e represents any position on the C-ring or D-ring that may be attached as a point of attachment.
For example, formula f represents a group-O- (CR mRn)p -which may be linked to the remainder of the molecule via the E-terminus or the E' -terminus.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH 2CH2SO2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature ：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991;and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not generally produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly in humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.
The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" of e.w. martin.
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound contains a hydroxyl group, i.e., it can be acylated to give the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents ：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345.
"Metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, and the like, or by other methods described in the literature such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of groups I to XII of the periodic table, and organic base salts, such as salts with primary, secondary and tertiary amines.
"Solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "therapeutically effective amount" means that the amount of the compound, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of other suitable salts can be found in the nature, selection and application (Handbook of Pharmaceutical Salts：Properties,Selection,and Use)",Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and 125 I. Isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation herein as using a suitable isotopically-labeled reagent in place of the originally used unlabeled reagent.
All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
The term "cancer" as used herein refers to or describes a physiological condition in a patient that is generally characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or malignant lymphoproliferative disease (lymphoid malignancies). More specific examples of such cancers include squamous cell carcinoma (such as epithelial squamous cell carcinoma), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung), esophageal cancer, cancer of the peritoneum, hepatocellular carcinoma (hepatocellular cancer), gastric cancer (gastric or stomach cancer) (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (LIVER CANCER), bladder cancer, hepatoma (hepatoma), breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, renal or renal cancer (kidney or RENAL CANCER), prostate cancer, vulval cancer, thyroid cancer, liver cancer (hepatic carcinoma), anal cancer, penile cancer, and head and neck cancer.
The term "KRAS G12C inhibitor" as used herein refers to a substance that binds to KRAS G12C and inhibits its activity.
Description of the Compounds of the invention
The present invention provides a compound or pharmaceutical composition thereof, which is useful as an inhibitor of KRAS G12C. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or disorders by inhibiting KRAS G12C activity with said compounds. The invention further describes a method for synthesizing the compounds. The compounds of the invention exhibit improved biological activity and pharmacokinetic properties.
In one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Wherein each R 1、R2, X, Y and W has the meaning described herein.
In some embodiments, X is-L-X 1 -, wherein L is a bond or-NH-, and X 1 is a 4-12 membered saturated or partially unsaturated monocyclic, fused, spiro, or bridged ring containing a nitrogen atom, which monocyclic, fused, spiro, and bridged rings are independently optionally substituted with m R x; wherein R x and m have the meaning described in the present invention.
In other embodiments, X is Wherein R x and m have the meaning described in the present invention.
In some embodiments, Y is />
Wherein R 3、Ry、Ri、Rj and n have the meaning described in the present invention.
In some embodiments, R 1 is -C(＝O)-CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rc or-S (=o) 2-C≡C-Rc; wherein R a、Rb and R c have the meaning described in the present invention.
In some embodiments, R a is hydrogen, deuterium, a halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R a is hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy may be independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R b is hydrogen, deuterium, a halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R b is hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy may be independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclyl, or 3-6 membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclyl, and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2,3,4, or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkoxy, and 3-6 membered heterocyclyl.
In other embodiments, R c is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl groups may be independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2OH、-OCH2CH2 OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and morpholinyl groups.
In some embodiments, W is-O- (CR mRn)p-、-S-(CRmRn)p -or-NR d-(CRmRn)p -, wherein R d、Rm、Rn and p have the meanings described herein.
In some embodiments, R d is hydrogen, deuterium, C 1-3 alkyl, or C 1-3 haloalkyl, wherein the C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1,2,3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy.
In other embodiments, R d is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl or difluoromethyl may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R 2 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 6-12 aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or-CR eRf-NRgRh, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 6-12 aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkoxy; wherein R e、Rf、Rg and R h have the meaning described in the present invention.
In other embodiments, R 2 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or-CR eRf-NRgRh, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy; wherein R e、Rf、Rg and R h have the meaning described in the present invention.
In other embodiments, R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CR eRf-NRgRh, wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl groups may be independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH; wherein R e、Rf、Rg and R h have the meaning described in the present invention.
In some embodiments, R m is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R m is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy are independently optionally substituted with 1,2,3,4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R n is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R n is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy are independently optionally substituted with 1,2,3,4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R e is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R e is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy are independently optionally substituted with 1,2,3,4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R f is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy may independently be optionally substituted with 1,2, 3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R f is hydrogen, deuterium, a halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, and isopropoxy are independently optionally substituted with 1,2,3,4, or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R g is hydrogen, deuterium, C 1-3 alkyl, or C 1-3 haloalkyl, wherein the C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1,2,3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy.
In other embodiments, R g is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R h is hydrogen, deuterium, C 1-3 alkyl, or C 1-3 haloalkyl, wherein the C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1,2,3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy.
In other embodiments, R h is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R f、Rg and the atoms to which they are attached together form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring may be independently optionally substituted with 1,2,3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy.
In other embodiments, R f、Rg and the atoms to which they are attached form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein the azetidine, pyrrolidine, piperidine ring, piperazine ring, and morpholine ring may independently be optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, and-OCH 2CH2 OH.
In some embodiments, R 3 is C 6-12 aryl or 5-12 membered heteroaryl, wherein the C 6-12 aryl and 5-12 membered heteroaryl may independently be optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atom, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkoxy.
In other embodiments, R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl and 5-10 membered heteroaryl may independently be optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atom, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1-4 hydroxyalkoxy.
In other embodiments, R 3 is Wherein said/>/> May be independently optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R x is deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl may independently be optionally substituted with 1, 2,3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R x is deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R x is deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are independently optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R y is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl may independently be optionally substituted with 1, 2,3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R y is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
In other embodiments, R y is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、 methoxy, ethoxy, n-propoxy, isopropoxy 、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、 methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are independently optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R i is hydrogen, deuterium, C 1-3 alkyl, or C 1-3 haloalkyl, wherein the C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1,2,3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy.
In other embodiments, R i is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, R j is hydrogen, deuterium, C 1-3 alkyl, or C 1-3 haloalkyl, wherein the C 1-3 alkyl and C 1-3 haloalkyl may independently be optionally substituted with 1, 2, 3, 4, or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 hydroxyalkoxy.
In other embodiments, R j is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and-OCH 2CH2 OH.
In some embodiments, m is 0,1, 2, 3, 4, 5, 6, 7, or 8.
In some embodiments, n is 0,1, 2, 3, 4, 5, 6, 7, or 8.
In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6.
In another aspect, the invention relates to stereoisomers, geometric isomers, tautomers, nitroxides, solvates, hydrates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof of one of the following compounds or of one of the following compounds, but in no way limited to:
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In another aspect, the present invention relates to a pharmaceutical composition comprising stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the aforementioned compounds, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or any combination thereof.
In another aspect, the invention relates to the use of a compound as described above or a pharmaceutical composition thereof for the manufacture of a medicament for preventing, treating or alleviating KRAS G12C-mediated diseases in a patient.
Some of these embodiments are where the KRAS G12C-mediated disease is cancer.
In some embodiments, the cancer of the invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, cholangiocarcinoma, breast cancer, colon cancer, leukemia, and melanoma.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds comprised by formula (I).
Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention
According to another aspect, the pharmaceutical composition of the invention is characterized by comprising a compound of formula (I), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the invention is effective to treat or ameliorate KRAS G12C-mediated diseases in a patient.
The compounds of the invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly according to the needs of the patient, the compounds described in other aspects of the present invention, metabolites thereof, or residues thereof.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, suitable for the particular target dosage form. ：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,, as described in the following documents, taken together with the content of the documents herein, demonstrate that various carriers can be used in the preparation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to the extent to which any conventional carrier vehicle is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
Materials that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffer, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.
Preferably, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier selected with regard to the form of administration and conventional pharmaceutical practice (referred to herein as a pharmaceutical carrier), which may be in the form of oral tablets, capsules, elixirs, syrups and the like.
For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical component may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Furthermore, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all dosage forms used being well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.
The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles or by transdermal routes using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the administration period.
The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
The compounds of the present invention are also coupled to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl amine methacrylate-phenol, polyhydroxyethyl asparaginol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
The dosage regimen of the compounds of the invention will vary with various factors known, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make the decision and prescribe an effective amount of the drug to prevent, counter or arrest the progress of the cancer.
In accordance with general guidelines, the daily oral dosage of each active ingredient employed is in the range of from about 0.001 to 1000mg/kg body weight, preferably from about 0.01 to 100mg/kg body weight, in order to achieve the indicated effect. And, most preferably, between about 1.0 and 20mg/kg body weight/day. For intravenous administration, the most preferred dosage range during conventional rate infusion is about 1 to about 10mg/kg body weight/minute. The compounds of the present invention may be administered once daily or may be administered in two, three or four times daily administrations.
Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1mg to about 100mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be about 0.5-95% of the total weight of the composition.
When the compounds of the present invention are administered with other therapeutic agents, generally, the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage when administered alone, given the additional or synergistic effect of the therapeutic agents when administered in combination.
The compound or a pharmaceutically acceptable salt or hydrate thereof according to the present invention is useful for preventing, treating or alleviating KRAS G12C-mediated diseases in patients, and in particular, is useful for treating lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, cholangiocarcinoma, breast cancer, colon cancer, leukemia, melanoma and the like.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined herein, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the present invention, and other methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as ALDRICH CHEMICAL Company, arco Chemical Company AND ALFA CHEMICAL Company and used without further purification. Unless otherwise indicated, general reagents were purchased from Shandong chemical plant, guangdong chemical plant, guangzhou chemical plant, tianjin good, chemical company, tianjin Fuchen chemical plant, wuhan Xinhua remote technology development Co., qingdao Teng chemical Co., and Qingdao ocean chemical plant.
Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.
1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1 H NMR spectra were taken with CDC1 3、DMSO-d6、CD3 OD or acetone-d 6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet, quartet), q (quartet ), m (multiplet, multiplet), br (broadened, broad), brs (broadened singlet, broad singlet), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constant J, expressed in hertz (Hz).
The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-MS (column model: zorbax SB-C18,2.1x 30mm,3.5 microns, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH 3 CN with 0.1% formic acid) in (H 2 O with 0.1% formic acid), electrospray ionization (ESI) was used, UV detection at 210nm/254 nm.
The pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following abbreviations are used throughout the present invention:
The following schemes describe the steps for preparing the compounds of the present invention. Unless otherwise indicated, where each R x、Ry, m, and n has the definition set forth herein, R A is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 hydroxyalkoxy, u is 0,1, 2,3, 4, or 5,s and t are each independently 1,2, or 3, R B is deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or C 1-3 hydroxyalkoxy, v is 0,1, 2,3, 4, or 5.
Reaction scheme 1
The compound of formula (2) can be prepared by reaction scheme 1: the compound shown in the formula (1) reacts under the action of lithium aluminum hydride to obtain the compound shown in the formula (2).
Reaction scheme 2
The compound of formula (12) can be prepared by reaction scheme 2: the compound shown in the formula (3) and the compound shown in the formula (4) react under the action of DIPEA to obtain the compound shown in the formula (5). The compound shown in the formula (5) and the compound shown in the formula (2) react under the action of palladium acetate, cesium carbonate and BINAP to obtain the compound shown in the formula (6). The compound shown in the formula (6) reacts under the action of trifluoroacetic acid to obtain the compound shown in the formula (7). The compound shown in the formula (7) and the compound shown in the formula (8) react under the action of Pd 2(dba)3, xantPhos and Cs 2CO3 to obtain the compound shown in the formula (9). The compound shown in the formula (9) reacts under the action of palladium-carbon and methanol ammonia solution to obtain the compound shown in the formula (10). The compound shown in the formula (10) and the compound shown in the formula (11) react under the action of triethylamine to obtain the compound shown in the formula (12).
Reaction scheme 3
The compound of formula (30) can be prepared by reaction scheme 3: the compound shown in the formula (13 a) is reacted under the action of pyridine chlorochromate to obtain the compound shown in the formula (13). The compound shown in the formula (13) and the compound shown in the formula (14) react under the action of sodium bis (trimethylsilyl) amide to obtain the compound shown in the formula (15). The compound shown in the formula (15) and the compound shown in the formula (16) react under the action of triethylamine and bis (triphenylphosphine) palladium dichloride to obtain the compound shown in the formula (17). The compound shown in the formula (17) reacts under the action of palladium-carbon and hydrogen to obtain the compound shown in the formula (18). The compound shown in the formula (18) reacts under the action of potassium bis (trimethylsilyl) amide to obtain the compound shown in the formula (19). The compound shown in the formula (19) and the compound shown in the formula (20) react under the action of methanol and sodium methoxide to obtain the compound shown in the formula (21). The compound shown in the formula (21) and the compound shown in the formula (22) react under the action of triethylamine and N, N-dimethylaminopyridine to obtain the compound shown in the formula (23). The compound shown in the formula (23) and the compound shown in the formula (4) react under the action of DIPEA to obtain the compound shown in the formula (24). The compound shown in the formula (24) reacts under the action of m-chloroperoxybenzoic acid to obtain the compound shown in the formula (25). The compound shown in the formula (25) and the compound shown in the formula (2) react under the action of sodium tert-butoxide to obtain the compound shown in the formula (26). The compound represented by formula (26) is reacted under the action of hydrochloric acid to obtain the compound represented by formula (27). The compound shown in the formula (27) and the compound shown in the formula (8) react under the action of Pd 2(dba)3, xantPhos and Cs 2CO3 to obtain the compound shown in the formula (28). The compound shown in the formula (28) reacts under the action of palladium-carbon and hydrogen to obtain the compound shown in the formula (29). The compound shown in the formula (29) and the compound shown in the formula (11) react under the action of triethylamine to obtain the compound shown in the formula (30).
Reaction scheme 4
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The compound of formula (34) can be prepared by reaction scheme 4: the compound represented by the formula (31) and the compound represented by the formula (32) are reacted at a low temperature to obtain the compound represented by the formula (33). The compound shown in the formula (33) is reacted under the action of Boc anhydride and triethylamine to obtain the compound shown in the formula (34).
Reaction scheme 5
The compound of formula (41) can be prepared by reaction scheme 5: the compound shown in the formula (35) and the compound shown in the formula (36) react under the action of boron trifluoride diethyl ether to obtain the compound shown in the formula (37). The compound shown in the formula (37) and the compound shown in the formula (20) react under the action of methanol and sodium methoxide to obtain the compound shown in the formula (39). The compound represented by the formula (39) and the compound represented by the formula (40) are reacted under the action of triethylamine to obtain the compound represented by the formula (41).
Reaction scheme 6
The compound of formula (54) can be prepared by reaction scheme 6: the compound shown in the formula (42) and the compound shown in the formula (43) react under the action of sodium carbonate and potassium iodide to obtain the compound shown in the formula (44). The compound represented by formula (44) and the compound represented by formula (45) are reacted under the action of sodium carbonate to obtain the compound represented by formula (46). The compound represented by formula (46) is reacted under the action of potassium carbonate and potassium iodide to obtain the compound represented by formula (47). The compound represented by the formula (47) and the compound represented by the formula (20) are reacted under the action of potassium carbonate to obtain the compound represented by the formula (49). The compound shown in the formula (49) and the compound shown in the formula (4) react under the action of BOP and DBU to obtain the compound shown in the formula (50). The compound shown in the formula (50) reacts under the action of m-chloroperoxybenzoic acid to obtain the compound shown in the formula (51). The compound shown in the formula (51) and the compound shown in the formula (2) react under the action of sodium tert-butoxide to obtain the compound shown in the formula (52). The compound shown in the formula (52) reacts under the action of palladium-carbon to obtain the compound shown in the formula (53). The compound shown in the formula (53) and the compound shown in the formula (11) react under the action of triethylamine to obtain the compound shown in the formula (54).
Reaction scheme 7
The compound of formula (63) can be prepared by reaction scheme 7: the compound represented by formula (55) and the compound represented by formula (20) are reacted under the action of methanol and sodium methoxide to obtain the compound represented by formula (56). The compound represented by formula (56) and the compound represented by formula (4) are reacted under the action of BOP and DBU to obtain the compound represented by formula (57). The compound shown in the formula (57) is reacted under the action of m-chloroperoxybenzoic acid to obtain the compound shown in the formula (58). The compound shown in the formula (58) and the compound shown in the formula (2) react under the action of sodium tert-butoxide to obtain the compound shown in the formula (59). The compound represented by formula (59) is reacted under the action of trifluoroacetic acid to obtain the compound represented by formula (60). The compound shown in the formula (60) and the compound shown in the formula (8) react under the action of Pd 2(dba)3, xantPhos and Cs 2CO3 to obtain the compound shown in the formula (61). The compound shown in the formula (61) reacts under the action of palladium-carbon and hydrogen to obtain the compound shown in the formula (62). The compound represented by the formula (62) and the compound represented by the formula (11) are reacted under the action of triethylamine to obtain the compound represented by the formula (63).
Reaction scheme 8
The compound of formula (74) can be prepared by reaction scheme 8: the compound represented by formula (42) and the compound represented by formula (64) are reacted under the action of sodium acetate to obtain the compound represented by formula (65). The compound represented by formula (65) and the compound represented by formula (66) are reacted under the action of sodium carbonate to obtain the compound represented by formula (67). The compound represented by formula (67) is reacted under the action of sodium hydride to obtain a compound represented by formula (68). The compound represented by formula (68) and the compound represented by formula (20) are reacted under the action of sodium carbonate to obtain the compound represented by formula (69). The compound shown in the formula (69) and the compound shown in the formula (4) react under the action of BOP and triethylamine to obtain the compound shown in the formula (70). The compound shown in the formula (70) reacts under the action of m-chloroperoxybenzoic acid to obtain the compound shown in the formula (71). The compound shown in the formula (71) and the compound shown in the formula (2) react under the action of sodium tert-butoxide to obtain the compound shown in the formula (72). The compound represented by formula (72) is reacted under the action of palladium on charcoal and hydrogen to obtain the compound represented by formula (73). The compound represented by formula (73) and the compound represented by formula (11) are reacted under the action of DIPEA to obtain the compound represented by formula (74).
