CN115785088A - Compounds as SOS1 inhibitors and uses thereof - Google Patents
Compounds as SOS1 inhibitors and uses thereof Download PDFInfo
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- CN115785088A CN115785088A CN202111057111.2A CN202111057111A CN115785088A CN 115785088 A CN115785088 A CN 115785088A CN 202111057111 A CN202111057111 A CN 202111057111A CN 115785088 A CN115785088 A CN 115785088A
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Abstract
The invention belongs to the field of medical chemistry,the invention relates to a compound serving as an SOS1 inhibitor and application thereof, and particularly provides a compound shown in a formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating SOS1 related diseases.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a compound serving as an SOS1 inhibitor or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating SOS1 related diseases.
Background
In 1992, bonfini et al first discovered the SOS (son of seven) protein in a study of the Drosophila eye. The SOS protein is the product of the SOS gene encoding guanosine releasing protein. SOS plays an important role in growth and development of Drosophila, nematodes, mice and humans. SOS1 (son of seven homology 1) is a guanine nucleotide exchange factor for Ras and plays an important role in RAS signaling by regulating GDP/GTP exchange of G protein.
The SOS1 protein consists of 1333 amino acids, and the structure thereof from the N-terminus comprises a histidine domain, a Db1 homology domain, a pleckstrin homology domain, a Ras-exchanged domain, a cell division cycle 25 domain and a proline-rich domain. CDC25 activates Ras in yeast and facilitates the exchange of nucleotides in the Ras protein. A REM domain; contains a site that binds Ras-GTP and results in allosteric activation of the CDC25 domain. Thus, two sites in SOS1 can bind to RAS and a catalytic site binds to GDP-RAS, facilitating nucleotide exchange; the allosteric site binds with GTP-RAS, improving the catalytic activity of SOS 1.
SOS1 has been shown to play an important role in KRAS mutant oncogenic signals. The deletion of SOS1 in KRAS-mutated tumor cells can inhibit the proliferation of tumor cells, and the introduction of SOS1 with a mutated catalytic site can not restore the proliferation of cells (MIA PaCa-2).
The research on the Ras protein-SOS 1 protein related drug effect has been carried out for many years, and has a certain research basis. However, there is still a need to develop more excellent SOS1 inhibitors, such as increasing activity, decreasing influence on liver drug enzymes, etc., so as to obtain drugs with good activity and higher safety for treating SOS 1-related diseases.
Disclosure of Invention
The invention provides a compound shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
wherein the content of the first and second substances,
R 1 selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl;
R 2 selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and haloalkyl;
R 3 each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclyl and cycloalkyl;
R 4 selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclyl, heterocyclyl, and cycloalkyl;
R 5 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;
R 6 selected from the group consisting of dimethylphosphinyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclylheteroaryl, the aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyAlkyl acyl, cycloalkyl sulfonyl, heterocyclyl acyl, heterocyclyl sulfonyl, cycloalkyl alkyl acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups; or
R 6 is-n-R 6a N is selected from NH and O, R 6a (ii) is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl, and heterocycloheteroaryl, which is optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, heterocycloyi, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo groups; and
m is 1,2, 3 or 4.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 1 selected from hydrogen, C 1-6 Alkyl, halogen and halogeno C 1-6 An alkyl group;
further preferably, hydrogen, C 1-3 Alkyl, halogen and halogeno C 1-3 An alkyl group;
even more preferably, R 1 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine, halogenated C 1-3 An alkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 2 selected from hydrogen, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl and halogeno C 1-6 An alkyl group;
further preferably, R 2 Selected from hydrogen, C 1-3 Alkyl, hydroxy C 1-3 Alkyl and halo C 1-3 An alkyl group;
more preferably, R 2 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, hydroxy C 1-3 Alkyl and halo C 1-3 An alkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 3 selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy, 3-8 heterocyclyl and C 3-8 A cycloalkyl group;
further preferably, R 3 Selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl, hydroxy-halogeno-C 1-3 Alkyl radical, C 1-3 Alkoxy, 3-6 heterocyclic group and C 3-6 A cycloalkyl group.
In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 4 selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 2-10 Alkenyl radical, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, hydroxy C 3-8 Cycloalkyl, hydroxy 3-8 A heterocyclic group, 3-8 Heterocyclyl and C 3-8 A cycloalkyl group;
further preferably, R 4 Selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C 2-6 Alkenyl radical, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl radicalHydroxy halogeno C 1-6 Alkyl radical, C 1-6 Alkoxy, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, hydroxy C 3-6 Cycloalkyl, hydroxy 3-6 A heterocyclic group, 3-6 Heterocyclyl and C 3-6 A cycloalkyl group;
even more preferably, R 4 Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, hydroxyisopropyl, 2-hydroxyisopropyl, nitro, carboxyl, cyano, amino, aminomethyl, formylamino, formyl, methylsulfonyl, aminoacyl, methylaminoacyl, dimethylamino, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl.
In some preferred embodiments, the compounds of the present invention are compounds of general formula (I) or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 5 selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy and C 3-6 A cycloalkyl group;
further preferably, R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, deuterated C 1-3 Alkyl, hydroxy C 1-3 Alkyl, amino C 1-3 Alkyl, hydroxy-halogeno-C 1-3 Alkyl radical, C 1-3 Alkoxy and C 3-6 A cycloalkyl group.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 6 selected from dimethylphosphinyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C 6-12 Aryl, 5-12 membered heteroaryl、C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl radical, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, di-C 1-6 Alkylamino radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl radical, C 3-12 Cycloalkyl acyl, C 3-12 Cycloalkylsulfonyl, 3-12 heterocycloyl, 3-12 heterocyclylsulfonyl, C 3-12 Cycloalkyl radical C 1-6 Alkyl acyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo;
further optimally, R 6 Is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl, said C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino radical, C 1-3 Alkylacylamino group, C 1-3 Alkyl acyl radical, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl radical, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkylsulfonyl, 3-8 heterocycloyl, 3-8 heterocyclylsulfonyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl acyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;
even more preferably, R 6 Selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, glycidylalkyl, oxetanyl and 4-8 membered azaheterocyclo 5-8 membered heteroaryl, which groups may be substituted by one or more groups selected from halogen, hydroxy, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino radical, C 1-3 Alkylacylamino group, C 1-3 Alkyl acyl radical, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl radical, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkylsulfonyl, 3-8 heterocycloyl, 3-8 heterocyclylsulfonyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl acyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 6 is-n-R 6a N is selected from NH and O, R 6a Selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoylSubstituted with radicals of the group, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo radicals;
further preferably, R 6 is-n-R 6a N is selected from NH and O, R 6a Is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl, said C 6-10 Aryl, 5-to 10-membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 3-10 membered heterocyclo 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino radical, C 1-3 Alkylacylamino group, C 1-3 Alkyl acyl, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl radical, C 3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo;
even more preferably, R 6 is-n-R 6a N is selected from NH and O, R 6a Selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, glycidylalkyl, oxetanyl and 4-8 membered azaheterocyclo 5-8 membered heteroaryl, which groups may be substituted by one or more groups selected from halogen, hydroxy, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy radicalRadical, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino radical, C 1-3 Alkylacylamino group, C 1-3 Alkyl acyl radical, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl radical, C 3-8 Cycloalkylacyl, 3-8 membered heterocycloyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, and oxo.