Reaction scheme 9
The compound of formula (87) can be prepared by reaction scheme 9: the compound shown in the formula (75) and the compound shown in the formula (76) react under the action of lithium bis (trimethylsilyl) amide to obtain the compound shown in the formula (77). The compound represented by formula (77) and the compound represented by formula (20) are reacted under the action of sodium acetate to obtain the compound represented by formula (78). The compound shown in the formula (78) and the compound shown in the formula (4) react under the action of BOP and triethylamine to obtain the compound shown in the formula (79). The compound shown in the formula (79) reacts under the action of m-chloroperoxybenzoic acid to obtain the compound shown in the formula (80). The compound shown in the formula (80) and the compound shown in the formula (2) react under the action of sodium tert-butoxide to obtain the compound shown in the formula (81). The compound shown in the formula (81) is reacted with palladium on charcoal under the action of trifluoroacetic acid to obtain the compound shown in the formula (82). The compound shown in the formula (82) and the compound shown in the formula (8) react under the action of Pd 2(dba)3, xantPhos and Cs 2CO3 to obtain the compound shown in the formula (83). The compound represented by formula (83) and the compound represented by formula (84) are reacted under the action of DIPEA to obtain the compound represented by formula (85). The compound represented by formula (85) is reacted under the action of a methanol solution of palladium on charcoal, hydrogen and ammonia to obtain the compound represented by formula (86). The compound represented by formula (86) and the compound represented by formula (11) are reacted under the action of DIPEA to obtain the compound represented by formula (87).
Reaction scheme 10
The compound of formula (91) can be prepared by reaction scheme 10: the compound shown in the formula (7) and the compound shown in the formula (88) react under the action of Pd 2(dba)3, xantPhos and Cs 2CO3 to obtain the compound shown in the formula (89). The compound shown in the formula (89) is reacted under the action of palladium-carbon and methanol ammonia solution to obtain the compound shown in the formula (90). The compound shown in the formula (90) and the compound shown in the formula (11) react under the action of triethylamine to obtain the compound shown in the formula (91).
Reaction scheme 11
The compound of formula (97) can be prepared by reaction scheme 11: the compound represented by the formula (92) and the compound represented by the formula (93) are reacted under the action of p-toluenesulfonic acid to obtain the compound represented by the formula (94). The compound shown in the formula (7) and the compound shown in the formula (94) react under the action of Pd 2(dba)3, xantPhos and Cs 2CO3 to obtain the compound shown in the formula (95). The compound shown in the formula (95) reacts under the action of palladium-carbon and methanol ammonia solution to obtain the compound shown in the formula (96). The compound shown in the formula (96) and the compound shown in the formula (11) react under the action of triethylamine to obtain the compound shown in the formula (97).
Reaction scheme 12
The compound of formula (107) can be prepared by reaction scheme 12: the compound shown in the formula (98) and the compound shown in the formula (43) react under the action of sodium carbonate and potassium iodide to obtain the compound shown in the formula (99). The compound shown in the formula (99) and the compound shown in the formula (45) react under the action of sodium carbonate to obtain the compound shown in the formula (100). The compound shown in the formula (100) reacts under the action of potassium carbonate and potassium iodide to obtain the compound shown in the formula (101). The compound shown in the formula (101) and the compound shown in the formula (20) react under the action of potassium carbonate to obtain the compound shown in the formula (102). The compound shown in the formula (102) and the compound shown in the formula (4) react under the action of BOP and DBU to obtain the compound shown in the formula (103). The compound shown in the formula (103) reacts under the action of m-chloroperoxybenzoic acid to obtain the compound shown in the formula (104). The compound shown in the formula (104) and the compound shown in the formula (2) react under the action of sodium tert-butoxide to obtain the compound shown in the formula (105). The compound shown in the formula (105) reacts under the action of palladium-carbon to obtain the compound shown in the formula (106). The compound shown in the formula (106) and the compound shown in the formula (11) react under the action of triethylamine to obtain the compound shown in the formula (107).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.
Examples
Example 12- ((S) -1-propenoyl-4- ((6S, 9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of 1-tert-butyl 2-methyl (S) -4-oxopyrrolidine-1, 2-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (2S, 4R) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester (50.00 g,203.90 mmol) and methylene chloride (500 mL) were added to a reaction flask, cooled to 0℃and pyridine chlorochromate (87.89 g,407.70 mmol) was added in portions, stirred at room temperature overnight, filtered, the reaction system had a large amount of brown mud, which was diluted with methylene chloride (300 mL) and filtered again, the organic phase was combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =10/1) to give the title compound as a colorless transparent liquid (27.6 g, 56%).
Second step Synthesis of 1- (tert-butyl) 2-methyl (S) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate
Di (trimethylsilyl) sodium amide (68.0 mL,136.00 mmol) and tetrahydrofuran (60.0 mL) were added to a reaction flask, nitrogen-protected, cooled to-78deg.C, then a solution of 1-tert-butyl 2-methyl (S) -4-oxopyrrolidine-1, 2-dicarboxylic acid ester (30.00 g,123.30 mmol) in tetrahydrofuran (100 mL) was added dropwise, the reaction was stirred for 30min after completion, then a solution of N-phenylbis (trifluoromethanesulfonyl) imine (46.25 g,129.50 mmol) in tetrahydrofuran (130 mL) was added dropwise, stirring was completed for 2h, then stirring at room temperature overnight, cooled to 0deg.C, ethyl acetate (200 mL) and 10% aqueous citric acid (200 mL) were added, the separated liquid was extracted with ethyl acetate (100 mL. Times.3), the organic phase was combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then the column chromatography (PE/EA (v/v) =20/1) gave the title compound as colorless oil (30.00 g, 65%).
Third step Synthesis of 1- (tert-butyl) 2-methyl (S, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (S) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester (30.00 g,79.94 mmol), methyl acrylate (13.76 g,159.80 mmol), triethylamine (22.0 mL,158.00 mmol), bis (triphenylphosphine) palladium dichloride (2.80 g,3.99 mmol) and N, N-dimethylformamide (300 mL) were added to a reaction flask, nitrogen protected, the reaction was stirred overnight at 105℃and ethyl acetate (100 mL) and crushed ice (100 mL) were added, the fractions were extracted with ethyl acetate (100 mL. Times.3) in aqueous phase, the combined organic phases were washed with saturated brine (200 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =7/1) to give the title compound (15.00 g, 68%).
MS(ESI,pos.ion)m/z:212.2[M-Boc+H]+。
Fourth step Synthesis of 1- (tert-butyl) 2-methyl (2S) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (S, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester (15.00 g,48.19 mmol), ethyl acetate (300.0 mL) and 10% palladium on charcoal (2.00 g) were sequentially added to the reaction flask, the mixture was stirred at room temperature for 48H, the temperature was raised to 50℃and stirred for 8H, cooled to room temperature, palladium on charcoal was removed by filtration, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =10/1) to give the title compound (9.48 g, 62%).
MS(ESI,pos.ion)m/z:216.2[M-Boc+H]+。
Fifth step Synthesis of 6- (tert-butyl) 3-methyl (1S, 5S) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (2S) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (8.90 g,28.20 mmol) and tetrahydrofuran (560 mL) were added sequentially to the flask, the mixture was cooled to-78deg.C, potassium bis (trimethylsilyl) amide (61.5 mL,61.50mmol,1.00 mol/L) was added dropwise, stirring was continued overnight at a constant temperature, ethyl acetate (100 mL) and 10% aqueous citric acid solution (500 mL) were added, the aqueous phase was extracted with ethyl acetate (200 mL) after separation, the organic phase was combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a colorless oil (4.00 g, 50%).
MS(ESI,pos.ion)m/z:228.1[M-55]+。
Sixth step Synthesis of (6S, 9S) -4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylic acid tert-butyl ester
To the reaction flask was added 6- (tert-butyl) 3-methyl (1 s,5 s) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylic acid ester (4.00 g,14.10 mmol), 2-methyl thiourea sulfate (3.45 g,18.30 mmol), methanol (40 mL) and sodium methoxide (3.81 g,70.60 mmol) in this order, stirred overnight at room temperature, saturated aqueous citric acid (20 mL) was added to the mixture, ethyl acetate (20 ml×2) was extracted, the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a white solid (500.0 mg, 11%).
MS(ESI,pos.ion)m/z:324.2[M+H]+。
Seventh step Synthesis of tert-butyl (6S, 9S) -2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate
N-phenyl bis (trifluoromethanesulfonyl) imine (828.0 mg,2.318 mmol), (6S, 9S) -4-hydroxy-2- (methylsulfanyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (500.0 mg,1.55 mmol), triethylamine (312.0 mg,3.08 mmol), dichloromethane (8 mL) and N, N-dimethylaminopyridine (9.0 mg,0.07 mmol) were added sequentially to the reaction flask, stirred at room temperature for 2H, then water (20 mL) and dichloromethane (10 mL) were added sequentially, the aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) 10/1) to give the title compound as a colorless oil (366.0 mg, 52%).
Eighth step Synthesis of tert-butyl (6S, 9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylate
(6S, 9S) -2- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (500.0 mg,1.10 mmol), N-dimethylformamide (6 mL), N-diisopropylethylamine (0.3 mL,2.00 mmol) and benzyl (2S) -2- (cyanomethyl) piperazine-1-carboxylate (313.0 mg,1.21 mmol) were added sequentially to the reaction flask, the reaction was warmed to 85 ℃ and stirred for 2H, cooled to room temperature, ethyl acetate (30 mL) and water (30 mL) were added sequentially, the fractions were separated, ethyl acetate (20 ml×2) was extracted, the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound (320.0 mg, 52%).
Synthesis of tert-butyl (6S, 9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylate
To the reaction flask was added successively tert-butyl (6S, 9S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate (320.0 mg,0.57 mmol) and dichloromethane (6.0 mL), cooled to 0 ℃, 85% m-chloroperoxybenzoic acid (120.0 mg,0.59 mmol) was added in portions, stirred at room temperature for 10min, dichloromethane (20 mL) and water (20 mL) were added, the aqueous phase was extracted with dichloromethane (20 ml×2), the organic phases were combined, washed with saturated aqueous sodium bicarbonate (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then column chromatographed (DCM/v) =20/1) to give the title compound as a colorless oil (300.0 mg, 91%).
MS(ESI,pos.ion)m/z:581.2[M+H]+。
Synthesis of tert-butyl (6S, 9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylate
(6S, 9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (300.0 mg,0.52 mmol), N-methyl-L-prolinol (89.0 mg,0.77 mmol) and toluene (5 mL) were added sequentially to the reaction flask, cooled to 0℃and sodium tert-butoxide (99.0 mg,1.03 mmol) was added, incubated for 1H, concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a light brown solid (230.0 mg, 70%). MS (ESI, pos.ion) m/z 632.3[ M+H ] +.
Synthesis of benzyl (S) -2- (cyanomethyl) -4- ((6S, 9S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (6S, 9S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (230.0 mg,0.36 mmol), ethyl acetate (2.0 mL) and aqueous hydrochloric acid (2.0 mL,12mmol,6.00 mol/L), stirred at room temperature for 30min, pH adjusted to 9-10 by adding saturated aqueous sodium carbonate, extracting the mixed solvent (15 ml×3, DCM/MeOH (v/v) =8/1), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and then purifying by column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a light brown solid (180.0 mg, 93%).
MS(ESI,pos.ion)m/z:532.3[M+H]+。
Synthesis of benzyl (S) -2- (cyanomethyl) -4- ((6S, 9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- ((6S, 9S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (180.0 mg,0.34 mmol), 1-bromo-8-methyl-naphthalene (150.0 mg,0.68 mmol), tris (dibenzylideneacetone) dipalladium (16.0 mg,0.02 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (25.0 mg,0.04 mmol), cesium carbonate (220.0 mg,0.67 mmol) and toluene (4 mL), nitrogen protection, warmed to 90 ℃ stirred overnight, cooled to room temperature, filtered, concentrated, and then column chromatographed (DCM/v) 9/1) to give the title compound (97.5 mg, 43%).
MS(ESI,pos.ion)m/z:672.4[M+H]+。
Synthesis of thirteenth step 2- ((S) -4- ((6S, 9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- ((6S, 9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (90.0 mg,0.13 mmol), methanol (4 mL) and 10% palladium on charcoal (20.0 mg), protected with hydrogen, stirred overnight at room temperature, 2 drops of acetic acid were added dropwise, the mixture was stirred overnight at room temperature, the palladium on charcoal was filtered off, and the filtrate was concentrated to give the title compound (30.0 mg, 42%) as thick preparation plate (DCM/MeOH (v/v) =8/1). MS (ESI, pos.ion) m/z 538.3[ M+H ] +.
Synthesis of fourteenth step 2- ((S) -1-propenoyl-4- ((6S, 9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- ((6S, 9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (30.0 mg,0.06 mmol), dichloromethane (2 mL) and triethylamine (11.0 mg,0.11 mmol) were added sequentially to the reaction flask, cooled to-20℃and then acryloyl chloride (6.0 mg,0.07 mmol) was added dropwise, stirred at room temperature for 30min, the reaction concentrated, and isolated (DCM/MeOH (v/v) =10/1) via thick prep plate to give the title compound (20.0 mg, 61%).
MS(ESI,pos.ion)m/z:592.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.60(d,J＝4.4Hz,1H),7.45(d,J＝7.9Hz,1H),7.33–7.27(m,1H),7.23(d,J＝6.8Hz,1H),7.06(dd,J＝14.6,7.4Hz,1H),6.56(dd,J＝18.3,7.0Hz,2H),6.38(d,J＝16.8Hz,1H),5.86–5.76(m,1H),5.06(s,1H),4.16–3.74(m,5H),3.69–3.52(m,3H),3.15–2.85(m,8H),2.85–2.39(m,6H),2.37–1.97(m,10H).
Example 2 2- ((S) -1-propenoyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of 2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine
6-Benzyl-2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine (5.00 g,17.00 mmol) and dichloromethane (60.0 mL) were sequentially added to the reaction flask, cooled to-5 ℃, then 1-chloroethylchloroformate (5.5 mL,51.0 mmol) was added dropwise, the reaction was stirred at room temperature for 4 hours, saturated brine (100 mL) was added, the solution was separated, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and then purified by column chromatography (PE/EA (v/v) =3/1) to give a colorless transparent oil, which was dissolved in methanol (30 mL) and stirred at room temperature overnight, and filtered to give the title compound as a white solid (2.48 g, 72%).
MS(ESI,pos.ion)m/z:204.1[M+H]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)10.19(s,1H),4.26(s,2H),3.44(t,J＝6.1Hz,2H),3.18(t,J＝6.2Hz,2H).
Second step Synthesis of tert-butyl 2, 4-dichloro-7, 8-dihydropyrido [4,3-d ] pyrimidine-6 (5H) -carboxylate
2, 4-Dichloro-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine (2.48 g,12.20 mmol), dichloromethane (30.0 mL), boc anhydride (B, 3.5mL,15.00 mmol), triethylamine (3.5 mL,25.00 mmol) were added sequentially to the reaction flask, the mixture was stirred for 2h at room temperature, dichloromethane (30 mL) and water (50 mL) were added, the liquid was separated, the aqueous phase was extracted with dichloromethane (50 ml×2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a colorless transparent liquid (3.30 g, 89%).
MS(ESI,pos.ion)m/z:304.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)4.56(s,2H),3.75(t,J＝5.8Hz,2H),2.97(t,J＝5.5Hz,2H),1.50(s,9H). Third step Synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-7, 8-dihydropyridine [4,3-d ] pyrimidine-6 (5H) -carboxylate
To the reaction flask was added tert-butyl 2, 4-dichloro-7, 8-dihydropyrido [4,3-d ] pyrimidine-6 (5H) -carboxylate (1.00 g,3.29 mmol), (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.00 g,3.86 mmol), N-diisopropylethylamine (1.0 mL,5.7 mmol) and N, N-dimethylacetamide (8.0 mL) in this order, and the reaction was stirred for 5H at 70℃and cooled to room temperature, ethyl acetate (50 mL) and water (100 mL) were added, the separated liquid, ethyl acetate (100 mL. Times.2) was extracted in aqueous phase, the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a pale solid (1.38 g, 79%).
MS(ESI,pos.ion)m/z:527.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.37(s,5H),5.18(s,2H),4.65(s,1H),4.44(dd,J＝43.6,15.9Hz,2H),4.11(dd,J＝14.2,7.1Hz,1H),3.92(d,J＝12.5Hz,1H),3.83–3.72(m,2H),3.69–3.58(m,1H),3.41(d,J＝12.9Hz,1H),3.31(s,1H),3.12(td,J＝12.3,3.1Hz,1H),2.90(d,J＝5.8Hz,2H),2.83–2.63(m,2H),1.47(s,9H).
Fourth step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7, 8-dihydropyridine [4,3-d ] pyrimidine-6 (5H) -carboxylate
To the reaction flask was added tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-7, 8-dihydropyridine [4,3-d ] pyrimidine-6 (5H) -carboxylate (3.60 g,6.83 mmol), [ (2S) -1-methylpyrrolidin-2-yl ] methanol (1.02 g,8.88 mmol), (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (425.0 mg,0.68 mmol), palladium acetate (76.0 mg,0.34 mmol), cesium carbonate (4.45 g,13.70 mmol) and toluene (50.0 mL), nitrogen protection, warmed to 90 ℃ and stirred for 10H, filtered, the filtrate was concentrated to dryness, and then column chromatography was purified (DCM/MeOH) =30/1) to give the title compound as a pale yellow solid (4.14 g, 100%).
Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7, 8-dihydropyridine [4,3-d ] pyrimidine-6 (5H) -carboxylate (4.14 g,6.84 mmol), dichloromethane (32.0 mL) and trifluoroacetic acid (8.0 mL), the reaction was stirred at room temperature and evaporated to dryness under reduced pressure, EA (30 mL) and aqueous sodium carbonate solution were added to adjust the pH to 9-10, the mixed solvent (80 ml×3, DCM/MeOH (v/v) =10/1) was extracted, the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (DCM/MeOH v/v) =10/1) to give the title compound as a pale yellow solid (1.60 g, 46%). MS (ESI, pos.ion) m/z 506.3[ M+H ] +;
1H NMR(400MHz,DMSO-d6):δ(ppm)7.58–7.24(m,5H),5.14(t,J＝12.2Hz,2H),4.58(s,1H),4.21(dd,J＝10.7,4.9Hz,1H),4.10–3.86(m,2H),3.84–3.56(m,4H),3.18–2.76(m,7H),2.59(s,2H),2.32(s,3H),2.15(dd,J＝17.0,8.6Hz,1H),1.95–1.83(m,1H),1.73–1.49(m,3H).
sixth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (700.0 mg,1.38 mmol), 1-bromo-8-methyl-naphthalene (460.0 mg,2.08 mmol), tris (dibenzylideneacetone) dipalladium (63.0 mg,0.07 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (60.0 mg,0.10 mmol), cesium carbonate (902.0 mg,2.77 mmol) and toluene (10.0 mL), nitrogen protection, stirring the reaction at 110 ℃ overnight, cooling to room temperature, adding ethyl acetate (20 mL), filtering the resulting mixture, concentrating, and then purifying by column chromatography (DCM/MeOH (v/v) =30/1) to give the compound as a light brown solid (809.0 mg, 90%).
MS(ESI,pos.ion)m/z:646.3[M+H]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.77–7.62(m,2H),7.50–7.27(m,8H),7.23(t,J＝7.6Hz,1H),5.07(q,J＝12.6Hz,2H),4.51(d,J＝25.2Hz,1H),4.26(td,J＝10.4,5.0Hz,1H),4.05(ddd,J＝21.8,14.5,7.4Hz,1H),3.94–3.63(m,5H),3.47–3.37(m,1H),3.28–2.65(m,12H),2.54(s,1H),2.35(s,3H),2.18(dd,J＝16.6,8.3Hz,1H),1.97–1.87(m,1H),1.73–1.52(m,3H).
Seventh step Synthesis of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (200.0 mg,0.31 mmol), meOH (10 mL) and palladium on charcoal (27.0 mg,10 mass%) and the mixture was stirred at room temperature after hydrogen substitution overnight, filtered, the filtrate was concentrated and then purified by column chromatography (DCM/MeOH (v/v) =20/1), and the resulting product was isolated again via thick prep plate to give the title compound (120.0 mg, 76%).
MS(ESI,pos.ion)m/z:512.3[M+H]+。
Eighth step Synthesis of 2- ((S) -1-propenoyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (120.0 mg,0.23 mmol), dichloromethane (3.0 mL) and N, N-diisopropylethylamine (60.0 mg,0.46 mmol) were added sequentially to the reaction flask, cooled to-5 ℃, then acryloyl chloride (25.0 mg,0.28 mmol) was added dropwise, stirred for 20min after the dropwise addition, washed with DCM (20 mL) and saturated brine (20 mL), dried, filtered, concentrated, and then purified by column chromatography (DCM/MeOH (v/v) =30/1) to give the title compound as a pale yellow solid (65.0 mg, 49%).
MS(ESI,pos.ion)m/z:566.3[M+H]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.77–7.63(m,2H),7.51–7.30(m,3H),7.23(t,J＝7.5Hz,1H),6.77(ddd,J＝32.0,21.8,11.5Hz,1H),6.12(d,J＝16.3Hz,1H),5.72(d,J＝9.5Hz,1H),4.80(d,J＝66.3Hz,1H),4.26(td,J＝10.3,5.0Hz,1H),4.06(ddd,J＝26.4,13.5,6.7Hz,1H),3.87(s,3H),3.74(t,J＝15.8Hz,2H),3.42(dd,J＝11.6,7.2Hz,1H),3.32–2.76(m,9H),2.71(d,J＝12.2Hz,3H),2.55(s,1H),2.36(s,3H),2.19(q,J＝8.6Hz,1H),1.94(dd,J＝7.9,3.7Hz,1H),1.64(ddd,J＝19.0,13.1,7.3Hz,3H).
Example 3 2- ((S) -1-propenoyl-4- ((6R, 9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of 1-tert-butyl 2-methyl (R) -4-oxopyrrolidine-1, 2-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (2R, 4R) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester (5.00 g,20.40 mmol), methylene chloride (60.0 mL) and dessert-Martin oxidant (10.4 g,24.50 mmol) are sequentially added into a reaction bottle, stirred at room temperature for reaction for 4h, filtered, saturated aqueous sodium sulfite solution (50 mL) is added into the filtrate, stirred for 10min, separated, washed with saturated saline solution (50 mL) of an organic phase, dried over anhydrous sodium sulfate of the organic phase, filtered, and the filtrate is concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =4/1) to obtain the title compound as colorless transparent oily substance (2.75g,56％).1H NMR(400MHz,CDCl3):δ(ppm)4.76(dd,J＝40.0,9.8Hz,1H),3.89(d,J＝11.8Hz,2H),3.76(s,3H),2.93(dd,J＝27.6,17.1Hz,1H),2.58(d,J＝18.8Hz,1H),1.46(d,J＝7.1Hz,9H).
Second step Synthesis of 1- (tert-butyl) 2-methyl (R) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate
Tetrahydrofuran (1 mL) and sodium bis (trimethylsilyl) amide (0.3 mL,0.60 mmol) were added to the flask, nitrogen was used to protect, the flask was cooled to-78 ℃, then a solution of 1-tert-butyl 2-methyl (R) -4-oxopyrrolidine-1, 2-dicarboxylate (120.0 mg,0.49 mmol) in tetrahydrofuran (1 mL) was added dropwise, the reaction was stirred for 30min after the dropwise addition, then a solution of N-phenylbis (trifluoromethanesulfonyl) imide (200.0 mg,0.56 mmol) in tetrahydrofuran (2 mL) was added dropwise, stirring at room temperature for 2h was added, ethyl acetate (20 mL) and water (20 mL) were added, the aqueous phase was extracted with ethyl acetate (20 ml×2), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =20/1) to give the title compound as a colorless oil (100.0 mg, 54%).
MS(ESI,pos.ion)m/z:376.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)5.72(dd,J＝18.9,1.9Hz,1H),5.09–4.96(m,1H),4.43–4.22(m,2H),3.77(s,3H),1.45(d,J＝22.2Hz,9H).
Third step Synthesis of 1- (tert-butyl) 2-methyl (R, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (R) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester (100.0 mg,0.27 mmol), methyl acrylate (45.0 mg,0.52 mmol), triethylamine (0.2 mL,1 mmol), bis (triphenylphosphine) palladium dichloride (18.0 mg,0.03 mmol) and N, N-dimethylformamide (2 mL) were added to a reaction flask, nitrogen protected, the reaction was stirred at 70℃overnight, ethyl acetate (20 mL) and water (20 mL) were added, the solution was separated, the aqueous ethyl acetate (10 mL) was extracted, the organic phases were combined, saturated brine (20 mL) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =10/1) to give the title compound (32.6 mg, 39%).
MS(ESI,pos.ion)m/z:256.1[M-55]+。
Fourth step Synthesis of 1- (tert-butyl) 2-methyl (2R) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (R, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester (240.0 mg,0.77 mmol), ethyl acetate (30 mL) and 10% palladium on charcoal (200 mg) were sequentially added to the reaction flask, hydrogen was replaced, stirred at room temperature for 48H, palladium on charcoal was filtered off, the filtrate was added to silica gel, and then column chromatography was performed (PE/EA (v/v) =3/1) to give the title compound as a colorless transparent oil (90.0 mg, 37%).
MS(ESI,pos.ion)m/z:216.2[M-Boc+H]+。
Fifth step Synthesis of 6- (tert-butyl) 3-methyl (1R, 5R) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylic acid ester
1- (Tert-butyl) 2-methyl (2R) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (270.0 mg,0.86 mmol) and tetrahydrofuran (20 mL) were added sequentially to the reaction flask, the mixture was cooled to-78deg.C, KHMDS (2.0 mL,2.0 mmol) was added dropwise, stirring was continued for 3h at the end of the drop, ethyl acetate (10 mL) and 10% aqueous citric acid solution (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL) after separation, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a colorless oil (90.0 mg, 37%).
MS(ESI,pos.ion)m/z:284.1[M+H]+。
Sixth step Synthesis of (6R, 9R) -4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylic acid tert-butyl ester
To the reaction flask was added 6- (tert-butyl) 3-methyl (1 r,5 r) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylic acid ester (90.0 mg,0.32 mmol), 2-methyl thiourea sulfate (77.0 mg,0.41 mmol), sodium methoxide (85.0 mg,1.57 mmol) and methanol (2 mL) in this order, stirred overnight at room temperature, water (10 mL) and ethyl acetate (10 mL) were added to the mixture, the liquid was separated, the aqueous ethyl acetate (10 mL) was extracted, the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =1/1) to give the title compound as a white solid (36.9 mg, 36%).
MS(ESI,pos.ion)m/z:324.1[M+H]+。
Seventh step Synthesis of tert-butyl (6R, 9R) -2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate
N-phenyl bis (trifluoromethanesulfonyl) imine (1.73 g,4.84 mmol), (6R, 9R) -4-hydroxy-2- (methylsulfanyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (1.044 g,3.23 mmol), N-dimethylpyridine (19.0 mg,0.16 mmol), triethylamine (0.9 mL,6.00 mmol) and dichloromethane (10 mL) were added sequentially, the reaction was stirred for 20min at 40℃and then water (20 mL) and dichloromethane (10 mL) were added sequentially, the aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined, saturated brine (30 mL) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =10/1) to give the title compound as a colorless oil (1.2 g, 82%).
Eighth step Synthesis of tert-butyl (6R, 9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylate
Benzyl (2S) -2- (cyanomethyl) piperazine-1-carboxylate (717.0 mg,2.76 mmol), N-dimethylformamide (12 mL), N-diisopropylethylamine (0.7 mL,4.00 mmol) and (6 r,9 r) -2- (methylsulfanyl) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate (1.20 g,2.63 mmol) were added sequentially to the reaction flask, the mixture was warmed to 60 ℃ and stirred for 2H, cooled to room temperature, ethyl acetate (20 mL) and water (20 mL) were added sequentially, the fractions were separated, the aqueous ethyl acetate (20 mL) extracted, the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified (PE/EA (v/v) =2/1) to give the title compound (1.14 g, 77%).
MS(ESI,pos.ion)m/z:565.2[M+H]+。
Synthesis of tert-butyl (6R, 9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylate
To the reaction flask was added successively tert-butyl (6 r,9 r) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate (1.14 g,2.02 mmol) and dichloromethane (15 mL), cooled to-20 ℃, 93% m-chloroperoxybenzoic acid (382.0 mg,2.06 mmol) was added in portions, stirred for 30min after addition, filtered, the filtrate was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and then purified by column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as a light brown solid (1.10 g, 94%).
MS(ESI,pos.ion)m/z:581.2[M+H]+。
Synthesis of tert-butyl (6S, 9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylate
(6R, 9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepin-8-carboxylic acid tert-butyl ester (1.10 g,1.89 mmol), [ (2S) -1-methylpyrrolidin-2-yl ] methanol (240.0 mg,2.08 mmol) and toluene (15 mL) were added sequentially to the reaction flask, nitrogen protection, cooled to 0deg.C, sodium t-butoxide (273.0 mg,2.84 mmol) was added, incubated for 0.5H after addition, ethyl acetate (20 mL) and water (30 mL) were added, the mixture was separated, ethyl acetate (20 mL. Times.2) was extracted, the organic phase was combined, the saturated brine (30 mL) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography (DCM/MeOH (v/v) =20/v) was purified to afford the title compound as a light brown solid (57.57%).
MS(ESI,pos.ion)m/z:632.3[M+H]+。
Synthesis of benzyl (S) -2- (cyanomethyl) -4- ((6S, 9S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added in order (6 r,9 r) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (680.0 mg,1.08 mmol), ethyl acetate (6.0 mL) and aqueous hydrochloric acid (2.0 mL,8mmol,4.00 mol/L), stirred at room temperature for 3H, sodium carbonate solid was added to adjust pH to 9-10, water (10 mL) was added, the mixed solvent (20 ml×3, dichloromethane/methanol=10/1) was extracted, the organic phase was combined, saturated brine (10 mL) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and then the column chromatography was purified (MeOH/v) =8/1) to give the title compound as a light brown solid (550.0 mg, 96%).
MS(ESI,pos.ion)m/z:532.3[M+H]+。
Synthesis of benzyl (S) -2- (cyanomethyl) -4- ((6R, 9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- ((6 r,9 r) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (500.0 mg,0.94 mmol), 1-bromo-8-methyl-naphthalene (365.0 mg,1.65 mmol), tris (dibenzylideneacetone) dipalladium (43.0 mg,0.05 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (40.0 mg,0.07 mmol), cesium carbonate (612.0 mg,1.88 mmol) and toluene (8 mL), nitrogen protection, stirring reaction was carried out at 110 ℃, ethyl acetate (20 mL) was added, filtered through celite, concentrated, and then column chromatography (DCM/MeOH (v/v=30/1) afforded the title compound as a pale brown solid (40.0.0 mg, 0mg,0.07 mmol).
MS(ESI,pos.ion)m/z:672.4[M+H]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.69–7.59(m,1H),7.51–7.20(m,8H),7.07(dd,J＝14.5,7.4Hz,1H),6.61(dd,J＝26.6,7.4Hz,1H),5.14(q,J＝12.4Hz,2H),4.57(s,1H),4.06–3.78(m,4H),3.67–3.37(m,3H),3.27–3.09(m,3H),3.08–2.59(m,10H),2.44–1.86(m,8H),1.72–1.44(m,3H).
Synthesis of thirteenth step 2- ((S) -4- ((6R, 9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- ((6 r,9 r) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (130.0 mg,0.19 mmol), methanol (4 mL) and 10% palladium on charcoal (28.0 mg), protected with hydrogen, stirred at room temperature for 8H, supplemented with 10% palladium on charcoal (10.0 mg), stirred at room temperature overnight, the above mixture was filtered off palladium on charcoal, and the filtrate was concentrated and purified by column chromatography (DCM/MeOH (v) =20/1) to give the title compound as a pale yellow solid (86.0 mg, 77%).
MS(ESI,pos.ion)m/z:538.3[M+H]+。
Synthesis of fourteenth step 2- ((S) -1-propenoyl-4- ((6R, 9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methylpyrimidinyl [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- ((6 r,9 r) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (80.0 mg,0.15 mmol), dichloromethane (2 mL) and triethylamine (30.0 mg,0.30 mmol) were added sequentially to the reaction flask, cooled to 0 ℃, then acryloyl chloride (16.0 mg,0.18 mmol) was added dropwise, stirring at room temperature was completed for 30min, methanol (2 mL), water (2 mL) and dichloromethane (10 mL), the fractions were added, aqueous dichloromethane (10 ml×2) was extracted, the combined organic phases were washed with anhydrous brine, dried over sodium sulfate, filtered, the filtrate was concentrated, and then the column chromatography was purified (MeOH/v) =20/1) to give the title compound as a pale yellow solid (62.7 mg, 71%).
MS(ESI,pos.ion)m/z:592.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.65(s,1H),7.47(d,J＝7.2Hz,1H),7.31(dd,J＝19.7,12.2Hz,2H),7.16–7.02(m,1H),6.86(s,1H),6.72–6.53(m,1H),6.18(d,J＝16.5Hz,1H),5.77(d,J＝9.7Hz,1H),4.84(d,J＝81.3Hz,1H),4.41(s,1H),4.12–3.76(m,4H),3.57(d,J＝78.6Hz,4H),3.27–3.17(m,2H),3.12–2.64(m,12H),2.22(dt,J＝53.6,17.6Hz,8H),1.63(s,4H).
Example 4 2- ((S) -1-propenoyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of 1-tert-butyl 3-ethyl 4-oxoazaane-1, 3-dicarboxylic acid ester
N-t-Butoxycarbonyl-3-piperidone (15.20 g,76.29 mmol) and diethyl ether (150 mL) were added sequentially to the flask, nitrogen was purged, cooled to-30deg.C, boron trifluoride diethyl ether solution (12.5 mL,99.50 mmol) was added dropwise, stirred for 30min after completion of the dropwise addition, 95% ethyl diazoacetate (10.5 mL,94.90 mmol) was added dropwise, stirred for 1h at room temperature, saturated aqueous sodium bicarbonate solution (200 mL) was added, stirred for 60min at room temperature, the separated solution, aqueous ethyl acetate (50 mL. Times.2) was extracted, the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a bright yellow transparent oil (21.76 g, 100%).
Second step Synthesis of tert-butyl 4-hydroxy-2- (methylthio) -5,7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepine-6-carboxylate
To a single port flask were added 1-tert-butyl 3-ethyl 4-oxazane-1, 3-dicarboxylic acid ester (21.00 g,73.61 mmol), S-methylisothiourea sulfate (20.78 g,110.40 mmol), methanol (200 mL) and sodium methoxide (19.87 g,368.00 mmol) in this order, the mixture was stirred overnight at room temperature, diluted with ethyl acetate (100 mL) to adjust pH to neutral, ethyl acetate (200 mL. Times.3) was extracted, the organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as an off-white solid (11.77 g, 51%).
MS(ESI,pos.ion)m/z:312.1[M+H]+。
Step three Synthesis of tert-butyl 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) butyl-5, 7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepin-6-carboxylate
To the reaction flask was added tert-butyl 4-hydroxy-2- (methylsulfanyl) -5,7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepine-6-carboxylate (100.0 mg,0.32 mmol), dichloromethane (3 mL) and triethylamine (64.0 mg,0.63 mmol), nitrogen protection, cooled to 0 ℃, then triflic anhydride (108.0 mg,0.38 mmol) was added dropwise, the mixture was transferred to room temperature with stirring for 30min, water (10 mL) was added, the liquid was separated, the aqueous phase was extracted with dichloromethane (10 ml×2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) =10/1) to give the title compound as a pale solid (48.50 mg, 34%).
MS(ESI,pos.ion)m/z:444.1[M+H]+。
Synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -5,7,8, 9-tetrahydro-6H-pyrimidinyl [5,4-c ] azepine 6-carboxylate
To the reaction flask was added tert-butyl 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) 2- (((3.51 g,9.68 mmol) 2- (cyanomethyl) piperazine-1-carboxylate (2.51 g,9.68 mmol), N-dimethylacetamide (50 mL) and N, N-diisopropylethylamine (3.0 mL,17.00 mmol) in this order, the reaction was stirred at 100℃for 1H, cooled to room temperature, dichloromethane (50 mL) and water (100 mL) were added as a separate liquid, the aqueous phase was extracted with dichloromethane (50 mL. Times.2), the organic phases were combined, washed with saturated brine (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, followed by column chromatography purification (PE/EA (v/v) =3/1) to give the compound (900.00 mg, 82%).