In some embodiments, the present invention provides a compound represented by general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia),
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m has the meaning described above for formula (I); r 7 、R 8 Each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, haloalkylamino, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylsulfonyl, heterocycloyl, heterocyclyloxy, cycloalkylamino, heterocyclylamino, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylsulfonyl, cycloalkylalkanoyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
In some embodiments, a compound according to formula (Ia) of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein:
R 1 selected from hydrogen, C 1-6 Alkyl, halogen and halogeno C 1-6 An alkyl group, a carboxyl group,
R 2 selected from hydrogen, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl and halogeno C 1-6 An alkyl group, a carboxyl group,
R 3 selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy, 3-8 heterocyclyl and C 3-8 Cycloalkyl, m is 1,2, 3 or 4,
R 4 selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 2-10 Alkenyl radical, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, hydroxy C 3-8 Cycloalkyl, hydroxy 3-8 A heterocyclic group, 3-8 Heterocyclyl and C 3-8 A cycloalkyl group,
R 5 selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy and C 3-6 A cycloalkyl group,
R 6 selected from dimethylphosphinyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 An alkyl acyl group,C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, di-C 1-6 Alkylamino radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl, C 3-12 Cycloalkyl acyl, C 3-12 Cycloalkylsulfonyl, 3-12 heterocycloyl, 3-12 heterocyclylsulfonyl, C 3-12 Cycloalkyl radical C 1-6 Alkyl acyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo; and
R 7 、R 8 each independently selected from halogen, hydroxy, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, halo C 1-6 Alkylamino radical, hydroxy radical C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, di-C 1-6 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl radical, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkyl radical C 1-6 Alkoxy radical, C 3-8 Cycloalkylsulfonyl, 3-8 membered heterocycloyl, 3-8 membered heterocyclyloxy, C 3-8 Cycloalkylamino, 3-8 membered heterocyclylamino C 1-6 Alkoxy, 3-to 8-membered heterocyclyl C 1-6 Alkylamino, 3-8 membered heterocyclylsulfonyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl acyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl.
In some embodiments, a compound according to the present invention is represented by formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, wherein R is 7 、R 8 Each independently selected from halogen, hydroxy, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halo C 1-3 Alkylamino radical, hydroxy radical C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino radical, C 1-3 Alkylacylamino group, C 1-3 Alkyl acyl radical, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl radical, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkyl radical C 1-3 Alkoxy radical, C 3-8 Cycloalkylsulfonyl, 3-8 membered heterocycloyl, 3-8 membered heterocyclyloxy, C 3-8 Cycloalkylamino, 3-8 membered heterocyclylamino C 1-3 Alkoxy, 3-to 8-membered heterocyclyl C 1-3 Alkylamino, 3-8 membered heterocyclylsulfonyl, C 3-8 Cycloalkyl radical C 1-3 Alkyl acyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl.
In some preferred embodiments, the compounds of the present invention are of the general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R 6 is selected from
The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
in another aspect, the present invention provides a process for the preparation of a compound of formula (I) according to the invention, comprising the steps of:
1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (3);
2) Reacting a compound of formula (3) with a compound of formula (4) to produce a compound of formula (5);
3) Reacting the compound of formula (5) with the compound of formula (6) to obtain a compound of formula (7);
4) Reacting the compound of formula (7) with the compound of formula (8) to obtain a compound of formula (9);
5) The compound of formula (9) is prepared into the compound of formula (I) through a series of reactions;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m has the meaning described for general formula (I), X is halogen, the compounds of formula (1), of formula (2), of formula (4), of formula (6), of formula (8) are commercially available compounds or can be synthesized by other techniques customary to those skilled in the art.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
In some embodiments, the present invention provides a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof and a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof for use in treating a disease associated with SOS 1.
In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a method for treating a disease associated with SOS1 and the use of a compound of formula (I), formula (Ia), or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, for the treatment of a disease associated with SOS1, and in the manufacture of a medicament for the treatment of a disease associated with SOS 1.
In some preferred embodiments, the present invention provides a method for treating a disease associated with SOS1 and the use of a compound of formula (I), formula (Ia), or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, for the treatment of a disease associated with SOS1, and the use thereof in the manufacture of a medicament for treating a disease associated with SOS1, wherein the disease associated with SOS1 includes, but is not limited to: cancer, proliferative disease, hematological disease, or metabolic disease. In some embodiments, the SOS 1-associated disease described herein is cancer.
In some embodiments, the SOS 1-associated diseases described herein include, but are not limited to: pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.
Definition of terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, and isotopes of carbon include 12 C、 13 C and 14 c, isotopes of oxygen including 16 O and 18 o, and the like.
"isomers" as used herein refers to molecules having the same atomic composition and attachment pattern but different three-dimensional spatial arrangements, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of a molecule. The prefixes D, L or (+), (-) are used to designate the sign of the compound's plane-polarized light rotation, with (-) or L meaning that the compound is left-handed and the prefix (+) or D meaning that the compound is right-handed. The chemical structures of these stereoisomers are identical, but the stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is generally referred to as a mixture of enantiomers. A mixture of enantiomers of 50. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). The optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine. "halo" in the context of the present invention means substituted by fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention means a straight or branched chain saturated aliphatic hydrocarbon group, preferably a straight or branched chain group having 1 to 6 carbon atoms, further preferably a straight or branched chain group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
The "carbonyl group" and "acyl group" in the present invention are each-C (O) -.
"Sulfonyl" of the present invention means-S (O) 2 -。
The "sulfonamide group" of the present invention means-S (O) 2 NH-。
"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.
"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
"heterocyclyl" in the present invention refers to a group of a 3-to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-12 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. The heterocyclyl group can be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system (also referred to as "bicyclic heterocyclyl") and can be saturated or partially unsaturated, wherein the bicyclic heterocyclyl includes, but is not limited to, benzoazaheterocyclyl, benzoxaheterocyclyl, benzothiaheterocyclyl, benzodiazaheterocyclyl, benzodioxoheterocyclyl, benzodiazaheterocyclyl, benzoxaazaheterocyclyl, and benzothioxaheterocyclyl. Suitable heterocyclic groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroquinazolinyl, oxapiperazinyl, dihydroquinazolinyl, and dihydroquinazolinyl,
Dihydrobenzoxelocyclohexenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl, and the like. Each instance of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
"aryl" in the context of the present invention means an aromatic system which may comprise a monocyclic ring or fused polycyclic ring, preferably a monocyclic ring or fused bicyclic ring, which contains from 6 to 12 carbon atoms, preferably from about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.
The "heteroaryl group" in the present invention means an aryl group having at least one carbon atom replaced with a heteroatom, preferably consisting of 5 to 12 atoms (5-12 membered heteroaryl group), more preferably consisting of 5 to 10 atoms (5-10 membered heteroaryl group), said heteroatom being O, S, N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
"cycloalkylalkoxy" according to the present invention refers to an alkoxy group wherein at least one hydrogen atom of the alkoxy group has been substituted by a cycloalkyl group as defined herein.
"Heterocyclylalkoxy" according to the invention means an alkoxy group in which at least one hydrogen atom of the alkoxy group has been substituted by a heterocyclyl group as defined herein.
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute amount thereof, and the like.
The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of formula (I). As mentioned above, the in vivo effects of the compounds of formula (I) may also be exerted via precursor compound ("prodrug") metabolism. The "prodrug" of the present invention refers to a compound which is converted into the compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into the compound of the present invention by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into the compound of the present invention by hydrolysis reaction of gastric acid or the like, or the like.
The "crystal" of the present invention is a solid having an internal structure in which constituent atoms (or a group thereof) are regularly repeated in three dimensions, and is different from an amorphous solid having no such regular internal structure.
The term "pharmaceutical composition" as used herein is intended to encompass a mixture comprising any one of the compounds of the present invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.
The "pharmaceutically acceptable carrier" of the present invention means a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, and cellulose acetate; malt, gelatin, and the like.
"excipients" in the context of the present invention refer to inert substances added to pharmaceutical compositions to further facilitate administration of the compounds. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
Detailed Description
The present invention will be further illustrated in detail with reference to the following examples, but the present invention is not limited to these examples. The materials used in the following examples are all commercially available unless otherwise specified.
Intermediate 1 (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine
Step 8978 preparation of zxft 8978-bromo-3- (difluoromethyl) -2-fluorobenzene
3-bromo-2-fluorobenzaldehyde (50g, 250.0 mmol) was weighed into a 500mL three-necked flask, and anhydrous dichloromethane (300 mL) was added and dissolved with stirring at 0 ℃ followed by slow addition of diethylaminosulfur trifluoride (48.0 g,300.0 mmol) and stirring at room temperature for 5 hours, and TLC showed completion of the reaction. Quenched by addition of 500mL of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (500 mL. Times.3 mL), and the organic layer dried over anhydrous sodium sulfate and concentrated to give the title compound.
Step 8978 preparation of zxft 8978- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one
1-bromo-3- (difluoromethyl) -2-fluorobenzene (55g, 250mmol), bis (triphenylphosphine) palladium dichloride (0.5g, 0.75mmol) and triethylamine (70mL, 500mmol) were weighed out and placed in a 500mL three-necked flask, and 1,4-dioxane 300mL was added thereto and dissolved, followed by replacement with argon, and tributyl (1-ethoxyethylene) tin (90g, 250mmol) was added thereto and stirred at 90 ℃ for 4 hours. TLC showed the reaction was complete. Adding concentrated hydrochloric acid to adjust pH to 1-2, and stirring for 1 hr. TLC showed the reaction was complete. Saturated potassium fluoride solution was added thereto, stirred overnight, extracted with ethyl acetate (500X 3 mL), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give the title compound.
Step 3 preparation of (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropan-2-sulfinamide
1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one (22g, 120mmol) was weighed into a 500mL three-necked flask, and 500mL of tetrahydrofuran, (R) -2-methylpropane-2-sulfinamide (17g, 140mmol), tetraethyltitanate (41g, 180mmol) were added under argon and stirred at 90 ℃ under reflux for 4h. LC-MS showed the reaction was complete. Cool to room temperature, quench with saturated sodium bicarbonate solution, filter, extract with ethyl acetate (500 × 3 mL), dry the organic layer over anhydrous sodium sulfate, and concentrate to give the title compound. ESI-MS m/z 292.1[ 2 ] M + H] + . Step 4 preparation of (R) -N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
(R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide (35g, 120mmol) was weighed into a 500mL three-necked flask, and anhydrous tetrahydrofuran (200mL) was added thereto, and sodium borohydride (4.6 g, 120mmol) was slowly added thereto at 0 ℃ to warm to room temperature for 2h. LC-MS showed the reaction was complete. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate (500X 3 mL), drying the organic layer over anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography to give the title compound. ESI-MS m/z:294.1[ 2 ] M + H] + 。
Step 5 preparation of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine
(R) -N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (12g, 42mmol) was weighed into a 100mL three-necked flask, and a hydrogen chloride-dioxane solution (10 mL) was added and reacted at room temperature overnight. LC-MS showed the reaction was complete. Direct spin-drying afforded the title compound. ESI-MS m/z:190.1[ 2 ], [ M + H ]] + 。
Intermediate 2 (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine
Step 8978 preparation of zxft 8978-methoxy-N, 2-dimethyl-3- (trifluoromethyl) benzamide
2-methyl-3- (trifluoromethyl) benzoic acid (100g, 490.0mmol) was weighed out and placed in a 1000mL three-necked flask, and anhydrous N, N-dimethylformamide (500 mL) was added thereto, and N, O-dimethylhydroxylamine hydrochloride (52.38g, 540.0mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (103.5g, 540.0mmol), 1-hydroxybenzotriazole (73.0g, 540.0mmol), and N, N-diisopropylethylamine (158.0g, 1225.0mmol) were added in this order, and stirred at room temperature for 2 hours, and LC-MS showed completion of the reaction. Water (500 mL) was added, extraction was performed with ethyl acetate (500 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z:248.1[ 2 ] M + H] + 。
Step 8978 preparation of zxft 8978- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one
Weighing N-methoxy-N, 2-dimethyl-3- (trifluoromethyl) benzamide (110g, 440mmol), placing in a 1000mL three-necked flask, adding anhydrous500mL of tetrahydrofuran was added dropwise to methyl magnesium bromide (880mL, 880mmol) at-20 ℃ and stirred at room temperature for 2 hours. LC-MS showed the reaction was complete. Quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (500 × 3 mL), and the organic layer dried over anhydrous sodium sulfate and concentrated to give the title compound. ESI-MS m/z 203.1[ 2 ] M + H] + 。