MS(ESI,pos.ion)m/z:553.2[M+H]+。
Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -5,7,8, 9-tetrahydro-6H-pyrimidinyl [5,4-c ] azepine 6-carboxylate (773.7 mg,1.40 mmol), dichloromethane (12 mL) and TFA (3 mL) in sequence, and the reaction was stirred at room temperature and evaporated to dryness to give the title compound as a transparent oil (633.6 mg, 100%).
Sixth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -benzyl 2- (cyanomethyl) -4- (2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate (2.34 g,5.17 mmol), 1-bromo-8-methylnaphthalene (1.37 g,6.20 mmol), tris (dibenzylideneacetone) dipalladium (237.0 mg,0.26 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (239.0 mg,0.41 mmol), cesium carbonate (3.37 g,10.30 mmol) and toluene (25 mL), nitrogen-protected, warmed to 110 ℃ and stirred for 24H, cooled to room temperature, ethyl acetate (20 mL) diluted and filtered, the filtrate concentrated, then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a yellow solid (900.0 mg, 29%).
MS(ESI,pos.ion)m/z:593.3[M+H]+。
Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (methylsulfonyl) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (100.0 mg,0.17 mmol) and dichloromethane (10 mL), cooled to 0 ℃, then m-chloroperoxybenzoic acid (34.0 mg,0.17mmol,85 mass%) was added, stirred at heat-retaining for 20min, diluted with dichloromethane (10 mL) and water (10 mL), the aqueous phase was extracted with dichloromethane (10 mL), the organic phases combined, washed with saturated aqueous sodium bicarbonate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (DCM/v) =50/1) to give the title compound as a yellow solid (83.0 mg, 81%).
MS(ESI,pos.ion)m/z:625.3[M+H]+。
Eighth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (methylsulfonyl) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (660.0 mg,1.08 mmol), N-methyl-L-prolinol (139.0 mg,1.21 mmol) and toluene (20 mL), cooled to 0 ℃, then sodium tert-butoxide (211.0 mg,2.20 mmol) was added, the reaction was stirred at room temperature for 30min, ethyl acetate (20 mL) and water (20 mL) were added, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as a pale yellow solid (500.0 mg, 70%).
MS(ESI,pos.ion)m/z:660.3[M+H]+。
Synthesis of ninth step 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (100.0 mg,0.15 mmol), palladium on charcoal (10.0 mg,10 mass%) and methanol (4 mL), hydrogen protected, stirred at room temperature overnight, palladium on charcoal was filtered off and the resulting filtrate concentrated to give thick preparation plate isolated (DCM/MeOH (v/v) =10/1) as a pale yellow solid (79.7 mg, 100%).
MS(ESI,pos.ion)m/z:526.3[M+H]+。
Synthesis of tenth step 2- ((S) -1-propenoyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (80.0 mg,0.152 mmol), dichloromethane (4.0 mL) and N, N-diisopropylethylamine (39.0 mg,0.30 mmol) were added sequentially to the reaction flask, cooled to-10 ℃, then acryloyl chloride (16.0 mg,0.18 mmol), incubated for 10min after completion, warmed to room temperature, and the mixture was concentrated to thick prep plate separated (DCM/MeOH (v/v) =20/1) to give the title compound as a pale yellow solid (30.3 mg, 34%).
MS(ESI,pos.ion)m/z:580.3[M+H]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.81–7.65(m,2H),7.46(d,J＝13.6Hz,2H),7.36(dd,J＝15.2,7.9Hz,1H),7.25(t,J＝6.2Hz,1H),6.81–6.39(m,1H),6.03(d,J＝16.6Hz,1H),5.66(dd,J＝10.4,2.2Hz,1H),4.69(d,J＝67.9Hz,1H),4.23(d,J＝52.0Hz,4H),3.57(s,2H),3.43(d,J＝13.4Hz,2H),3.11(dd,J＝30.9,19.9Hz,4H),2.97–2.72(m,7H),2.67(s,2H),2.44(s,3H),2.33(s,1H),2.02–1.89(m,4H),1.68(d,J＝36.3Hz,3H).
Example 5 2- ((S) -1-propenoyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of ethyl 4- ((8-chloronaphthalen-1-yl) amino) -3-oxobutyrate
To a solution of 8-chloronaphthalene-1-amine (8.00 g,45.0 mmol), potassium iodide (14.98 g,90.0 mmol) and sodium carbonate (7.58 g,90.1 mmol) in acetonitrile (200 mL) was added ethyl 4-chloro-3-oxobutyrate (14.85 g,90.2 mmol), the reaction was heated to reflux for 10h, cooled to room temperature, the reaction solution was concentrated, saturated sodium sulfite (100 mL) and water (100 mL), ethyl acetate (200 ml×3) were added to extract, and the organic phases were combined, washed successively with saturated sodium sulfite (100 mL), water (100 ml×2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =1/4) to give the title compound as a brownish red solid (7.57 g, 55%).
MS(ESI,pos.ion)m/z:306.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.67(dd,J＝8.1,0.5Hz,1H),7.70-7.65(m,1H),7.53(s,1H),7.42(dd,J＝7.4,1.0Hz,1H),7.33(t,J＝7.9Hz,1H),7.28(t,J＝7.8Hz,1H),7.21(d,J＝8.0Hz,1H),6.41(d,J＝7.7Hz,1H),4.28-4.23(m,4H),3.61(s,2H),1.32(t,J＝7.1Hz,3H).
Second step Synthesis of ethyl 4- (3-chloro-N- (8-chloronaphthalen-1-yl) propanamide) -3-oxobutyrate
To a solution of ethyl 4- ((8-chloronaphthalen-1-yl) amino) -3-oxobutyrate (7.00 g,22.9 mmol) and sodium carbonate (4.87 g,46.0 mmol) in dichloromethane (120 mL) was added dropwise a solution of 3-chloropropionyl chloride (4.37 g,33.4 mmol) in anhydrous dichloromethane (5.0 mL) at 0 ℃ C.) and the reaction was stirred at room temperature for 2h, water (150 mL) was added to quench the reaction, the separated liquid, the aqueous phase was extracted with dichloromethane (100 mL. Times.2), the organic phases were combined, then washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried under reduced pressure and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a brownish red liquid (8.90 g, 98%).
MS(ESI,pos.ion)m/z:396.1[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.96(d,J＝8.2Hz,1H),7.91-7.85(m,2H),7.67(dd,J＝7.5,0.7Hz,1H),7.56(t,J＝7.8Hz,1H),7.47(t,J＝7.8Hz,1H),5.20(d,J＝17.8Hz,1H),4.15(q,J＝7.1Hz,1H),3.86(t,J＝12.7Hz,1H),3.81-3.68(m,2H),3.61(d,J＝15.9Hz,1H),3.53(d,J＝15.9Hz,1H),2.61(ddd,J＝16.7,7.8,6.7Hz,1H),2.39(ddd,J＝16.7,7.9,6.3Hz,1H),1.22(t,J＝7.1Hz,3H).
Third step Synthesis of ethyl 1- (8-chloronaphthalen-1-yl) -3, 7-dioxaazepin-4-carboxylate
To a solution of ethyl 4- (3-chloro-N- (8-chloronaphthalen-1-yl) propanamide) -3-oxobutanoate (0.71 g,1.79 mmol) in acetone (10.0 mL) was added potassium carbonate (0.51 g,3.66 mmol) and potassium iodide (0.45 g,2.70 mmol), heated to reflux for 10h, dried under reduced pressure, dichloromethane (10 mL) and water (10 mL) were added, then 3M HCl was added to adjust the system to ph=5, the separated liquid was taken up, the aqueous phase was extracted with dichloromethane (10 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, dried over reduced pressure, and then purified by column chromatography (PE/EA (v/v) =1/1) to give the title compound as a pale yellow viscous liquid (0.27 g, 42%).
MS(ESI,pos.ion)m/z:360.1[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.89(d,J＝8.1Hz,1H),7.84(d,J＝8.1Hz,1H),7.67(d,J＝6.7Hz,0.5H),7.64-7.58(m,1H),7.57-7.49(m,1H),7.48-7.43(m,0.5H),7.40(t,J＝7.8Hz,1H),4.94(d,J＝7.9Hz,0.5H),4.87(s,0.5H),4.46-4.40(m,0.5H),4.25-4.08(m,1.5H),3.98(q,J＝7.1Hz,1H),3.41(q,J＝15.7Hz,1H),2.97-2.85(m,0.5H),2.76-2.57(m,2.5H),2.39-2.29(m,0.5H),2.25-2.16(m,0.5H),1.25(t,J＝7.1Hz,1.5H),1.03(t,J＝7.1Hz,1.5H).
Fourth step Synthesis of 8- (8-chloronaphthalen-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepin-4, 7-dione
To ethyl 1- (8-chloronaphthalen-1-yl) -3, 7-dioxan-4-carboxylate (3.60 g,10.0 mmol) and S-methylisothiourea sulfate (2.79 g,10.0 mmol) were added potassium carbonate (5.58 g,40.4 mmol) and water (100 mL), the reaction was stirred vigorously overnight, then 2M HCl was added to adjust pH to 5, dichloromethane (100 mL. Times.6) was extracted, the organic phases combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a white solid (2.30 g, 60%). MS (ESI, pos.ion) m/z 386.1[ M+H ] +;
1H NMR(400MHz,CDCl3):δ(ppm)12.77(s,1H),7.84(t,J＝7.6Hz,2H),7.64(d,J＝6.9Hz,1H),7.40(dt,J＝11.2,7.9Hz,2H),7.06-6.98(m,1H),5.79(s,1H),4.76(d,J＝6.9Hz,1H),3.08-2.91(m,1H),2.83-2.66(m,2H),2.64(s,3H),2.37-2.21(m,1H).
Fifth step Synthesis of benzyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To a solution of 8- (8-chloronaphthalen-1-yl) -2- (methylsulfanyl) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepine-4, 7-dione (1.10 g,2.86 mmol) in acetonitrile (20.0 mL) was added BOP (1.64 g,3.71 mmol) and DBU (0.90 g,5.88 mmol), stirred at room temperature for 30min, (S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (0.83 g,3.19 mmol) was added, the reaction was stopped by heating to 60℃overnight, dried under reduced pressure, dichloromethane (100 mL) was added, washed sequentially with water (50 mL. Times.2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =1/2) to give the title compound as a yellow solid (1.0 g, 56%).
MS(ESI,pos.ion)m/z:627.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.87-7.76(m,2H),7.67-7.60(m,1H),7.46-7.32(m,7H),7.12(dd,J＝12.9,6.8Hz,1H),5.81(d,J＝7.1Hz,1H),5.18(s,2H),4.88-4.78(m,1H),4.60-4.48(m,1H),4.38-4.19(m,1H),4.10-3.80(m,2H),3.49-3.31(m,1H),3.29-2.93(m,3H),2.80-2.61(m,3H),2.59(s,3H),2.53-2.44(m,1H),2.36-2.19(m,1H).
Synthesis of benzyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfinyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To a solution of benzyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfanyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.50 g,0.80 mmol) in dichloromethane (20.0 mL) at 0deg.C was added m-chloroperoxybenzoic acid (0.17 g,0.90 mmol), stirred for 30min with heat, dichloromethane (50 mL) was added, washed sequentially with saturated sodium carbonate (30 mL. Times.2), water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to afford the title compound as an off-white solid (0.50 g, 97%). MS (ESI, pos.ion) m/z 643.3[ M+H ] +.
Seventh step Synthesis of benzyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To a solution of benzyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfonyl) oxy-7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.50 g,0.78 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (0.10 g,0.89 mmol) in dichloromethane (20.0 mL) was added sodium tert-butoxide (0.16 g,1.66 mmol), stirred at constant temperature for 1H, evaporated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a yellow solid (0.45 g, 83%). 200mg of the mixture was taken and purified by thick prep plate (DCM/MeOH (v/v) =15/1) to give 0.17g of a pale yellow solid.
MS(ESI,pos.ion)m/z:694.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.86-7.76(m,2H),7.67-7.59(m,1H),7.47-7.30(m,7H),7.14(dd,J＝10.4,7.4Hz,1H),5.81(d,J＝4.2Hz,1H),5.18(s,2H),4.90-4.81(m,1H),4.57-4.41(m,2H),4.36-4.26(m,1H),4.14-3.85(m,5H),3.57-3.38(m,2H),3.36-3.25(m,1H),3.24-2.95(m,4H),2.79-2.65(m,3H),2.58-2.44(m,4H),2.40-2.28(m,2H),2.13-2.01(m,1H).
Eighth step Synthesis of 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To a solution of benzyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.15 g,0.22 mmol) in methanol (10.0 mL) was added palladium on charcoal (0.15 g, 10%) and the reaction stirred at room temperature under a hydrogen atmosphere for 30min, filtered and the filtrate concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =7/1) to give the title compound as a yellow solid (97 mg, 80%).
MS(ESI,pos.ion)m/z:560.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.81(dd,J＝8.1,3.4Hz,2H),7.65-7.60(m,1H),7.44-7.32(m,2H),7.18-7.13(m,1H),5.82(d,J＝1.4Hz,1H),4.89-4.79(m,1H),4.63-4.48(m,1H),4.40-4.18(m,2H),4.00-3.77(m,1H),3.34-3.16(m,1H),3.08-2.95(m,4H),2.92-2.84(m,1H),2.78-2.72(m,2H),2.72-2.65(m,2H),2.64-2.56(m,3H),2.49-2.41(m,2H),2.37-2.28(m,2H),2.18-2.07(m,2H),1.91-1.78(m,3H).
Synthesis of ninth step 2- ((S) -1-propenoyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To a solution of 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (87.0 mg,0.16 mmol) and triethylamine (33.6 mg,0.33 mmol) in dichloromethane (10.0 mL) was slowly added dropwise a solution of acryloyl chloride (22.3 mg,0.25 mmol) in dry dichloromethane (0.5 mL) and stirred at room temperature for 30min, quenched with water (10 mL), the aqueous phase was extracted with DCM (10 ml×4), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, followed by column chromatography (DCM/v) =15/1) to give the title compound as an off-white solid (43.4 mg, 46%).
MS(ESI,pos.ion)m/z:614.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.86-7.74(m,2H),7.61(d,J＝6.7Hz,1H),7.44-7.30(m,2H),7.10(dd,J＝20.4,7.3Hz,1H),6.61-6.45(m,1H),6.39-6.29(m,1H),5.85-5.74(m,1H),4.91-4.80(m,1H),4.70-4.57(m,1H),4.48-4.35(m,1H),4.32-4.10(m,1H),4.05-3.83(m,1H),3.13-2.90(m,3H),2.84-2.45(m,8H),2.25-2.07(m,4H),2.05-1.96(m,1H),1.95-1.82(m,2H),1.34-1.18(m,4H);
13C NMR(151MHz,CDCl3)δ(ppm)177.4,170.0,165.1,164.0,136.9,132.0,131.0,130.8,130.3,130.2,129.5,128.8,128.1,127.1,126.5,126.3,126.2,126.0,115.3,95.7,67.8,57.4,45.8,41.3,31.5,30.3,30.1,29.7,28.2,25.1,22.5,22.5,8.6.
Example 6 (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-1-yl) prop-2-en-1-one
First step Synthesis of tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepine-8 (9H) -carboxylate
To the reaction flask was added 4-tert-butyl 7-ethyl 6-oxo-1, 4-oxazepan-4, 7-dicarboxylic acid ester (3.0 g,10.1 mmol) and methanol (50 mL), stirred at room temperature, then sodium methoxide (2.82 g,50.6 mmol) and S-methylisothiourea sulfate (3.5 g,18.2 mmol) were added, reacted overnight at room temperature, adjusted to pH=3 with 1N hydrochloric acid, concentrated to remove methanol, water (50 mL) was added, stirred for 20min, filtered to give the title compound as a white solid (2.78 g, 88%).
MS(ESI,pos.ion)m/z:314.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)11.76(s,1H),4.52(d,J＝38.2Hz,2H),4.18(d,J＝19.1Hz,2H),3.86(m,2H),2.55(s,3H),1.44(s,9H).
Second step Synthesis of tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylsulfanyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate
To the reaction flask was added tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (500 mg,1.6 mmol), BOP (936 mg,2.1 mmol), DBU (0.4 mL,3 mmol) and acetonitrile (7 mL), reacted at room temperature for 20min, benzyl piperazine-1-carboxylate (0.5 mL,3 mmol) was added, reacted at 40℃for 5H, cooled to room temperature, concentrated to remove the solvent, and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a yellow solid (576 mg, 70%).
MS(ESI,pos.ion)m/z:516.2[M+H]+。
Third step Synthesis of tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylsulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate
To the reaction flask was added tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylsulfanyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxaazepan-8 (9H) -carboxylate (550 mg,1.1 mmol) and ethyl acetate (5 mL), stirred at 0deg.C, m-chloroperoxybenzoic acid (238 mg,1.2 mmol) was added, reacted at 0deg.C for 1H, ethyl acetate (200 mL) was added, diluted with saturated aqueous sodium bicarbonate (16 mL) and the organic phase was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (480 mg, 85%).
MS(ESI,pos.ion)m/z:532.1[M+H]+。
Synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate
To the reaction flask was added tert-butyl 4- (4- ((benzyloxy) carbonyl) -piperazin-1-yl) -2- (methylsulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxaazepan-8 (9H) -carboxylate (1.054 g,2.0 mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (433 mg,3.6 mmol) and toluene (10 mL), cooled to 0 ℃, sodium tert-butoxide (385 mg,4.0 mmol) was added, the reaction was continued at 0℃for 1H, ethyl acetate (200 mL) was added, then water (20 mL) was used to wash the organic phase, and then column chromatography purification (dichloromethane: 1.1M methanolic (v/v) =100/1) afforded a yellow solid (1.06 g, 92%).
MS(ESI,pos.ion)m/z:583.3[M+H]+。
Fifth step Synthesis of benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate
To the reaction flask was added tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (480 mg,0.82 mmol), trifluoroacetic acid (4 mL) and dichloromethane (8 mL) and reacted at room temperature for 2H, concentrated to remove solvent and the concentrate was used directly in the next reaction (417 mg, 100%).
Sixth step Synthesis of benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate
To the flask was added benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (410 mg,0.85 mmol), 1-bromonaphthalene (0.4 mL,3 mmol), pd 2(dba)3 (79 mg,0.085 mmol), xantphos (100 mg,0.17 mmol), cesium carbonate (847 mg,2.6 mmol) and toluene (5 mL), nitrogen protection, reacted overnight at 100 ℃, cooled to room temperature, the reaction concentrated to dryness, then column chromatography purified (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (417.0 mg, 81%). MS (ESI, pos.ion) m/z 609.3[ M+H ] +.
Seventh step Synthesis of (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan
To the reaction flask was added benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (140 mg,0.23 mmol), palladium on charcoal (70 mg,0.066 mmol), 7M ammonia in methanol (4 mL) and methanol (4 mL), and the reaction was carried out overnight at room temperature under hydrogen protection, filtered through celite, the filtrate was concentrated to dryness and the concentrate was used directly for the next reaction (113 mg, 100%).
MS(ESI,pos.ion)m/z:475.3[M+H]+。
Eighth step Synthesis of (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-1-yl) prop-2-en-1-one
To the reaction flask was added (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan (60 mg,0.13 mmol), DIPEA (40 mg,0.31 mmol) and dichloromethane (2 mL), cooled to 0 ℃, acryloyl chloride (20 mg,0.22 mmol) was slowly added dropwise, stirred at room temperature for 2h, the reaction concentrated to dryness, and then purified by column chromatography (EtOAc/MeOH (v/v) =90/10) to give the title compound as a yellow solid (25 mg, 37%).
MS(ESI,pos.ion)m/z:529.3[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)8.27(m,1H),7.89(m,1H),7.56(d,J＝8.1Hz,1H),7.46(m,2H),7.37(t,J＝7.7Hz,1H),7.16(d,J＝7.3Hz,1H),6.60(m,1H),6.34(d,J＝16.7Hz,1H),5.75(d,J＝10.6Hz,1H),4.36(s,2H),4.17(s,2H),3.89(s,4H),3.80(s,2H),3.66(m,4H),3.15(t,J＝7.4Hz,1H),2.76(s,1H),2.52(s,1H),2.33(m,1H),2.14(m,1H),2.00(s,3H),1.86(m,1H),1.78(s,2H),0.87(m,1H).
Example 7 (S) -1- (4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazin-1-yl) prop-2-en-1-one
First step Synthesis of benzyl (S) -4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate
To the reaction flask was added benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (934 mg,1.9 mmol), 1-bromo-8-methylnaphthalene (771 mg,2.9 mmol), pd 2(dba)3 (181 mg,0.19 mmol), xantphos (231mg, 0.39 mmol), cesium carbonate (1.93 g,5.8 mmol) and toluene (10 mL), reacted overnight under nitrogen protection at 100 ℃ and cooled to room temperature, the reaction was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (0.84 g, 70%).
MS(ESI,pos.ion)m/z:623.4[M+H]+。
Second step Synthesis of (S) -8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan
To the flask was added benzyl (S) -4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (420 mg,0.67 mmol), palladium on charcoal (210 mg,0.2 mmol), 7M ammonia in methanol (4 mL) and methanol (4 mL), and the mixture was reacted overnight at room temperature under hydrogen protection, filtered through celite, the filtrate was concentrated to dryness and the concentrate was used directly for the next reaction (331 mg, 100%).
MS(ESI,pos.ion)m/z:489.3[M+H]+。
Synthesis of benzyl (S) -4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate
To the reaction flask was added (S) -8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan (100 mg,0.20 mmol), DIPEA (60 mg,0.46 mmol) and dichloromethane (3 mL), cooled to 0 ℃, acryloyl chloride (30 mg,0.33 mmol) was slowly added dropwise, stirred at room temperature for 2h, the reaction concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (6 mg, 5%).
MS(ESI,pos.ion)m/z:543.3[M+H]+。
Example 8 2- ((S) -1-propenoyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate
To the reaction flask was added tert-butyl 4-hydroxy-2- (methylsulfanyl) -6, 7-dihydropyrimido-o [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (1.2 g,3.8 mmol), BOP (2.25 g,5.0 mmol), DBU (0.9 mL,6.0 mmol) and acetonitrile (20 mL), reacted at room temperature for 30min, benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.12 g,4.2 mmol), reacted at 40℃for 5H, cooled to room temperature, concentrated to remove the solvent, and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a yellow solid (1.35 g, 64%).
MS(ESI,pos.ion)m/z:555.2[M+H]+。
Second step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate
To the reaction flask was added tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (1.3 g,2.3 mmol) and ethyl acetate (12 mL), stirred at 0 ℃, m-chloroperoxybenzoic acid (803 mg,2.6 mmol) was added, reacted for 2H at 0 ℃, ethyl acetate (200 mL) was added, diluted, saturated aqueous sodium bicarbonate (20 mL) was added, the organic phase was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (0.84 g, 63%).
MS(ESI,pos.ion)m/z:571.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.36(m,5H),5.19(s,2H),4.72(m,5H),4.24(m,2H),4.12(m,1H),3.98(m,1H),3.78(m,1H),3.34(m,3H),2.88(s,4H),2.62(d,J＝16.1Hz,1H),1.42(s,9H).
Step 3 Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate
To the reaction flask was added tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxaazepane-8 (9H) -carboxylate (840 mg,1.5 mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (321 mg,2.7 mmol) and toluene (10 mL), cooled to 0 ℃, sodium tert-butoxide (284 mg,3.0 mmol) was added, the reaction was continued at 0 ℃ for 1H, ethyl acetate (200 mL) was added, then water (20 mL) was washed, and the organic phase was concentrated to dryness, then purified by column chromatography (dichloromethane/methanol (v/v) =100/1) to give the title compound as a yellow solid (933 mg, 100%).
MS(ESI,pos.ion)m/z:622.5[M+H]+。
Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate
To the reaction flask was added 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester (833 mg,1.3 mmol), trifluoroacetic acid (4 mL) and dichloromethane (8 mL), reacted for 2H at room temperature, dichloromethane (200 mL) was added, saturated aqueous sodium bicarbonate solution (15 mL) was washed and the organic phase concentrated to give the title compound as a yellow solid (740 mg, 100%).
MS(ESI,pos.ion)m/z:522.3[M+H]+。
Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate
To the flask was added benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (740 mg,1.4 mmol), 1-bromo-8-methylnaphthalene (480 mg,2.1 mmol), pd 2(dba)3 (133 mg,0.14 mmol), xantphos (169 mg,0.28 mmol), cesium carbonate (1.42 g,4.3 mmol) and toluene (10 mL), protected with nitrogen, reacted overnight at 100 ℃ to room temperature, the reaction was concentrated to dryness, and then column chromatography purified (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (670.0 mg, 71%).
MS(ESI,pos.ion)m/z:662.3[M+H]+。
Sixth step Synthesis of 2- ((S) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added benzyl (S) -2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (330 mg,0.50 mmol), palladium on charcoal (165 mg,0.16 mmol), 7M ammonia in methanol (6 mL) and methanol (6 mL), and the reaction was allowed to proceed overnight at room temperature under hydrogen protection, filtered through celite, and the filtrate concentrated to dryness and the concentrate was used directly in the next reaction (281mg, 100%).
MS(ESI,pos.ion)m/z:528.3[M+H]+。
Seventh step Synthesis of 2- ((S) -1-propenoyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile (281mg, 0.53 mmol), DIPEA (0.2 mL,1.0 mmol) and dichloromethane (4 mL) were added to the reaction flask, cooled to 0deg.C, acryloyl chloride (60 mg,0.65 mmol) was slowly added dropwise, stirred at room temperature for 3h, the reaction was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (65 mg, 21%).
MS(ESI,pos.ion)m/z:582.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.66(d,J＝8.0Hz,1H),7.62(d,J＝7.9Hz,1H),7.33(m,3H),7.22(d,J＝6.9Hz,1H),6.68(m,1H),6.39(d,J＝16.1Hz,1H),5.82(d,J＝10.4Hz,1H),5.05(s,1H),4.75(m,1H),4.68(m,2H),4.45(m,4H),4.14(m,1H),3.96(s,1H),3.65(m,5H),3.21(m,3H),2.87(s,3H),2.69(m,4H),2.55(s,1H),2.16(m,1H),2.02(m,1H),1.89(m,2H).
Example 9 2- ((S) -1-propenoyl-4-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of ethyl 5- (naphthalen-1-ylamino) valerate
1-Aminonaphthalene (3.5 g,24.2 mmol), ethyl 5-bromopentanoate (5.16 g,24.2 mmol), sodium acetate (2.1 g,25 mmol) and absolute ethanol (50 mL) were added to the reaction flask, the reaction was refluxed overnight, cooled to room temperature, diluted with ethyl acetate (200 mL), washed once with water (25 mL), and the organic phase was concentrated to dryness, then purified by column chromatography (PE/EA (v/v) =10/1) to give the title compound as a yellow solid (5.92 g, 90%).
MS(ESI,pos.ion)m/z:272.2[M+H]+。
Second step Synthesis of ethyl 5- (2-ethoxy-N- (naphthalen-1-yl) -2-oxoacetamido) valerate
Ethyl 5- (naphthalen-1-ylamino) valerate (2.12 g,7.8 mmol), sodium carbonate (996 mg,9.4 mmol) and toluene (16 mL) were added to the reaction flask, stirred at 0℃and oxalyl chloride monoethyl ester (803 mg,2.6 mmol) was added to react at room temperature for 2h, the reaction solution was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =5/1) to give the title compound as a yellow solid (2.05 g, 71%).
MS(ESI,pos.ion)m/z:372.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.89(m,3H),7.64(m,2H),7.44(t,J＝7.7Hz,1H),7.37(dd,J＝7.1,0.7Hz,1H),4.35(m,1H),4.08(q,J＝7.1Hz,2H),3.87(m,2H),3.46(m,1H),2.30(t,J＝7.0Hz,1H),1.81(m,2H),1.66(m,1H),1.20(t,J＝7.1Hz,3H),0.57(t,J＝7.1Hz,3H).
Third step Synthesis of ethyl 3-hydroxy-1- (naphthalen-1-yl) -2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-carboxylate
Ethyl 5- (2-ethoxy-N- (naphthalen-1-yl) -2-oxoacetamido) valerate (1.01 g,5.5 mmol) and tetrahydrofuran (25 mL) were added to the reaction flask, cooled to 0deg.C, 60% sodium hydride (331 mg,8.3 mmol) was added, reacted at room temperature for 2h, diluted with ethyl acetate (200 mL), washed once with saturated aqueous ammonium chloride (12 mL), and the organic phase was concentrated to dryness, then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a yellow solid (1.01 g, 56%).
MS(ESI,pos.ion)m/z:326.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)12.29(s,1H),8.01(m,2H),7.84(m,1H),7.65(m,3H),7.36(m,1H),4.50(m,2H),3.98(m,1H),3.60(m,1H),2.94(m,1H),2.63(m,1H),2.27(m,1H),1.93(m,1H),1.39(t,J＝7.1Hz,3H).
Fourth step Synthesis of 4-hydroxy-2- (methylthio) -8- (naphthalen-1-yl) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one
Ethyl 3-hydroxy-1- (naphthalen-1-yl) -2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-carboxylate (657 mg,2.0 mmol), S-methylisothiourea sulfate (700 mg,3.7 mmol), sodium carbonate (1.072 g,10.1 mmol) and toluene (10 mL) were added to a microwave tube, reacted at 110℃for 6H, cooled to room temperature, diluted with ethyl acetate (100 mL), adjusted to pH=4 with 1N aqueous hydrochloric acid, the organic phase concentrated to dryness and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a yellow solid (104 mg, 15%).
MS(ESI,pos.ion)m/z:352.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)11.61(s,1H),8.01(m,3H),7.64(m,3H),7.45(d,J＝6.9Hz,1H),4.01(m,1H),3.76(m,1H),3.31(m,1H),2.87(m,1H),2.68(s,3H),2.29(m,1H),2.12(m,1H).
Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added 4-hydroxy-2- (methylthio) -8- (naphthalen-1-yl) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one (185 mg,0.53 mmol), BOP (320 mg,0.71 mmol), triethylamine (0.15 mL,1.1 mmol) and acetonitrile (3 mL), reacted at room temperature for 30min, benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (155 mg,0.59 mmol) was added, reacted overnight at 80 ℃, cooled to room temperature, the reaction concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a yellow solid (151 mg, 48%).
MS(ESI,pos.ion)m/z:593.2[M+H]+。
Sixth step Synthesis of benzyl (2S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added benzyl (S) -2- (cyanomethyl) -4- (2- (methylsulfanyl) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (142 mg,0.24 mmol) and ethyl acetate (3 mL), stirred at 0 ℃, m-chloroperoxybenzoic acid (55 mg,0.27 mmol) was added, reacted for 2H at 0 ℃, ethyl acetate (100 mL) was added, diluted, saturated aqueous sodium bicarbonate (8 mL) was added, the organic phase was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (184 mg, 100%).
MS(ESI,pos.ion)m/z:609.4[M+H]+。
Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added benzyl (2S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (184 mg,0.30 mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (70 mg,0.58 mmol) and toluene (4 mL), cooled to 0 ℃, sodium tert-butoxide (60 mg,0.62 mmol) was added, reacted at 0 ℃ for 1H, diluted with ethyl acetate (100 mL), washed once with water (10 mL) and the organic phase concentrated to dryness before column chromatography purification (DCM/MeOH (v/v) =100/1) gave the title compound as a yellow solid (84 mg, 42%).
MS(ESI,pos.ion)m/z:660.5[M+H]+。
Eighth step Synthesis of 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To the flask was added benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (84 mg,0.13 mmol), palladium on charcoal (42 mg,0.039 mmol), 7M ammonia in methanol (6 mL) and methanol (6 mL), protected with hydrogen, reacted overnight at room temperature, the reaction was filtered with celite, the filtrate concentrated and the concentrate was used directly in the next reaction (84 mg, 100%).
Synthesis of ninth step 2- ((S) -1-propenoyl-4-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (50 mg,0.095 mmol), DIPEA (30 mg,0.23 mmol) and dichloromethane (2 mL) were added to the reaction flask, cooled to 0 ℃, acryloyl chloride (15 mg,0.16 mmol) was slowly added dropwise, stirred at room temperature for 2H, the reaction concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (3 mg, 5%).
MS(ESI,pos.ion)m/z:580.3[M+H]+。
Example 10- ((S) -1-propenoyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of ethyl 5- ((8-chloronaphthalen-1-yl) amino) valerate
8-Chloro-1-aminonaphthalene (5.0 g,27.7 mmol), ethyl 5-bromopentanoate (11.8 g,55.3 mmol), sodium bicarbonate (4.68 g,55.4 mmol) and acetonitrile (60 mL) were added to the reaction flask, the reaction was refluxed overnight, cooled to room temperature, diluted with ethyl acetate (200 mL), washed once with water (25 mL), the organic phase concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =50/1) to give the title compound as a yellow solid (9.55 g, 100%). MS (ESI, pos.ion) m/z 306.1[ M+H ] +.
Second step Synthesis of ethyl 5- (N- (8-chloronaphthalen-1-yl) -2-ethoxy-2-oxoacetamido) valerate
To the reaction flask was added 5- ((8-chloronaphthalen-1-yl) amino) ethyl valerate (9.55 g,31.2 mmol), sodium carbonate (3.98 g,37.5 mmol) and toluene (70 mL), stirred at 0 ℃ and then oxalyl chloride monoethyl ester (5.0 mL,44 mmol) was added, reacted at room temperature for 4h, the reaction was concentrated to dryness and then purified by column chromatography (PE/EA (v) =5/1) to give the title compound as a yellow solid (8.09 g, 64%).
MS(ESI,pos.ion)m/z:406.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.92(dd,J＝8.3,0.9Hz,1H),7.82(dd,J＝8.1,0.7Hz,1H),7.67(dd,J＝7.5,1.1Hz,1H),7.45(m,2H),7.36(dd,J＝7.2,1.2Hz,1H),4.43(m,1H),4.09(q,J＝7.1Hz,2H),3.84(m,2H),3.06(m,1H),2.32(m,2H),1.84(m,2H),1.67(m,2H),1.22(t,J＝7.1Hz,3H),0.68(t,J＝7.1Hz,3H).
Third step Synthesis of ethyl 1- (8-chloronaphthalen-1-yl) -3-hydroxy-2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-carboxylate
Ethyl 5- (N- (8-chloronaphthalen-1-yl) -2-ethoxy-2-oxoacetamido) valerate (8.09 g,19.9 mmol) and tetrahydrofuran (100 mL) were added, cooled to 0deg.C, 60% sodium hydride (1.2 g,30 mmol) was added, reacted for 5h at room temperature, diluted with ethyl acetate (400 mL), washed once with saturated aqueous ammonium chloride (40 mL), the organic phase concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =3/1) to afford the title compound as a yellow solid (4.14 g, 58%).
MS(ESI,pos.ion)m/z:360.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)12.16(s,1H),7.90(d,J＝7.9Hz,1H),7.82(d,J＝8.1Hz,1H),7.60(d,J＝7.4Hz,1H),7.56(m,1H),7.40(t,J＝7.8Hz,1H),7.35(d,J＝7.2Hz,1H),4.46(m,2H),4.07(m,1H),3.41(dd,J＝15.0,6.0Hz,1H),2.99(dd,J＝14.9,6.4Hz,1H),2.49(m,1H),2.26(m,1H),1.94(m,1H),1.38(t,J＝7.1Hz,3H).
Fourth step Synthesis of 8- (8-chloronaphthalen-1-yl) -4-hydroxy-2- (methylthio) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one
Ethyl 1- (8-chloronaphthalen-1-yl) -3-hydroxy-2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-carboxylate (2.1 g,5.8 mmol), S-methylisothiourea sulfate (1.24 g,8.7 mmol), sodium acetate (2.42 g,17.5 mmol) and toluene (35 mL) were added to the reaction flask, reacted overnight at 110℃to room temperature, diluted with ethyl acetate (400 mL), adjusted to pH=4 with 1N aqueous hydrochloric acid, the separated liquid, the organic phase concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a yellow solid (480 mg, 21%).