Step 3 preparation of (R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide
1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one (87g, 430mmol) was weighed into a 1000mL three-necked flask, and 500mL of anhydrous tetrahydrofuran, (R) -2-methylpropane-2-sulfinamide (58g, 470mmol), tetraethyltitanate (294g, 1290mmol) were added under argon protection and stirred at 80 ℃ under reflux for 4h. LC-MS showed the reaction was complete. Cool to room temperature, quench with saturated sodium bicarbonate solution, filter, extract with ethyl acetate (500 × 3 mL), dry the organic layer over anhydrous sodium sulfate, and concentrate to give the title compound. ESI-MS m/z 306.1[ 2 ] M + H] + 。
Step 4 preparation of (R) -2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide
(R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylidene) propane-2-sulfinamide (131g, 430mmol) is weighed into a 1000mL three-necked flask, 500mL of anhydrous tetrahydrofuran is added, and lithium borohydride tetrahydrofuran solution (230mL, 473mmol) is added dropwise at-78 ℃ under the protection of argon and the mixture is heated to room temperature for reaction for 4h. LC-MS showed the reaction was complete. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate (500X 3 mL), drying the organic layer over anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography to give the title compound. ESI-MS m/z 308.1[ 2 ] M + H] + 。
Step 5 preparation of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine
(R) -2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (30g, 97.4 mmol) was weighed into a 100mL three-necked flask, and a hydrogen chloride-dioxane solution (10 mL) was added and reacted at room temperature for 2h. LC-MS showed the reaction was complete. Direct spin-drying afforded the title compound. ESI-MS m/z:204.1[ 2 ], [ M + H ]] + 。
Example 1 (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethan-1-one
Step 3238 preparation of zxft 3238-chloro-2-methylpyrido [3,4-d ] pyrimidin-4-ol
5-amino-2-chloroisonicotinic acid (100.0g, 581.4mmol), acetamidine hydrochloride (136.0g, 1460mmol), sodium acetate (120.0g, 1460mmol) and ethylene glycol monomethyl ether (500 mL) were placed in a 1L single-necked flask, protected with nitrogen, and stirred at 130 ℃ overnight. The mixture was cooled to room temperature, quenched with ice water, the solid precipitated, filtered, the filter cake dried, the filtrate extracted with ethyl acetate (200 × 3 mL), the organic layer dried over anhydrous sodium sulfate, concentrated, combined with the filter cake, and dried to give the title compound. Yield: 84 percent. ESI-MS m/z:196.1[ 2 ], [ M + H ]] + 。
Step 3236 preparation of zxft 3236-chloro-2-methoxypyrido [3,4-d ] pyrimidin-4-yl-2,4,6-triisopropylbenzenesulfonate
6-chloro-2-methylpyrido [3,4-d ] pyrimidin-4-ol (19.5 g, 100mmol), triethylamine (20g, 200mmol) and N, N-dimethylformamide (100 mL) were added thereto at room temperature, and 2,4,6-triisopropylbenzenesulfonyl chloride (36.34g, 120mmol) with stirring and stirred at room temperature for 2 hours. After the reaction is completed, the reaction system is introduced into ice water, filtered, and the filter cake is dried (50 ℃) to obtain 30g of yellow solid which is directly used for the next reaction.
Step 3 preparation of (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3,4-d ] pyrimidin-4-amine
(R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (8g, 42mmol) was weighed and placed in a 100mL three-necked flask, dissolved in 50mL of N, N-dimethylformamide, triethylamine (18mL, 125mmol) was added, and then 6-chloro-2-methyl-4- ((2,4,6-triisopropylphenyl) sulfonyl) pyrido [3,4-d]Pyrimidine (19g, 42mmol). Stirring at room temperature for 2 hours LC-MS showed the reaction was complete. Quenching with saturated sodium bicarbonate solution, extraction with ethyl acetate (100X 3 mL), drying of the organic layer over anhydrous sodium sulfate, concentration, and chromatography on silica gel column gave the title compound. ESI-MS m/z:367.1[ 2 ] M + H] + 。
Step 4 preparation of (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -3,6-dihydropyridin-1 (2H) -yl) ethan-1-one
Weighing (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3,4-d]Pyrimidine-4-amine (9g, 24mmol), tetrakis (triphenylphosphine) palladium (1.4g, 1.2mmol), and cesium carbonate (39g, 120mmol) were placed in a 500mL three-necked flask, dissolved in 110mL of a 1, 4-dioxane/water mixed solvent (10), and stirred at 90 ℃ for 4 hours after argon substitution. LC-MS showed the reaction was complete. Water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3 mL), and the organic layer was dried over anhydrous sodium sulfateDried over sodium sulfate, concentrated and chromatographed on silica gel to give the title compound. ESI-MS m/z of 456.2[ 2 ] M + H] + 。
Step 5 preparation of (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-hydroxypiperidin-1-yl) ethan-1-one
Weighing (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d]Pyrimidin-6-yl) -3,6-dihydropyridin-1 (2H) -yl) ethan-1-one (10g, 22mmol), tris (2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (50mg, 0.111mmol), phenylsilane (15g, 144mmol) was dissolved in 160mL of a mixed solvent of anhydrous isopropanol/anhydrous dichloromethane (7:1). The reaction was carried out overnight at room temperature with replacement of oxygen. LC-MS showed the reaction was complete. And (4) concentrating. Silica gel column chromatography gave the title compound. ESI-MS m/z:474.2[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.97(d,J＝7.3Hz,1H),8.93(s,1H),8.58(s,1H),7.75-7.68(m,1H),7.55-7.48(m,1H),7.44–7.03(m,2H),6.00–5.72(m,1H),5.48(s,1H),4.35-4.30(m,1H),3.80-3.70(m,1H),3.59–3.44(m,1H),3.08–2.87(m,1H),2.39(s,3H),2.25-2.15(m,2H),2.05(s,3H),1.70-1.60(m,5H).
Example 2 (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
Step 1 preparation of (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-fluoropiperidin-1-yl) ethan-1-one
(R)-1-(4-(4-((1-(3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d]Pyrimidine-6-yl) -4-hydroxypiperidine-1-yl) ethan-1-one (0.3 g,0.6 mmol) is added into dichloromethane (10 mL), DAST (0.12mL, 0.9mmol) is added dropwise at 0 ℃, reaction is carried out for one hour at 0 ℃, saturated sodium bicarbonate is added after the reaction is completed for quenching, water is added, dichloromethane is extracted, and concentration is carried out. ESI-MS m/z:476.2[ 2 ], [ M + H ]] + 。
Step 2 preparation of (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
(R) -1- (4-fluoro-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyridinyl)][3,4-d]Pyrimidin-6-yl) piperidin-1-yl) ethan-1-one (0.3 g, 0.63mmol) was added to methanol (10 mL) and acetonitrile (10 mL), sodium methoxide (540 mg, 10mmol) was added, reaction was carried out at 50 ℃ and after completion of the reaction, quenching was carried out with saturated ammonium chloride, water was added, extraction was carried out with ethyl acetate, and concentration was carried out. And (4) performing column chromatography to obtain a target compound. ESI-MS m/z:488.2[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.98(s,2H),8.48(s,1H),7.72-7.70(m,1H),7.53–7.51(m,1H),7.39–6.12(m,2H),5.84–5.80(m,1H),4.24-4.21(m,1H),3.73-3.70(m,1H),3.46-3.43(m,1H),3.01(s,4H),2.41(s,3H),2.21-1.95(m,7H),1.66(t,J＝6.8Hz,3H).