MS(ESI,pos.ion)m/z:386.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.93(d,J＝8.0Hz,1H),7.84(d,J＝8.1Hz,1H),7.65(m,2H),7.45(d,J＝7.1Hz,1H),7.41(t,J＝7.8Hz,1H),4.12(m,1H),4.00(m,1H),3.53(m,2H),2.64(s,3H),2.51(m,1H),1.95(s,1H).
Fifth step Synthesis of tert-butyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To the reaction flask was added 8- (8-chloronaphthalen-1-yl) -4-hydroxy-2- (methylsulfanyl) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one (400 mg,1.0 mmol), BOP (608 mg,1.4 mmol), triethylamine (0.25 mL,1.8 mmol) and acetonitrile (5 mL), reacted at room temperature for 30min, benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (280 mg,1.2 mmol) was added, reacted overnight at 80℃down to room temperature, the reaction concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a yellow solid (255 mg, 42%).
MS(ESI,pos.ion)m/z:593.2[M+H]+。
Synthesis of (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
To the reaction flask was added tert-butyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfanyl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (319 mg,0.44 mmol) and ethyl acetate (4 mL), stirred at 0 ℃, m-chloroperoxybenzoic acid (100 mg,0.49 mmol) was added, reacted at 0 ℃ for 2H, ethyl acetate (100 mL) was added, saturated aqueous sodium bicarbonate (8 mL) was washed, the organic phase concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (277 mg, 100%).
MS(ESI,pos.ion)m/z:609.2[M+H]+。
Seventh step Synthesis of tert-butyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To the reaction flask was added tert-butyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfanyl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (277 mg,0.45 mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (100 mg,0.83 mmol) and toluene (4 mL), cooled to 0 ℃, sodium tert-butoxide (100 mg,0.83 mmol) was added, reacted at 0 ℃ for 2H, diluted with ethyl acetate (100 mL), washed once with water (10 mL), and the organic phase was concentrated to dryness before column chromatography purification (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (121 mg, 40%).
MS(ESI,pos.ion)m/z:660.2[M+H]+。
Eighth step Synthesis of 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimidinone [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added (S) -tert-butyl 4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (120 mg,0.18 mmol), trifluoroacetic acid (2 mL) and dichloromethane (4 mL), reacted at room temperature for 2H, the reaction was concentrated, and the concentrate was used directly for the next reaction (241 mg, 100%).
MS(ESI,pos.ion)m/z:526.3[M+H]+。
Synthesis of ninth step 2- ((S) -1-propenoyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimidinone [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (241 mg,0.31 mmol), DIPEA (0.25 mL,1.4 mmol) and dichloromethane (4 mL) were added to the reaction flask, cooled to 0 ℃, acryloyl chloride (40 mg,0.43 mmol) was slowly added dropwise, stirred at room temperature for 2H, the reaction concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (10 mg, 5%).
MS(ESI,pos.ion)m/z:614.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.93(d,J＝8.2Hz,1H),7.83(d,J＝8.2Hz,1H),7.68(m,2H),7.50(m,2H),6.58(m,1H),6.40(d,J＝16.6Hz,1H),5.84(d,J＝10.4Hz,1H),4.66(m,1H),4.47(m,1H),3.97(m,2H),3.58(m,2H),3.38(m,1H),3.17(m,1H),3.01(m,2H),2.88(m,1H),2.76(s,1H),2.62(d,J＝5.0Hz,3H),2.58(m,2H),2.39(m,5H),2.20(m,2H),2.07(m,3H).
Example 11- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -1-propenoylpiperazin-2-yl) acetonitrile
First step Synthesis of 1, 4-Di-tert-butyl 5-ethyl 6-oxo-1, 4-diaza-1, 4, 5-tricarboxylic acid ester
LiHMDS (23 mL,23 mmol), stirring at 78deg.C, dropwise adding di-tert-butyl 6-oxo-1, 4-diaza-1, 4-dicarboxylate (5.0 g,15.4 mmol) and tetrahydrofuran (30 mL), reacting at-40deg.C for 1h, then dropwise adding ethyl carbamate (2.4 mL,23 mmol), reacting at room temperature for 5h, adding ethyl acetate (400 mL), diluting, washing with saturated ammonium chloride (30 mL), concentrating the organic phase to dryness, and purifying by column chromatography (PE/EA (v/v) =5/1) to give the title compound as a yellow solid (3.57 g, 60%).
MS(ESI,pos.ion)m/z:231.1[M-Boc-55+H]+。
Second step Synthesis of 4-hydroxy-2- (methylthio) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylic acid di-tert-butyl ester
1, 4-Di-tert-butyl 5-ethyl 6-oxo-1, 4-diaza-1, 4, 5-trimethyl ester (1.1 g,2.9 mmol), S-methylisothiourea sulfate (1.01 g,7.1 mmol), sodium acetate (1.18 g,14.2 mmol) and toluene (8 mL) were added to the reaction flask, reacted overnight at 110℃to room temperature, diluted with ethyl acetate (200 mL), the aqueous phase was adjusted to pH=3 with 1N aqueous hydrochloric acid, the organic phase was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a yellow solid (0.43 g, 37%).
MS(ESI,pos.ion)m/z:413.2[M+H]+。
Synthesis of di-tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylate
To a microwave tube was added 4-hydroxy-2- (methylthio) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylic acid di-tert-butyl ester (420 mg,1.0 mmol), BOP (600 mg,1.3 mmol), triethylamine (0.25 mL,1.8 mmol) and acetonitrile (5 mL), reacted at room temperature for 30min, then (S) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (300 mg,1.1 mmol) was added, reacted for 12H at 90℃under microwave, cooled to room temperature, the reaction concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =3/1) to give the title compound as a yellow solid (390 mg, 59%).
MS(ESI,pos.ion)m/z:654.2[M+H]+。
Fourth step Synthesis of di-tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylate
To the reaction flask was added (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfanyl) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylic acid di-tert-butyl ester (740 mg,1.1 mmol) and ethyl acetate (6 mL), stirred at 0 ℃, then m-CPBA (803 mg,1.3 mmol) was added, reacted at 0 ℃ for 1H, diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (12 mL) and the organic phase concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (603 mg, 80%).
MS(ESI,pos.ion)m/z:670.1[M+H]+。
Synthesis of di-tert-butyl fifth step 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepin-5, 8 (9H) -dicarboxylate
To the reaction flask was added 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylic acid di-tert-butyl ester (600 mg,0.90 mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (195 mg,1.6 mmol) and toluene (6 mL), cooled to 0 ℃, sodium tert-butoxide (174 mg,1.8 mmol) was added, reacted for 1H at 0 ℃, ethyl acetate (100 mL) was added for dilution, water (10 mL) was washed, the organic phase concentrated to dryness, and then column chromatography purification (DCM/MeOH (v) =100/1) gave the title compound as a yellow solid (569 mg, 86%).
MS(ESI,pos.ion)m/z:721.4[M+H]+。
Sixth step Synthesis of 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5-carboxylic acid
To the flask was added 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8 (9H) -dicarboxylic acid di-tert-butyl ester (510 mg,0.71 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), stirred at room temperature for 5H, the reaction mixture was concentrated and the concentrate was used directly for the next reaction (439 mg, 100%).
MS(ESI,pos.ion)m/z:565.2[M+H]+。
Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazine-1-carboxylate
To the reaction flask was added 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5-carboxylic acid (378 mg,0.73 mmol), 1-bromo-8-methylnaphthalene (197mg, 0.87 mmol), pd 2(dba)3 (68 mg,0.073 mmol), xanthos (87 mg,0.15 mmol), cesium carbonate (483 g,1.5 mmol) and DMSO (4 mL), nitrogen protection, reacted overnight at 100 ℃, cooled to room temperature, the reaction solution was concentrated to dryness, and then column chromatography purified (DCM/MeOH (v) =100/1) to give the title compound as a yellow solid (105 g, 22%).
MS(ESI,pos.ion)m/z:661.2[M+H]+。
Eighth step Synthesis of benzyl (S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To the reaction flask was added (S) -2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazine-1-carboxylate (105 mg,0.16 mmol), DIPEA (50 mg,0.38 mmol) and dichloromethane (2 mL), stirred at room temperature, acetyl chloride (20 mg,0.25 mmol) was added dropwise, stirred at room temperature for 4H, the reaction concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (110 mg, 99%).
MS(ESI,pos.ion)m/z:703.2[M+H]+。
Synthesis of ninth step 2- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazin-2-yl) acetonitrile
To the reaction flask was added (S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (416 mg,0.59 mmol), palladium on charcoal (200 mg,0.19 mmol), 7M ammonia in methanol (6 mL) and methanol (6 mL), protected with hydrogen, reacted overnight at room temperature, the reaction solution was filtered with celite, the filtrate was concentrated, and the concentrate was used directly for the next reaction (300 mg, 100%).
MS(ESI,pos.ion)m/z:569.3[M+H]+。
Synthesis of tenth step 2- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -1-propenylpiperazin-2-yl) acetonitrile
2- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazin-2-yl) acetonitrile (300 mg,0.53 mmol), DIPEA (140 mg,1.1 mmol) and dichloromethane (4 mL) were added to the reaction flask, cooled to 0 ℃, acryloyl chloride (60 mg,0.65 mmol) was slowly added dropwise, stirred at room temperature for 2H, the reaction concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a yellow solid (6 mg, 2%).
MS(ESI,pos.ion)m/z:623.2[M+H]+。
Example 12- ((S) -4- (6- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one
First step Synthesis of 3- (benzyloxy) -1-bromonaphthalene
4-Bromonaphthalene-2-hydroxy (1.0 g,4.5 mmol), tetrahydrofuran (25 mL) and (bromomethyl) benzene (782.0 mg,4.6 mmol) were added to the reaction flask, heated to 75℃for 18h, water (20 mL) was added, ethyl acetate was extracted (50 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, followed by column chromatography purification (PE/EA (v/v) =100/10) to give the title compound as a white solid (1.1 g, 76%).
1H NMR(400MHz,DMSO-d6):δ(ppm)8.03(d,J＝8.2Hz,1H),7.87(d,J＝7.8Hz,1H),7.66(d,J＝2.3Hz,1H),7.57–7.48(m,5H),7.42(t,J＝7.3Hz,2H),7.36(d,J＝7.2Hz,1H),5.24(s,2H).
Second step Synthesis of benzyl (S) -4- (6- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To the reaction flask was added (S) -3-methyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (450 mg,0.76 mmol), 3- (benzyloxy) -1-bromonaphthalene (390 mg,1.2 mmol), pd 2(dba)3 (182 mg,0.2 mmol), xantphos (178 mg,0.3 mmol), cesium carbonate (946 mg,2.9 mmol) and toluene (20 mL), nitrogen protection, warmed to 105 ℃ for 23H, added water (10 mL), extracted with ethyl acetate (70 ml×3), combined with organic phase, saturated water washed (10 ml×2), the organic phase concentrated to dryness, then purified by column chromatography (DCM/MeOH) =100/5) to give the title compound (330 mg, 49%).
MS(ESI,pos.ion)m/z:699.4[M+H]+。
Third step Synthesis of 4- (4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-1-methylpyrrolidin-2-yl) methoxy) -5H-pyrrolo [3,4-d ] pyrimidin-6 (7H) -yl) naphthalen-2-ol
To the reaction flask was added (S) -4- (6- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid benzyl ester (300 mg,0.43 mmol), a methanol solution of ammonia (10 ml,7 mol/L) and 10% palladium on carbon (220 mg, 5%) under hydrogen at room temperature with stirring for 5.5H, filtered through celite and the filtrate concentrated to dryness to give the title compound (180 mg, 88%).
MS(ESI,pos.ion)m/z:475.3[M+H]+。
Synthesis of fourth step 1- ((S) -4- (6- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one
4- (4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-1-methylpyrrolidin-2-yl) methoxy) -5H-pyrrolo [3,4-d ] pyrimidin-6 (7H) -yl) naphthalen-2-ol (70 mg,0.15 mmol), DIPEA (40.2 mg,0.3 mmol) and dichloromethane (5 ml) were added to the reaction flask, cooled to-30 ℃, acryloyl chloride (10 mg,0.11 mmol) was added dropwise, stirred at constant temperature for 0.5H, the reaction concentrated to dryness, and then purified by column chromatography (EtOAc/MeOH (v/v) =100/10) to give the title compound (30 mg, 38%).
MS(ESI,pos.ion)m/z:529.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.73–7.69(m,2H),7.49(d,J＝7.7Hz,1H),7.23–7.14(m,3H),6.57–6.46(m,1H),6.34(t,J＝14Hz,1H),5.73(d,J＝10.3Hz,1H),4.90–4.71(m,2H),4.66–4.58(m,1H),4.47(s,3H),4.34(d,J＝11.1Hz,1H),4.01-3.90(m,1H),3.74–3.66(m,2H),3.52(s,1H),3.45(d,J＝12.0Hz,1H),3.17–3.31(m,2H),2.89(s,3H),2.29–2.16m,2H),2.03(s,2H),1.27(s,3H),1.15(d,J＝6.4Hz,3H).
Example 13- ((S) -1-propenoyl-4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of benzyl (S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To the reaction flask was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (500.0 mg,1.02 mmol), 1-bromo-8 chloronaphthalene (365.4mg,1.51mmol)、Pd2(dba)3(193.5mg,0.2mmol)、XantPhos(185.2mg,0.31mmol)、Cs2CO3(1.0g,3.01mmol), and toluene (30.0 mL), and the reaction was stirred at 105 ℃ for 18H under nitrogen protection, filtered through celite, and then purified by column chromatography (DCM/MeOH (v/v) =100/10) to give the title compound as a light brown solid (370.00 mg, 56%).
MS(ESI,pos.ion)m/z:652.2[M+H]+。
Second step Synthesis of 2- ((S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Palladium on carbon (100.0 mg, 10%) was added to a solution of benzyl (S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (120.0 mg,0.18 mmol) in NH 3/MeOH (40 ml,7 mol/L), stirred at room temperature for 5H under hydrogen, filtered through celite and the filtrate concentrated to dryness to give the title compound as a yellowish solid (80.0 mg, 84%).
MS(ESI,pos.ion)m/z:518.2[M+H]+。
Step three Synthesis of 2- ((S) -1-propenoyl-4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Acryloyl chloride (16.5 mg,0.18 mmol) was added to a solution of 2- ((S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (80.0 mg,0.15 mmol) in DCM (20.0 mL) at-10 ℃, then triethylamine (25.2 mg,0.25 mmol) was added, the reaction was stirred at-10 ℃ for 30min, the reaction solution was evaporated to dryness under reduced pressure, saturated sodium bicarbonate solution (15 mL) was added, dichloromethane (50 ml×2) was extracted, and the organic phase was concentrated to dryness, followed by column chromatography purification (DCM/MeOH (v/v) =10/1) to give the title compound as a white solid (24.8 mg, 24%).
MS(ESI,pos.ion)m/z:572.2[M+H]+。
1H NMR(400MHz,CDCl3):δ(ppm)7.77(d,J＝7.5Hz,1H),7.68–7.63(m,1H),7.54(dd,J＝7.4,0.9Hz,1H),7.51–7.46(m,2H),7.36(t,J＝7.8Hz,1H),6.61–6.51(m,1H),6.38(d,J＝16.6Hz,1H),5.82(d,J＝10.4Hz,1H),5.07-4.84(m,2H),4.60–4.40(m,5H),4.28-4.22(m,2H),3.48-3.25(m,3H),3.14(t,J＝7.6Hz,1H),2.80-2.72(m,2H),2.53(s,3H),2.37-2.30(m,2H),2.11-2.08(m,1H),1.90-1.77(m,3H),1.30-1.27(m,1H).
Example 14- ((S) -1-propenoyl-4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
First step (S) -2- (cyanomethyl) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester synthesis
To the reaction flask was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (430.0 mg,0.87 mmol), 2 bromo-3-fluoro-anisole (260.5mg,1.27mmol)、Pd2(dba)3(168.0mg,0.18mmol)、XantPhos(160.2mg,0.27mmol)、Cs2CO3(868.1mg,2.66mmol), and toluene (25.0 mL), nitrogen protection, the reaction was stirred at 105 ℃ for 20H, the reaction solution was filtered through celite, and then purified by column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a brown solid (160.00 mg, 30%).
MS(ESI,pos.ion)m/z:616.4[M+H]+。
Second step Synthesis of 2- ((S) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Palladium on carbon (120.0 mg, 10%) was added to a solution of benzyl (S) -2- (cyanomethyl) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (160.0 mg,0.26 mmol) in NH 3/MeOH (25 ml,7 mol/L), stirred at room temperature for 2H under hydrogen, filtered through celite and the filtrate concentrated to dryness to give the title compound as a light brown solid (110.0 mg, 88%).
MS(ESI,pos.ion)m/z:482.4[M+H]+。
Step three Synthesis of 2- ((S) -1-propenoyl-4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Acryloyl chloride (19.0 mg,0.2 mmol) was added to a solution of 2- ((S) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (100.0 mg,0.2 mmol) in DCM (20.0 mL) at-10 ℃, then triethylamine (243.5 mg,2.4 mmol) was added, the reaction was stirred at 0 ℃ for 30min, the reaction solution was evaporated to dryness under reduced pressure, saturated brine (15 mL) was added, dichloromethane (40 mL x 2) was extracted, and the organic phase was concentrated to dryness, followed by column chromatography purification (DCM/MeOH (v/v) =10/1) to give the title compound as a white solid (13.5 mg, 12.1%).
MS(ESI,pos.ion)m/z:536.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.09(dd,J＝14.6,8.3Hz,1H),6.77-6.72(m,2H),6.57(s,1H),6.39(d,J＝16.7Hz,1H),5.83(d,J＝9.9Hz,1H),4.78-4.71(m,2H),4.53(s,1H),4.46(dd,J＝10.7,5.5Hz,1H),4.26(dd,J＝10.7,6.1Hz,1H),3.87(s,3H),3.44(s,1H),3.20-3.18(m,2H),2.83-2.79(m,2H),2.74-2.66(m,1H),2.55(s,3H),2.36-2.22(m,4H),2.12-2.08(m,1H),1.92–1.87(m,1H),1.82-1.77(m,2H),1.29-1.27(m,2H),0.89-0.92(m,1H).