Example 3: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-cyclopropylmethoxypiperidin-1-yl) ethan-1-one
The title compound was obtained by substituting methanol and sodium methoxide for cyclopropylmethanol and cyclopropylsodium methoxide as in example 2. ESI-MS m/z:528.2[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ9.13(s,1H),7.80(s,1H),7.60-7.50(m,2H),7.25-7.20(m,1H),6.90(t,J＝54.9Hz,1H),6.23(s,1H),6.02–5.67(m,1H),4.50-4.45(m,1H),3.78-3.72(m,1H),3.65-3.55(m,1H),3.34–2.91(m,3H),2.60(s,3H),2.41–1.98(m,7H),1.74(d,J＝6.9Hz,3H),1.08(s,1H),0.57(d,J＝7.2Hz,2H),0.11(d,J＝7.2,2H).
Example 4: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d]Pyrimidin-6-yl) -4- (methoxy-d 3 ) Piperidin-1-yl) ethan-1-one
The synthesis method is the same as example 2, and methanol and sodium methoxide are replaced by methanol-d 4 And sodium methoxide-d 3 To obtain the title compound. ESI-MS m/z:491.2[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.02-8.93(m,2H),8.45(s,1H),7.70-7.66(m,1H),7.53-7.50(m,1H),7.38-7.11(m,2H),5.91–5.70(m,1H),4.25-4.15(m,1H),3.75-3.66(m,1H),3.46-3.43(m,1H),3.12–2.94(m,1H),2.42-2.28(m,3H),2.22–1.83(m,7H),1.64(d,J＝6.8Hz,3H).
Example 5: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4- (2,2,2-trifluoroethoxy) piperidin-1-yl) ethan-1-one
Synthesis the title compound was prepared as in example 2 substituting methanol and sodium methoxide for 2,2,2-trifluoroethanol and 2,2,2-trifluoroethanol sodium. ESI-MS m/z of 556.2[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ9.29(s,1H),7.63(s,1H),7.52(s,1H),7.23(s,2H),7.23–6.77(m,1H),5.88(s,1H),4.41(s,1H),3.86–3.38(m,4H),3.14–3.07(m,2H),2.68(s,3H),2.37–1.98(m,5H),1.78(d,J＝7.0Hz,3H),1.25(s,2H).
Example 6: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4- (2,2-difluoroethoxy) piperidin-1-yl) ethan-1-one
Synthesis the title compound was prepared as in example 2 substituting methanol and sodium methoxide for 2,2-difluoroethanol and 2,2-difluoroethanol sodium. ESI-MS m/z of 538.2[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ9.17(s,1H),7.87(s,1H),7.62–7.46(m,2H),7.22(s,1H),7.06–6.78(m,1H),6.14(s,1H),4.99(s,1H),4.51(d,J＝11.4Hz,1H),3.87–3.76(m,2H),3.61–3.44(m,2H),3.10(s,2H),2.62(s,3H),2.35-2.00(m,7H),1.74(d,J＝6.8Hz,3H).
Example 7: (R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridine [3,4-d ] pyrimidin-6-yl) dimethylphosphine oxide
Weighing (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3,4-d]Pouring pyrimidine-4-amine (200mg, 0.55mmol) into a 10mL microwave tube, adding palladium acetate (7mg, 0.03mmol), 4,5-bis diphenylphosphine-9,9-dimethyl xanthene (35mg, 0.03mmol) and potassium carbonate (150mg, 1.1mmol), dropwise adding 5mL 1, 4-dioxane for dissolution, adding dimethyl phosphine oxide (100mg, 1.1mmol) after argon replacement, carrying out microwave reaction at 100 ℃ for 4 hours, after the reaction is finished, extracting with ethyl acetate/water, separating by a silica gel column, and carrying out high performance liquid phase separation to prepare the title compound. ESI-MS m/z:409.0[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ9.24(s,1H),8.61(s,1H),7.58–7.49(m,2H),7.20(t,J＝7.7Hz,1H),6.98(d,J＝55.0Hz,2H),5.88–5.79(m,1H),2.62(s,3H),1.82(d,J＝13.4Hz,6H),1.72(d,J＝7.0Hz,3H).
Example 8: (R) -1- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) amino) piperazin-1-yl) ethan-1-one
Step 1: preparation of tert-butyl (R) -1- (4- ((4- ((1- (3-difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) amino) piperazine-1-carboxylate
Weighing (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyridine [3,4-d]Pyrimidin-4-amine (500mg, 1370mmol), 1-carboxylic acid tert-butyl ester-4-aminopiperazine (304mg, 1640mmol), pd 2 (dba )3 (12.4mg,13.7mmol)，Ruphos(12.4mg,13.7mmol)，Cs 2 CO 3 (892mg, 2740mmol), adding into a 50mL three-necked flask, dissolving in toluene (4 mL), reacting under nitrogen atmosphere, vacuum distilling, spin drying, and performing column chromatography to obtain the final product. ESI-MS m/z:532.2[ 2 ], [ M + H ]] + 。
And 2, step: (R) -N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-N 6 - (piperazin-1-yl) piperidino [3,4-d]Pyrimidine-4,6-hydrazines
Taking (R) -1- (4- ((4- ((1- (3-difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d]Pyrimidin-6-yl) amino) piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.37mmol), trifluoroacetic acid/dichloromethane =3:1 (6 mL) was added, the reaction was stirred at room temperature, and after the experiment was completed, the reaction was evaporated under reduced pressure and dried. ESI-MS m/z:432.2[ 2 ], [ M + H ]] + 。
And step 3: preparation of (R) -1- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) amino) piperazin-1-yl) ethan-1-one
Taking (R) -N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-N 6 - (piperazin-1-yl) piperidino [3,4-d]Pyrimidine-4,6-hydrazine (200mg, 0.46mmol) is dissolved by adding dichloromethane (4 mL), triethylamine (2 mL) and acetic anhydride (0.2mL, 1.89mmol) are added, the mixture is stirred at normal temperature for reaction, after the experiment is finished, reduced pressure distillation and spin drying are carried out, and the product is obtained by column chromatography. ESI-MS m/z:474.2[ 2 ] M + H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.99–8.91(m,1H),8.57(s,1H),7.70(s,1H),7.51(s,2H),7.39–7.26(m,2H),7.23(s,1H),7.09(s,1H),5.82(s,1H),5.47(s,1H),4.33(d,J＝11.5Hz,2H),3.75(d,J＝12.6Hz,2H),3.05–2.95(m,2H),2.39(s,3H),2.05(s,3H),1.63(d,J＝6.2Hz,3H).
Example 9: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4- (2- (dimethylamino) ethoxy) piperidin-1-yl) ethan-1-one
Synthesis the title compound was prepared as in example 2, substituting methanol and sodium methoxide for 2- (dimethylamino) ethanol and sodium 2- (dimethylamino) ethoxide. ESI-MS m/z of 545.2[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ9.08(s,1H),8.33(s,1H),7.61(s,1H),7.50(s,1H),7.25-7.20(m,2H),6.91(t,J＝55.1Hz,1H),5.90-5.75(m,1H),4.50-4.42(m,1H),3.75-3.70(m,1H),3.58-3.45(m,1H),3.34(s,2H),3.21–3.03(m,1H),2.58(s,6H),2.30-1.80(m,12H),1.74(d,J＝6.4Hz,3H).
Example 10: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-1-yl) ethan-1-one
Weighing (S) -1- (4-fluoro-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyrido [3,4-d]Pyrimidin-6-yl) Piperidin-1-yl) ethan-1-one 200mg was dissolved in tetrahydrofuran 10mL under argon protection, cooled to 0 deg.C, added with methyl magnesium bromide 1.2mL (3 mol/L, 15e.q.), and reacted overnight. Quenching with saturated ammonium chloride, extracting with ethyl acetate, spin-drying, and isolating to obtain the title compound. ESI-MS m/z:472.2[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.64(d,J＝6.4Hz,2H),8.06(s,1H),7.70-7.65(m,1H),7.55-7.50(m,1H),7.40-7.20(m,2H),5.96–5.55(m,1H),3.70-3.20(m,4H),2.74(s,3H),2.39(s,2H),2.30-2.20(m,2H),2.00(s,3H),1.76-1.60(m,4H),1.34(s,3H).
Example 11: (R) -1- (4-methoxy-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyrido [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
Synthesis procedure as in example 2, substituting (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine with (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine gave the title compound. ESI-MS m/z 502.2[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.04(d,J＝6.4Hz,1H),8.95(s,1H),8.46(s,1H),7.78(d,J＝7.6Hz,1H),7.55(d,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,1H),5.75-5.70(m,1H),4.23-4.18(m,1H),3.74-3.67(m,1H),3.46-3.42(m,1H),3.01(s,4H),2.63(s,3H),2.39(s,3H),2.23–1.86(m,7H),1.59(d,J＝6.6Hz,3H).
Example 12: (R) -1- (4- (methoxy-d) 3 ) -4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyrido [3,4-d]Pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
The synthesis was carried out as in example 11, replacing methanol and sodium methoxide by methanol-d 4 And sodium methoxide-d 3 To obtain the title compound. ESI-MS m/z of 505.2[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.02(d,J＝6.5Hz,1H),8.95(s,1H),8.45(s,1H),7.77(d,J＝7.7Hz,1H),7.55(d,J＝7.6Hz,1H),7.37(t,J＝7.7Hz,1H),5.76-5.72(m,1H),4.23-4.18(m,1H),3.74-3.67(m,1H),3.46-3.42(m,1H),3.11–2.93(m,1H),2.63(s,3H),2.38(s,3H),2.23–1.89(m,7H),1.59(d,J＝6.8Hz,3H).
Example 13: (R) -1- (4-methyl-4- (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) pyrido [3,4-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
Synthesis procedure as in example 10, substituting (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine with (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine gave the title compound. ESI-MS m/z 486.2[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )8.64(d,J＝6.4Hz,1H),8.06(s,1H),7.70-7.64(m,1H),7.55-7.45(m,1H),7.40-7.05(m,2H),6.13–5.54(m,1H),3.65-3.40(m,4H),2.74(s,3H),2.39(s,3H),2.26(s,3H),2.00(s,3H),1.74(s,1H),1.63(d,J＝6.9Hz,3H),1.34(s,2H).
Example 14:1- (4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4- (((S) -tetrahydrofuran-3-yl) oxy) piperidin-1-yl) ethan-1-one
Synthesis the title compound was obtained by substituting methanol and sodium methoxide for (S) -tetrahydrofuran-3-ol and sodium (S) -tetrahydrofuran-3-ol as in example 2.
ESI-MS m/z:544.2[M+H] +1 。 1 HNMR(400MHz,CDCl 3 )δ9.05(s,1H),7.83–7.11(m,3H),6.85(t,J＝55.0Hz,1H),6.36(s,1H),5.92–5.64(m,1H),4.40-4.21(m,1H),4.05(s,1H),3.95–3.82(m,1H),3.74–3.37(m,6H),3.18(d,J＝10.7Hz,1H),2.52(s,3H),2.20-1.80(m,9H),1.66(d,J＝6.8Hz,3H).
Example 15: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) -4- (oxetan-3-ylmethoxy) piperidin-1-yl) ethan-1-one
Synthesis the title compound was prepared as in example 2, substituting methanol and sodium methoxide for oxetan-3-yl methanol and oxetan-3-yl sodium methoxide.
ESI-MS m/z:544.2[M+H] + 。 1 H NMR(400MHz,CDCl 3 )δ9.17(s,1H),7.88–7.17(m,4H),6.91(t,J＝54.9Hz,1H),5.94–5.75(m,1H),5.35(s,1H),4.78-4.70(m,2H),4.55–4.34(m,2H),3.73(s,1H),3.63–3.50(m,1H),3.48–3.31(m,2H),3.28–3.06(m,2H),2.61(s,3H),2.35–2.08(m,8H),1.74(d,J＝6.8Hz,3H).
Example 16: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2,8-dimethylpyrido [3,4-d]Pyrimidin-6-yl) -4- (methoxy-d 3 ) Piperidin-1-yl) ethan-1-one
Step 1: preparation of (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2,8-dimethylpyrido [3,4-d ] pyrimidin-4-amine
Weighing (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3,4-d]2g of pyrimidin-4-amine was dissolved in DMSO (15 mL), DBU (4.6 g, 10.92mmol) and nitromethane (1.6 g,27.3 mmol) were added and reacted at room temperature for 169, and after monitoring by LC-MS, washing with water, EA extraction and column chromatography were carried out to obtain 2.6g of the objective compound as a brown oil. ESI-MS m/z 381.1[ 2 ] M + H] + 。
Step 2: ((R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl)) Amino) -2,8-dimethylpyrido [3,4-d]Pyrimidin-6-yl) -4- (methoxy-d 3 ) Piperidin-1-yl) eth-1-one
The synthesis method is the same as example 4, and (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3,4-d]Conversion of pyrimidin-4-amine to (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2,8-dimethylpyrido [3,4-d]Pyrimidin-4-amine to yield the title compound. ESI-MS m/z of 505.2[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.82(d,J＝6.8Hz,1H),8.27(s,1H),7.68-7.64(m,1H),7.52-7.48(m,1H),7.42–7.06(m,2H),5.85–5.59(m,1H),4.23-4.18(m,1H),3.74-3.67(m,1H),3.46-3.42(m,1H),3.10–2.89(m,1H),2.74(s,3H),2.40(s,3H),2.15-7.90(m,7H),1.63(d,J＝6.9Hz,3H).