Example 15- ((S) -1-propenoyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate
To a solution of benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.35 g,5.21 mmol) in n-butanol (30.0 mL) was added successively tert-butyl 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (1.50 g,5.17 mmol) and DIPEA (1.38 g,10.64 mmol), reacted at 100℃for 6H, cooled to room temperature, the reaction concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =2/1) to give the title compound as a pale yellow solid (2.58 g, 97%).
MS(ESI,pos.ion)m/z:513.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.45-7.35(m,5H),5.21(s,2H),4.85-4.69(m,2H),4.68-4.58(m,1H),4.58-4.30(m,3H),4.25-4.06(m,2H),3.64-3.46(m,1H),3.43-3.25(m,2H),2.87-2.70(m,1H),2.69-2.58(m,1H),1.52(s,9H).
Second step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate
To the reaction flask was added (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (2.10 g,4.09 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (0.61 g,5.33 mmol), palladium acetate (0.094 g,0.42 mmol), BINAP (0.26 g,0.42 mmol), cesium carbonate (2.68 g,8.22 mmol) and anhydrous toluene (60.0 mL), nitrogen protection, warmed to reflux reaction for 10H, reduced pressure concentration of the reaction solution, addition of DCM (50 mL) and methanol (10 mL), stirring at room temperature for 10min, filtration, DCM/MeOH (v/v=10/1, 50ml×2) filter cake concentration to dryness, followed by column chromatography purification (DCM/v/v=20/1) to give the title compound as a dark solid (0.88 g, 36%).
MS(ESI,pos.ion)m/z:592.3[M+H]+。
Third step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To a solution of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (0.88 g,1.50 mmol) in DCM (5.0 mL) was added dropwise a solution of hydrogen chloride in dioxane (20.0 mL,80.00mmol,4.0 mol/L) at 0 ℃, stirred for 10min after the dropwise addition, then stirred at room temperature for 2H, the reaction was concentrated under reduced pressure, the residue was added with methanolic ammonia (20.0 mL,7.0 mol/L), stirred for 10min, the reaction was concentrated to dryness, and then column chromatography (DCM/MeOH (v/v) =20/1) gave the title compound as a pale black solid (0.42 g, 58%).
MS(ESI,pos.ion)m/z:492.3[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.48-7.31(m,5H),5.20(s,2H),4.62(s,1H),4.47(d,J＝13.9Hz,1H),4.44-4.35(m,2H),4.35-4.29(m,1H),4.24-4.14(m,2H),4.11-4.00(m,2H),3.38(s,1H),3.28-3.08(m,3H),2.80-2.66(m,2H),2.62(dd,J＝16.6,5.2Hz,1H),2.54-2.45(m,3H),2.34-2.29(m,1H),2.10-1.99(m,1H),1.91-1.81(m,1H),1.81-1.70(m,2H).
Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To the reaction flask was added successively (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (0.40 g,0.81 mmol), 1-bromo-8-methylnaphthalene (0.27 g,1.24 mmol), pd 2(dba)3 (0.15 g,0.17 mmol), xanthos (0.15 g,0.26 mmol), sodium t-butoxide (0.18 g,1.85 mmol) and anhydrous toluene (20.0 mL), nitrogen protection, warmed to reflux reaction for 10H, cooled to room temperature, the reaction solution was concentrated to dryness, then column chromatography purification (DCM/MeOH (v/v) =25/1) afforded the title compound as an off-black solid which was further purified by thick preparation plate (DCM/=10/1, v/v) to afford off-black solid (0.14 g, 27%).
Fifth step Synthesis of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
To a solution of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (0.53 g,0.84 mmol) in methanolic ammonia (20.0 ml,7.0 mol/L) was added 10% palladium on charcoal (0.53 g), hydrogen protected, stirred at room temperature for 30min, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =20/1) to give the title compound as a pale yellow semi-solid (0.14 g, 34%).
MS(ESI,pos.ion)m/z:498.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.76-7.68(m,2H),7.55-7.49(m,1H),7.46(t,J＝7.6Hz,1H),7.37(t,J＝7.5Hz,1H),7.33-7.28(m,1H),4.69-4.56(m,1H),4.55-4.30(m,5H),4.28-4.16(m,1H),3.99(dd,J＝23.1,12.7Hz,1H),3.27-3.02(m,4H),3.01-2.82(m,5H),2.77-2.65(m,1H),2.61-2.44(m,5H),2.36-2.27(m,1H),2.14-2.05(m,1H),1.81-1.71(m,3H).
Sixth step Synthesis of 2- ((S) -1-propenoyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
To a solution of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (60.4 mg,0.12 mmol), triethylamine (29.4 mg,0.29 mmol) in anhydrous DCM (10.0 mL) was added dropwise acryloyl chloride (11.7 mg,013 mmol) and stirred at 0 ℃ for 30min, water (20 mL) was added to quench the reaction, the aqueous phase was extracted with DCM (20 ml×2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography was purified (MeOH/v) =50/1) to give the title compound as a pale yellow solid (39.1 mg, 58.4%).
MS(ESI,pos.ion)m/z:552.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.78-7.65(m,2H),7.56-7.48(m,1H),7.45(t,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,1H),7.29(d,J＝7.4Hz,1H),6.65-6.47(m,1H),6.38(d,J＝16.7Hz,1H),5.82(d,J＝10.2Hz,1H),4.97(s,1H),4.78-4.53(m,2H),4.52-4.36(m,4H),4.29-4.09(m,2H),3.64-3.40(m,1H),3.36-3.19(m,1H),3.13(t,J＝7.6Hz,1H),2.92(s,3H),2.87-2.61(m,3H),2.52(s,3H),2.39-2.27(m,1H),2.24-1.97(m,3H),1.91-1.70(m,3H);
13C NMR(151MHz,CDCl3):δ(ppm)172.6,167.7,166.1,164.9,159.3,148.1,136.2,134.7,134.7,131.3,130.9,129.8,129.7,128.8,127.1,126.9,126.6,125.7,122.1,122.0,105.5,105.3,70.1,65.6,64.1,60.4,60.3,60.1,59.9,57.7,45.1,41.8,29.7,29.0,23.2,23.0.
Example 16- ((S) -1-propenoyl-4- (6- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
4-Bromo-5-methyl-1H-indazole (3.0 g,14 mmol), dichloromethane (30 mL) and p-toluenesulfonic acid (272.6 mg,1.504 mmol) were added to the reaction flask, cooled to 15 ℃,3, 4-dihydro-2H-pyran (2.4 g,29 mmol) was added dropwise, the reaction was stirred overnight, the reaction concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =1/1) to give the title compound as a white solid (1.2 g, 29%).
MS(ESI,pos.ion)m/z:295.0[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.98(s,1H),7.44(d,J＝8.5Hz,1H),7.24(d,J＝8.5Hz,1H),5.68(dd,J＝9.1,2.7Hz,1H),4.04–3.95(m,1H),3.79–3.67(m,1H),2.60–2.50(m,1H),2.49(s,3H),2.11(ddd,J＝13.0,9.6,6.2Hz,2H),1.83–1.62(m,3H).
Second step Synthesis of benzyl (2S) -2- (cyanomethyl) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Toluene (15.0 mL), 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (259.1 mg,0.8777 mmol), (2S) -2- (cyanomethyl) -4- [2- [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl ] piperazine-1-carboxylate (280.0 mg,0.5696 mmol), xantPhos (103.2 mg, 0.1730mmol), cesium carbonate (561.0 mg,1.72 mmol) and Pd 2(dba)3 (108.2 mg,0.1146 mmol) were added to the reaction flask, reacted for 22H at 105℃with celite filtration, the filtrate was added to silica gel powder, and then column chromatography was purified (DCM/v) =5/1) to give the title compound as a light brown solid (165.0 mg, 41%).
MS(ESI,pos.ion)m/z:706.3[M+H]+。
Step 3 Synthesis of 2- ((2S) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
The reaction flask was charged with benzyl (2S) -2- (cyanomethyl) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (160.0 mg,0.2267 mmol), 7M ammonia in methanol (15.0 ml,105 mmol) and 10% palladium on charcoal (160.0 mg) separately, and the reaction was concentrated to dryness at room temperature to give the title compound as a yellowish solid (105.0 mg, 81%).
MS(ESI,pos.ion)m/z:572.3[M+H]+。
Fourth step Synthesis of 2- ((2S) -1-propenoyl-4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
2- ((2S) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (105.0 mg,0.1837 mmol), dichloromethane (10.0 mL), acryloyl chloride (19.5 mg,0.215 mmol) and triethylamine (32.1 mg,0.317 mmol) were added to the reaction flask, the reaction was stirred at room temperature for 30min, the reaction was evaporated to dryness under reduced pressure and dichloromethane was added to afford the title compound (70.0 mg, 61%) which was isolated as a plate (DCM/MeOH (v/v) =10/1).
MS(ESI,pos.ion)m/z:626.3[M+H]+。
Fifth step Synthesis of 2- ((S) -1-propenoyl-4- (6- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
2- ((2S) -1-propenoyl-4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (150.0 mg,0.2397 mmol), dichloromethane (15.0 mL) and trifluoroacetic acid (3.0 mL) were added to the reaction flask, the reaction was continued with stirring for 30min, saturated sodium bicarbonate solution was added until no bubbles were formed in the system, dichloromethane (60 mL x 2) was extracted, the organic phases were combined, the organic phases were added to silica gel powder, and then column chromatography was purified (DCM/MeOH (v/v) =10/1) the title compound was light brown solid (150.0 mg, 28%).
MS(ESI,pos.ion)m/z:542.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.95(s,1H),7.29(s,3H),6.56(s,1H),6.39(d,J＝16.2Hz,1H),5.83(d,J＝8.0Hz,1H),4.87–4.85(m,2H),4.79–4.76(s,1H),4.59(s,2H),4.53–4.50(m,1H),3.55–3.46(m,2H),3.28(s,2H),2.82(s,3H),2.71–2.68(m,2H),2.46(s,3H),2.27-2.22(m,1H),2.02(s,2H),1.69–1.64(m,1H),1.39–1.27(s,6H).
Example 17- ((S) -1-propenoyl-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
First step Synthesis of ethyl 4- ((2-fluorophenyl) amino) -3-oxobutanoate
To a solution of 2-fluoroaniline (2.00 g,18.01 mmol), potassium iodide (5.99 g,36.08 mmol) and sodium carbonate (3.03 g,36.0 mmol) in acetonitrile (40.0 mL) was added ethyl 4-chloro-3-oxobutyrate (5.98 g,36.36 mmol), heated to reflux overnight, the solvent was removed by rotary evaporation under reduced pressure, dichloromethane (200 mL) was then added, washing was performed sequentially with water (100 ml×2) and saturated brine (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography was performed (PE/EA (v/v) =2/1) to give the title compound as a pale brown liquid (3.10 g, 72%).
MS(ESI,pos.ion)m/z:240.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.06-6.97(m,2H),6.74-6.66(m,1H),6.62-6.55(m,1H),4.23(q,J＝7.1Hz,2H),4.18(s,2H),3.56(s,2H),1.31(t,J＝7.2Hz,3H).
Second step Synthesis of ethyl 4- (3-chloro-N- (2-fluorophenyl) propionamide) -3-oxobutyrate
To a solution of ethyl 4- ((2-fluorophenyl) amino) -3-oxobutanoate (3.00 g,12.56 mmol) and sodium carbonate (1.99 g,18.81 mmol) in anhydrous dichloromethane (25.0 mL) was slowly added 3-chloropropionyl chloride (2.07 g,16.30 mmol) dropwise at 0℃overnight at room temperature, dichloromethane (100 mL) was added, washed sequentially with water (50 mL. Times.2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, followed by column chromatography purification (PE/EA (v/v) =2/1) to give the title compound as a pale brown liquid (3.20 g, 77%).
MS(ESI,pos.ion)m/z:330.1[M+H]+。
Third step Synthesis of ethyl 1- (2-fluorophenyl) -3, 7-dioxanone-4-carboxylate
To a solution of ethyl 4- (3-chloro-N- (2-fluorophenyl) propanamide) -3-oxobutanoate (1.51 g,4.58 mmol) in acetone (60.0 mL) was added potassium carbonate (1.28 g,9.29 mmol) and potassium iodide (1.14 g,6.84 mmol), the reaction was warmed to reflux overnight, cooled to room temperature, evaporated to dryness under reduced pressure, dichloromethane and methanol (50 mL, v/v=10/1) and water (50 mL), separated, the aqueous phase was extracted with dichloromethane (50 ml×3), the organic phases were combined, evaporated to dryness under reduced pressure, and then purified by column chromatography (PE/EA (v/v) =1/1) to give the title compound as a yellow solid (0.44 g, 33%).
MS(ESI,pos.ion)m/z:294.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.51(td,J＝8.0,1.7Hz,1H),7.44-7.36(m,1H),7.27-7.17(m,2H),5.03(d,J＝17.6Hz,1H),4.18(q,J＝7.1Hz,2H),4.09(d,J＝17.7Hz,1H),3.79-3.72(m,2H),3.63-3.45(m,2H),2.73-2.51(m,2H),1.25(dd,J＝9.5,4.7Hz,3H).
Fourth step Synthesis of 8- (2-fluorophenyl) -2- (methylthio) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepin-4, 7-dione
To ethyl 1- (2-fluorophenyl) -3, 7-dioxazepine-4-carboxylate (1.20 g,4.09 mmol) and S-methylisothiourea sulfate (1.15 g,4.14 mmol) were added potassium carbonate (2.26 g,16.4 mmol) and water (60 mL), stirred overnight at room temperature, the pH of the system was adjusted to 5-6 by adding 2M hydrochloric acid, extracted with dichloromethane (100 mL. Times.6), the organic phases were combined, the organic phases concentrated to dryness, and the post column chromatography purification (PE/EA (v/v) =1/4) gave the title compound as a white solid (1.20 g, 92%).
MS(ESI,pos.ion)m/z:320.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)12.43(s,1H),7.28-7.19(m,2H),7.16-7.06(m,2H),6.02(s,1H),5.00-4.90(m,1H),2.93-2.78(m,1H),2.70-2.60(m,2H),2.58(s,3H),2.30-2.17(m,1H).
Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To a solution of 8- (2-fluorophenyl) -2- (methylsulfanyl) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepine-4, 7-dione (1.20 g,3.76 mmol) in acetonitrile (35.0 mL) was added BOP (2.16 g,4.89 mmol) and DBU (1.16 g,7.63 mmol), stirred at temperature for 0.5H, (S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (1.08 g,4.17 mmol), heated to 40℃overnight, dried under reduced pressure, dichloromethane (100 mL) was added, washed sequentially with water (50 mL. Times.2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography was purified (PE/EA (v/v) =1/2) to give the title compound as a white solid (1.54 g, 73%).
MS(ESI,pos.ion)m/z:561.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.44-7.19(m,8H),7.19-7.10(m,1H),6.48-6.38(m,1H),5.76(s,1H),5.19-5.07(m,2H),5.06-4.97(m,1H),4.59-4.47(m,1H),3.98-3.87(m,1H),3.30-3.15(m,2H),3.09-2.92(m,1H),2.86-2.74(m,2H),2.72-2.54(m,2H),2.40(s,3H).
Sixth step Synthesis of benzyl (2S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylsulfonyl) oxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To a solution of benzyl (S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (0.19 g,0.34 mmol) in dichloromethane (10.0 mL) at 0deg.C was added m-chloroperoxybenzoic acid (70.3 mg,0.38 mmol), stirred with heat preservation for 0.5H, dichloromethane (20 mL) was added, washed successively with saturated sodium carbonate (20 mL. Times.2), water (20 mL) and saturated brine (20 mL), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness to afford the title compound as an off-white semi-solid (0.17 g, 87%).
MS(ESI,pos.ion)m/z:577.2[M+H]+。
Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate
To benzyl (2S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylsulfonyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (0.62 g,1.10 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (0.14 g,1.23 mmol) in dichloromethane was added sodium tert-butoxide (0.22 g,2.45 mmol), the reaction was stirred at 0 ℃ for 1H with heat, water (50 mL) and dichloromethane (30 mL), the aqueous phase was separated, extracted with dichloromethane (50 ml×3), the organic phases were combined, concentrated to dryness, and then column chromatography was performed (DCM/MeOH (v/v) =10/1) to give the title compound as a yellow solid (0.55 g, 81%).
MS(ESI,pos.ion)m/z:628.3[M+H]+。
Eighth step Synthesis of 2- ((S) -4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To a solution of benzyl (S) -2- (cyanomethyl) -4-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (0.25 g,0.40 mmol) in methanol (10.0 mL) was added 10% palladium on charcoal (0.25 g), the reaction was stirred at room temperature for 0.5H under hydrogen, filtered through a filter membrane, and the filtrate concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =15/1) to give the title compound as an off-white solid (0.14 g, 71%).
MS(ESI,pos.ion)m/z:494.3[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.33-7.29(m,1H),7.26-7.21(m,1H),7.16-7.10(m,2H),6.12(d,J＝5.1Hz,1H),5.09-5.02(m,1H),4.48(br,1H),4.25-4.16(m,1H),4.00-3.83(m,1H),3.25(br,1H),3.14-3.00(m,3H),2.89-2.75(m,4H),2.73-2.38(m,9H),2.26-2.06(m,3H),1.99-1.88(m,2H).
Synthesis of ninth step 2- ((S) -1-propenoyl-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile
To a solution of 2- ((S) -4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (0.10 g,0.20 mmol) and triethylamine (46.1 mg,0.46 mmol) in dichloromethane (10.0 mL) was added dropwise a solution of acryloyl chloride (21.7 mg,0.24 mmol) in dry dichloromethane (0.5 mL) with stirring at all for 30min, quenched with water (20 mL) and extracted with dichloromethane (20 ml×3), the organic phases were combined, concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =10/1) to give a pale yellow solid which was purified by preparative purification (DCM/v) =10/1) to give an off-white solid (42 mg, 38%).