Example 17: (R) -cyclopropyl (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d]Pyrimidin-6-yl) -4- (methoxy-d 3 ) Piperidin-1-yl) methyl ketones
The title compound was obtained in the same manner as in example 4. ESI-MS m/z of 517.2[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.98-8.95(m,2H),8.46(s,1H),7.70-7.68(m,1H),7.52-7.49(m,1H),7.38–7.10(t,J＝56Hz,1H),7.31(t,J＝8Hz,1H),5.99–5.70(m,1H),4.18-4.15(m,2H),3.55-3.45(m,1H),3.20–2.89(m,1H),2.39(s,3H),2.28–1.90(m,5H),1.64(d,J＝6.9Hz,3H),0.85-0.70(m,4H).
The compounds of examples 18 to 36 were synthesized according to the synthesis method of example 1 or example 2 of the present invention, using different commercially available starting materials, and the characterization parameters of these compounds are shown in table 1:
TABLE 1
Experimental example 1: cell proliferation inhibition assay
Cell: human non-small cell lung cancer cell line NCI-H358, purchased from American Type Culture Collection (ATCC)
Cell recovery: the NCI-H358 cell cryopreservation tube was taken out of the liquid nitrogen tank and placed in a 37 ℃ water bath kettle, and was thawed as soon as possible by gentle shaking. And (3) taking out the frozen tube after thawing, sterilizing the frozen tube by using an alcohol cotton ball, screwing off the cap, sucking out cell sap, injecting the cell sap into a centrifuge tube, adding 1mL of complete culture medium containing serum, uniformly mixing, putting the mixture into a centrifuge, and centrifuging the mixture at 1000rpm for 5min. And then, removing the supernatant, adding a complete culture medium, and repeatedly blowing and beating until the cells are completely blown away and resuspended. The culture dish is inoculated with the appropriate concentration. Placed at 37 ℃ and 5% CO 2 95% CO in humid air 2 Culturing in an incubator.
Cell passage: the cells were grown to about 80-90% confluence, the original culture medium was discarded (1640 medium +10% FBS +1% streptomycin +1mM sodium pyruvate), 1mL of PBS was added to wash the residual medium and discard it, 1mL of trypsin digest was added, digestion was carried out for 1-2min, the cells were observed under the mirror for pseudopodia retraction and rounding but the cells were not yet flaked, at which time pancreatin was aspirated and digestion was stopped with 1-2mL of complete medium, gently pipetting and collecting the cell suspension, centrifuging at 1000rpm for 5min. Removing the supernatant, resuspending the cells in complete medium, plating the cells in a petri dish at the desired density, and incubating at 37 ℃ and 5% CO 2 95% CO in humid air 2 Culturing in an incubator according to the growth condition of cellsThe culture medium is changed or subcultured every 2-3 days.
The experimental steps are as follows:
NCI-H358 cells were passaged and resuspended in fresh medium (1640 medium +10% FBS +1% streptomycin +1mM sodium pyruvate), and after cell counting, seeded at a density of 12800 cells/mL into 96-well cell culture plates, adding 125. Mu.L per well (i.e., 1600 cells/well). After 24h, 125 μ L of fresh medium containing different concentrations (2X) of drug was added based on the old medium. The final concentrations of the compounds were 10. Mu.M, 3.33. Mu.M, 1.11. Mu.M, 0.37. Mu.M, 0.123. Mu.M, 0.041. Mu.M, 0.014. Mu.M, 0.0046. Mu.M, 0.0015. Mu.M, respectively, with two duplicate wells per concentration group. Continuously placing the mixture into an incubator to be cultured for 14 days. After 14 days of drug treatment, the CellTiter-Glo luminescennt Cell Viability Assay was removed 30min before equilibration to room temperature. Remove 125. Mu.L of medium from the wells. Add 125. Mu.L of Celltiter-Glo reagent (3D) detection reagent into each well, shake for 5min at room temperature, continue incubating for 25min at room temperature, take 200. Mu.L of each well, transfer to opaque white board, detect chemiluminescence signal, and Read sample injection detection conditions are 500ms. The inhibition rate of each well relative to the solvent control wells was calculated from the microplate reader derived readings (Lum 500 ms):
inhibition (%) =100- (Lum experimental well-Lum blank)/(Lum solvent control well-Lum blank) x100
Results of the experiment
IC was performed using GraghPad 6.0 software based on different drug concentrations and their corresponding inhibition rates 50 Drawing a curve, analyzing data to obtain a final IC 50 The value is obtained. IC of partial compound 50 The results are shown in Table 2.
TABLE 2
| Compound (I) | H358(IC 50 nM) |
| Example 2 | 33.8 |
| Example 3 | 26.1 |
| Example 4 | 7.8 |
| Example 5 | 38.8 |
| Example 6 | 17.3 |
Experimental results show that the compound has good inhibitory activity on non-small cell lung cancer cells.
Experimental example 2 cell proliferation inhibition experiment
Cell: human colorectal adenocarcinoma cell line DLD-1, purchased from American Type Culture Collection (ATCC)
Cell recovery: and taking out the human colorectal adenocarcinoma cell strain DLD-1 cell cryopreservation tube from the liquid nitrogen tank, placing the tube in a water bath kettle at 37 ℃, and slightly shaking to thaw the tube as soon as possible. Thawing, taking out the frozen tube, sterilizing with alcohol cotton ball, unscrewing the cap, sucking out cell sap, injecting into a centrifuge tube, adding complete culture medium containing serum, mixing, placing in a centrifuge, centrifuging at 1000rpm for 5min. And then, removing the supernatant, adding a complete culture medium, and repeatedly blowing and beating until the cells are completely blown away and resuspended. The cells were inoculated into T75 dishes at appropriate concentrations. Placed at 37 ℃ and 5% CO 2 95% CO in humid air 2 Culturing in an incubator.
Cell passage: the cells were grown to about 80-90% confluence, the original culture medium (1640 medium + FBS +1% streptomycin) was aspirated away, DPBS was added to wash the residual medium and then aspirated away, 2mL TrypLE was added TM Express Enzyme digestion, observing cell pseudopodia retraction to round but thin under the mirrorThe cells are not broken off, and TrypLE is discarded at the moment TM Express Enzyme and stop digestion with 5mL complete medium, gently blow and collect cell suspension, 1000rpm, centrifuge for 5min. The supernatant was removed and used as Countess TM II Automated Cell Count, inoculation at desired density in T75 dishes, 5% CO at 37 ℃% 2 95% CO in humid air 2 Culturing in an incubator, and changing culture solution or subculturing every 2-3 days according to the growth condition of the cells.