MS(ESI,pos.ion)m/z:548.4[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.34-7.29(m,1H),7.27-7.20(m,1H),7.16-7.09(m,2H),6.64-6.53(m,1H),6.40(d,J＝16.7Hz,1H),6.14(d,J＝5.0Hz,1H),5.84(d,J＝10.5Hz,1H),5.08(dt,J＝8.1,4.0Hz,1H),5.01-4.84(m,1H),4.64-4.53(m,1H),4.38-4.21(m,2H),4.03-3.90(m,1H),3.65-3.52(m,1H),3.41-3.29(m,1H),3.26-3.11(m,1H),3.04-2.91(m,1H),2.84-2.55(m,8H),2.55-2.42(m,1H),2.26-2.08(m,3H),2.06-1.93(m,2H),1.91-1.81(m,2H);
13C NMR(151MHz,CDCl3):δ(ppm)175.1,170.5,166.3,165.0,164.3,164.2,157.4,130.0,128.8,128.3,126.6,125.1,124.7,116.7,93.0,65.9,64.9,57.4,41.3,30.3,30.1,29.7,28.5,28.4,26.7,26.5,22.6,15.3,14.1.
Example 18- ((S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
First step Synthesis of (S) -4- (4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester
DIPEA (5.6 g,42 mmol) and benzyl (S) -3-methylpiperazine-1-carboxylate (6.5 g,28 mmol) were added to a solution of tert-butyl 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (8.0 g,28 mmol) in DMF (25 mL), the reaction was stirred at 90℃for 3.5H, water (50 mL) was added to the reaction solution, ethyl acetate (80 mL. Times.3) was added to extract, the organic phases were combined, washed with saturated brine (10 mL. Times.4), the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) =90/10) to give the title compound as a white solid (10.4 g, 77%).
MS(ESI,pos.ion)m/z:488.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.42–7.32(m,5H),5.23–5.14(m,2H),4.80–4.62(m,2H),4.49(d,J＝22.5Hz,2H),4.30–4.09(m,2H),4.01(s,1H),3.39–3.12(m,2H),3.03(s,1H),1.78(s,1H),1.51(s,9H),1.25(s,3H).
Second step (S) - (1-methylpyrrolidin-2-yl) methanol Synthesis
(S) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (3.4 mg,17 mmol) was added to a dry tetrahydrofuran (80 mL) solution, then lithium aluminum hydride (1.0 g,26 mmol) was slowly added, the reaction was stirred at 0deg.C for 10min, then heated under reflux to react for 2.5h, cooled to 0deg.C, methanol (15 mL) was slowly added dropwise, then water (15 mL) was added, no bubbles were generated, sodium hydroxide solution (10 mL) was added, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) =80/10) to give the title compound as a brown oil (1.5 g, 77%).
MS(ESI,pos.ion)m/z:166.1[M+H]+。
Third step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate
(S) -4- (4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (1.25 g,2.5 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (400mg,3.5mmol)、Pd(OAc)2(63.5mg,0.27mmol)、BINAP(339.2mg,0.52mmol)、Cs2CO3(1.78g,5.2mmol) and toluene (25 mL) were added to the reaction flask under nitrogen, the reaction was stirred at 105 ℃ for 12H, the reaction solution was filtered through celite, the filtrate was concentrated to dryness by adding silica gel powder, and then purified by column chromatography (DCM/MeOH (v/v) =97/3) to give the title compound as a brown solid (550 mg, 38%).
MS(ESI,pos.ion)m/z:567.5[M+H]+。
Synthesis of benzyl (S) -3-methyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Trifluoroacetic acid (3.0 mL) was added to a solution of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (550 mg,0.97 mmol) in dichloromethane (10 mL), the reaction was stirred at room temperature for 4H, saturated NaHCO 3 solution (10 mL) and water (10 mL) were added, dichloromethane (50 mL x 2) was added to extract, the organic phase was added to anhydrous sodium sulfate and dried, filtered, and the filtrate was concentrated to dryness to give the title compound as a yellowish brown solid (450 mg, 99%).
MS(ESI,pos.ion)m/z:467.5[M+H]+。
Fifth step Synthesis of 1-bromo-8-methylnaphthalene
Methyl lithium (21 mL,34mmol;1.6M diethyl ether solution) was added to a solution of 1, 8-dibromonaphthalene (8 g,28 mmol) in THF (20 mL) at 0deg.C, the reaction was stirred for 30min at 0deg.C, CH 3 I (20 g,140 mmol) was added dropwise, the reaction was stirred at room temperature for 4h, the reaction solution was concentrated to dryness, ethyl acetate (120 mL) was added, saturated brine (10 mL. Times.3) was added to wash, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then the crude product was purified by column chromatography (PE) followed by recrystallization of IPA to give the title compound as a white solid (3.2 g, 52%).
Sixth step Synthesis of benzyl (S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate
(S) -3-methyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (300 mg,0.6 mmol), 1-bromo-8-methylnaphthalene (160mg,0.7mmol)、Pd2(dba)3(105mg,0.11mmol)、XantPhos(102mg,0.17mmol)、Cs2CO3(577mg,1.7mmol), and toluene (20 mL) were added to the reaction flask under nitrogen, the reaction was stirred at 105 ℃ for 23H, the reaction solution was filtered through celite, the filtrate concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) =90/10) to give the title compound as a yellow solid (120.0 mg, 30%).
MS(ESI,pos.ion)m/z:607.3[M+H]+。
Seventh step Synthesis of 6- (8-methylnaphthalen-1-yl) -4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine
Palladium on charcoal (73.5 mg,5%,10wt%,50% water) was added to a solution of benzyl (S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (70 mg,0.11 mmol) in NH 3/MeOH (5 mL,7 mol/L), meOH (3 mL) was added, the reaction was stirred at room temperature under hydrogen for 3H, filtered through celite, and the filtrate was concentrated to dryness to give the title compound as a yellow solid (54 mg, 99%).
MS(ESI,pos.ion)m/z:473.3[M+H]+。
Eighth step Synthesis of 1- ((S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Acryloyl chloride (13.8 mg,0.15 mmol) was added to a solution of 6- (8-methylnaphthalen-1-yl) -4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine (70 mg,0.15 mmol) in dichloromethane (5 ml) at 0 ℃, triethylamine (40.5 mg,0.4 mmol) was then added, the reaction was stirred at 0 ℃ for 0.5H, the reaction concentrated to dryness, and then purified by column chromatography (EtOAc/MeOH (v/v) =90/10) to give the title compound as a yellow solid (13 mg, 13.3%).
MS(ESI,pos.ion)m/z:527.3[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.71(d,J＝8.0Hz,2H),7.50(d,J＝6.3Hz,1H),7.47(d,J＝7.7Hz,1H),7.36(t,J＝7.5Hz,1H),7.29(s,1H),6.66-6.48(m,1H),6.35(d,J＝16.7Hz,1H),5.75(d,J＝10.2Hz,1H),5.01–4.94(m,1H),4.69-4.64(m,1H),4.62-4.53(m,2H),4.48(d,J＝13.7Hz,1H),4.45-4.34(m,3H),4.02(s,1H),3.78-3.74(m,2H),3.57-3.48(m,2H),3.29(d,J＝7.4Hz,2H),2.36-2.25(m,3H),2.18-2.04(m,3H),1.26-1.29(m,9H).
Biological assay
The LC/MS/MS system used for analysis was a Waters Xex G2-XS Qtof time-of-flight mass spectrometer. Mass spectrometry conditions are shown in table a:
Table A
Analysis Using Waters Acquity I Class Sepax Bio-C4, 2.1X10 mm, 3. Mu.M column, 10. Mu.L of sample was injected. Analysis conditions: the mobile phases were water (0.1% formic acid) (a) and acetonitrile (0.1% formic acid) (B). The flow rate was 0.6mL/min. The column temperature was 65 ℃. The mobile phase gradient is shown in table B:
Table B
Time of Gradient of mobile phase A Gradient of mobile phase B
0min 95％ 5％
0.75min 95％ 5％
1.0min 75％ 25％
6.0min 50％ 50％
6.25min 0％ 100％
7.5min 0％ 100％
7.75min 95％ 5％
9min 95％ 5％
Example a stability in human and rat liver microsomes
Human or rat liver microsomes were placed in polypropylene tubes double Kong Fuyo. Typical incubation mixtures include human or rat liver microsomes (0.5 mg protein/mL), target compound (1 μm) and NADPH (2.0 mM) potassium phosphate buffer (PBS, 100mM, ph 7.4) in a total volume of 15 μl, test compounds were dissolved in DMSO and diluted with PBS to give a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37℃in air, after 3min of pre-incubation, protein was added to the mixture and the reaction was started. At various time points (0, NCF,20 and 60 min), the reaction was quenched by the addition of the same volume of ice-cold acetonitrile. The samples were stored at-80℃until LC/MS/MS analysis was performed.
The concentration of the compound in the human or rat liver microsome incubation mixture was determined by LC/MS method.
Parallel incubation experiments were performed using denatured microsomes as negative control, incubated at 37℃and the reactions stopped at various time points (0, NCF,20 and 60 min).
Verapamil (1 μΜ) served as a positive control, incubated at 37 ℃, and the reactions were terminated at different time points (0, ncf,20 and 60 min).
Data analysis
For each reaction, the concentration of the compound (expressed as a percentage) in human or rat liver microsome incubation was plotted as a percentage of the time point of zero, to infer in vivo intrinsic liver clearance CLint(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.). results, see table 1, table 1 being the experimental results of the stability of the compounds provided in some examples of the invention in human and rat liver microsomes.
TABLE 1 Experimental results of the stability of the compounds provided in some examples of the invention in human and rat liver particles
As can be seen from table 1, the compounds of the present invention exhibited suitable stability when incubated in human and rat liver microsomes.
EXAMPLE B inhibition of SOS 1-mediated guanosine exchange by the inventive Compounds
The experimental method comprises the following steps: the AlphaLISA method detects the inhibition of SOS 1-mediated guanosine exchange by compounds.
The experimental steps are as follows:
1) His-KRAS G12C (aa 1-169) was incubated with GDP for 30min with low Mg 2+ solution and stopped using 10mM Mg 2+ solution.
2) Desalting was then performed using a desalting column and protein concentration was measured.
3) Compound preparation and drug adding treatment
A, preparing mother solution: the test compound was dissolved in DMSO to prepare a 10mM stock solution.
When the compound is used, the compound is diluted 3 times by DMSO to obtain 11 concentration gradient compounds, and 2 mu L of compound solution is added into 38 mu L of experiment buffer solution to obtain compound working solution.
4) To 384 test plates, 4. Mu.L of His-KRAS G12C-GDP and 2. Mu.L of compound working solution were added and pre-incubated at 25℃for 15min.
5) After adding 4. Mu.L of SOS1 protein and GTP for 2h incubation, 10. Mu.L of purified GST-cRAF (RBD domain, amino acids 1-149) was added, NICKLE CHELATE acceptor beads and glutethione donor beads (PERKIN ELMER) were mixed, centrifuged at 1000rpm for 1min, and incubated at 25℃for 2h.
6) Read plate detection
After 2h incubation the AlphaLISA signal was read using Envision (PERKIN ELMER, 2104).
7) Data analysis
GRAPHPAD PRISM 8.0.0 was used to fit the IC 50 of the compound.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
X is the logarithm of the concentration of the compound
Y alpha LISA signal
The experimental results show that in the experiment of inhibiting the guanosine exchange mediated by SOS1, the IC 50 of the compound is less than 100 mu M, and the compound has an inhibiting effect on the guanosine exchange mediated by SOS 1.
EXAMPLE C inhibitory Activity of the Compounds of the invention against cell proliferation
The experimental method comprises the following steps: CTG methods detect the inhibitory activity of compounds on cell proliferation.
The cell experimental conditions are shown in table C:
Table C
Cell name Cell (s)/well(s) Incubation time (h) Complete medium
H358 1000 72 RPMI1640+10％FBS
1) Cell culture
The cells were cultured using a suitable medium and placed in a 5% carbon dioxide incubator at 37 ℃. Cells were observed 1 time daily using an inverted microscope with medium changes every 2-4 days. Cells were collected and centrifuged at 1200rpm for 5min, the supernatant was discarded and transferred to a new sterile petri dish at a ratio of 1:3-1:8 for culture.
2) Cell plating
Cells in the exponential growth phase were collected and counted using a cytometer. Cells were resuspended in the corresponding medium and adjusted to the appropriate concentration. mu.L of cell suspension was added to each well in 96-well cell culture plates. The cells were cultured overnight at 37℃in a 5% carbon dioxide incubator.
3) Compound preparation and drug adding treatment
A, preparing mother solution: the test compound was dissolved in DMSO to prepare a 10mM stock solution.
And b, diluting the compound 3 times by using DMSO to obtain 9 concentration gradient compounds, diluting the gradient diluted compounds 20 times by using a complete culture medium, and uniformly mixing to obtain a 10-concentration drug working solution.
C, adding the medicine: the cell culture plate was removed, 10. Mu.L/well of the above-mentioned 10 Xconcentration drug working solution was added to the corresponding well of the cell culture plate, and incubated in an incubator at 37℃for 72 hours.
4) Read plate detection
After the compound a is treated for 72 hours, the cell morphology is observed under an inverted microscope, the cell growth state in the DMSO control wells is normal, no pollution phenomenon is seen, and whether the compound is precipitated in each well or not is judged.
B, placing the prepared CTG solution at room temperature for balancing for 10-20min.
C adding 50. Mu.L/well of CTG solution according to the instructions of CTG operation, and shaking the mixture for 20min in a shaker in the absence of light.
D, measuring the fluorescence signal value by using an enzyme label instrument.
5) Data analysis
Growth inhibition% = (V Negative group -V Experimental group )/(V Negative group -V Blank group ) ×100%, where V Negative group is the mean of the solvent control group, V Experimental group is the readout of the drug-treated group, and V Blank group is the readout of the cell-free drug-free treated group. The data was analyzed and IC 50 values were counted using GRAPHPAD PRISM 5.0.0 software. The results are shown in Table 2, and Table 2 shows the results of experiments for inhibiting cell proliferation of the compounds provided in some examples of the present invention.
TABLE 2 results of cell proliferation inhibition experiments with compounds provided in some examples of the invention
Example number IC50(μM)
Example 1 3.02
Example 2 1.96
Example 4 3.32
Example 8 0.50
Example 9 4.21
Example 10 2.85
Example 13 0.72
Example 15 0.58
The experimental results show that the compounds of the invention have inhibitory activity on cell proliferation in the test of the inhibitory activity on cell proliferation.
EXAMPLE D binding of the Compound of the invention to KRAS4B-G12C protein
The experimental method comprises the following steps: the LC-MS method detects the binding of the compound to KRAS4B-G12C protein.
The experimental steps are as follows:
1) Experiment buffer preparation is shown in Table D
Table D
2) Loading GDP into KRAS-4B-G12C protein
KRAS-4B-G12C protein was diluted 2-fold to 103. Mu.M, 2mL of protein was taken and 1mL of 2 XGDP-loading buffer was added, gently mixed, incubated at room temperature for 1.5h, split into 100. Mu.L/tube, rapidly frozen in liquid nitrogen and stored in a-80℃refrigerator.
3) KRAS-4B-G12C assay
The reagents of Table E below were mixed
Table E
Reagent(s) Dosage of
GDP-loaded KRAS-4B-G12C (20 uM) 5uL
Compound (10% DMSO solution) 5uL
10 Xincubation buffer 5uL
Ultrapure water 35uL
Sum up 50uL
4) Incubating for 30min and 3h at normal temperature
5) The reaction was stopped by adding 5. Mu.L of 5% formic acid
6) LC-MS detection
A total of 55. Mu.L of the reaction mixture was centrifuged at 15000rpm for 10min before being put on-line.
7) Calculation of Kras (G12C) binding% of
KRAS (G12C) binding ratio% = complex peak height/[ complex peak height + peak height not bound to KRAS G12C ] ×100
The results are shown in Table 3, and Table 3 shows the results of a 1-h experiment for protein binding of the compounds provided in some examples of the present invention.
TABLE 3 protein binding assay results for compounds provided in some examples of the invention
Example number Protein binding Rate (%)
Example 8 92
Example 9 89.7
Example 13 89.9
Example 15 95.8
Experimental results show that the compound has higher binding rate with KRAS4B-G12C protein.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (6)

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt of the compound represented by the formula (I),
Wherein:
x is
Y is
R 1 is-C (=o) -CR a＝CRb-Rc;
r a and R b are each independently hydrogen, deuterium or a halogen atom;
R c is hydrogen or deuterium;
w is-O- (CR mRn)p -;
R 2 is pyrrolidinyl, wherein said pyrrolidinyl is independently optionally substituted with 1,2,3,4, or 5 groups selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, and difluoromethyl; ;
r m and R n are each independently hydrogen or deuterium;
R 3 is Wherein said/>May independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl and difluoromethyl;
Each R x is independently deuterium or C 1-6 alkyl; wherein said C 1-6 alkyl groups are independently optionally substituted with 1,2, 3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro and cyano;
each R y is independently hydrogen or deuterium;
m is 0,1, 2,3, 4, 5, 6, 7 or 8;
n is 0,1, 2, 3 or 4;
p is 1.
2. The compound of claim 1, wherein each R x is independently deuterium or C 1-4 alkyl; wherein said C 1-4 alkyl groups may independently be optionally substituted with 1, 2, 3,4 or 5 groups selected from deuterium, halogen atoms, hydroxy, oxo, amino, nitro and cyano.
3. The compound of claim 1, wherein each R x is independently deuterium, methyl, ethyl, n-propyl, or isopropyl; wherein the methyl, ethyl, n-propyl and isopropyl groups may independently be optionally substituted with 1,2, 3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro and cyano.
4. A compound which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:
5. A pharmaceutical composition comprising a compound according to any one of claims 1-4; and
The pharmaceutical composition optionally further comprises a pharmaceutically acceptable carrier, adjuvant, or any combination thereof.
6. Use of a compound of any one of claims 1-4 or a pharmaceutical composition of claim 5 in the manufacture of a medicament for preventing, treating or alleviating KRAS G12C-mediated disease in a patient;
the KRAS G12C mediated disease is cancer;
The cancer is lung cancer.
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