The experimental steps are as follows:
cells were harvested according to the cell passage protocol described above and used Countess TM II Automated Cell Counter counts and inoculates in 384-well plates at the appropriate Cell density, 40. Mu.l medium/well. The diluted compounds were added to each well plate using an Echo 550Liquid Handler, 200nl of the drug solution/well, to give final concentrations of 10. Mu.M, 3.33. Mu.M, 1.11. Mu.M, 0.37. Mu.M, 0.123. Mu.M, 0.041. Mu.M, 0.014. Mu.M, 0.0046. Mu.M, 0.0015. Mu.M, and 0.0005. Mu.M, and two duplicate wells were placed at each concentration group. Continuously placing the mixture into an incubator to be cultured for 7 days. 3D CTD was added 7 days after drug treatment. The signal values were detected using Envision. Calculate the inhibition rate of each well relative to the solvent control wells from the signal values:
Cell viability inhibition,％＝(Average_DMSO-Sample)/(Average_DMSO-Average_Medium)x 100
results of the experiment
Analyzing the data according to different drug concentrations and corresponding inhibition rates thereof to obtain the final IC 50 The value is obtained. IC of partial compound 50 The results are shown in Table 3.
TABLE 3
| Compound (I) | DLD-1(IC 50 nM) |
| Example 2 | 55.9 |
| Example 3 | 86.2 |
| Example 4 | 44.7 |
| Example 5 | 67.1 |
| Example 6 | 45.3 |
Experimental results show that the compound has good inhibitory activity on human colorectal adenocarcinoma.
EXAMPLE 3 phosphorylation-activated extracellular regulatory protein kinase (pERK) assay
ERK is downstream of the SOS1 signal path. The molecular mode of action of SOS1 inhibitors on RAS family protein signaling is demonstrated by the inhibition of ERK phosphorylation in KRAS-mutated cancer cells by SOS1 inhibitor compounds. Inhibition of ERK phosphorylation reflects inhibition of tumor cells by SOS1 inhibitor compounds.
Cell: human non-small cell lung cancer cell line NCI-H358, purchased from American Type Culture Collection (ATCC)
Cell recovery: the human non-small cell lung cancer cell strain NCI-H358 cell cryopreservation tube is taken out from a liquid nitrogen tank and placed in a water bath kettle at 37 ℃, and the tube is gently shaken to be thawed as soon as possible. Thawing, taking out the frozen tube, sterilizing with alcohol cotton ball, unscrewing the cap, sucking out cell sap, injecting into a centrifuge tube, adding complete culture medium containing serum, mixing, placing in a centrifuge, centrifuging at 1000rpm for 5min. And then, removing the supernatant, adding a complete culture medium, and repeatedly blowing and beating until the cells are completely blown away and resuspended. The cells were inoculated into T75 dishes at appropriate concentrations. Placed at 37 ℃ and 5% CO 2 95% moist airCO of gas 2 Culturing in an incubator.
Cell passage: the cells were grown to about 80-90% confluence, the original culture medium (1640 medium +10% FBS +1% streptomycin) was discarded, DPBS was added to wash the residual medium and discard it, 2mL TrypLE was added TM Express Enzyme digestion, observing the cell pseudopodia retraction and rounding under a mirror, but the cell is not flaked and shed, and then absorbing and discarding trypLE TM Express Enzyme and stop digestion with 5mL complete medium, gently blow and collect cell suspension, 1000rpm, centrifuge for 5min. The supernatant was removed and used as Countess TM II Automated Cell Counter, at the desired density (3.5-4 x 10) 6 One/dish) was inoculated into T75 petri dishes at 37 ℃ and 5% CO 2 95% CO in humid air 2 Culturing in an incubator, and changing culture solution or subculturing every 2-3 days according to the growth condition of the cells.
The experimental steps are as follows:
cells were harvested according to the cell passage protocol described above and used Countess TM II Automated Cell Counter counts and inoculates 384-well plates at the appropriate Cell density. The diluted compounds were added to each well plate using Echo 550Liquid Handler, 200nl of the drug solution/well, to give final concentrations of 50. Mu.M, 12.5. Mu.M, 3.125. Mu.M, 0.781. Mu.M, 0.195. Mu.M, 0.0488. Mu.M, 0.0122. Mu.M, 0.00305. Mu.M, 0.000763. Mu.M, 0.000191. Mu.M, two duplicate wells per concentration group, 37 ℃,5% CO 2 2 95% CO in humid air 2 Incubate in incubator for one hour. After fixation and washing of the cells, cell permeabilization is performed. After washing the cells once with PBS, they were blocked for 1h at room temperature. Subsequently, the blocking solution was removed, and a primary antibody (phospho-p 44/42MAPK (T202/Y204) Rabbit mAb or GAPDH (D4℃ 6R) Mouse mAb) was added and incubated overnight at 4 ℃. Remove primary antibody, add PBST,2 min/time, three times total cell cleaning. After removal of PBST, secondary antibodies (IRDye 800CW Goat anti-Rabbit IgG (H + L) (0.5 mg) or IRDye 680RD Goat anti Mouse IgG (H + L) (0.5 mg)) were added and incubated protected from light. After removal of the secondary antibody, the cells were washed with PBST 2 min/time for a total of three times. The 384 well plate was inverted, 1000rpm, centrifuged for 1min. Odyssey CLx reads the signal value.
Relative Signal＝Signal Value(total channel 800)/Signal Value(total channel 700)
Relative pERK＝(Sample-Ave(1μM AMG510))/(Ave(DMSO)-Ave(1μM AMG510))
Results of the experiment
Analyzing the data according to different drug concentrations and corresponding inhibition rates thereof to obtain the final IC 50 The value is obtained. IC of partial compound 50 The results are shown in Table 4.
TABLE 4
| Compound (I) | p-ERK(IC 50 nM) |
| Example 1 | 53 |
| Example 2 | 15 |
| Example 3 | 37 |
| Example 4 | 24 |
| Example 5 | 49 |
| Example 6 | 48 |
| Example 7 | 101 |
| Practice ofExample 8 | 528 |
| Example 9 | 12 |
| Example 10 | 19 |
| Example 12 | 7.2 |
| Example 16 | 20 |
Experimental results show that the compound has good inhibitory activity on human non-small cell lung cancer.
Although the present invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the present invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.
Claims (10)
1. A compound shown in a general formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
wherein the content of the first and second substances,
R 1 selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl;
R 2 selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and haloalkyl;
R 3 each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, ammoniaAlkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, heterocyclyl and cycloalkyl;
R 4 selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, alkenyl, alkyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxy, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, hydroxycycloalkyl, hydroxyheterocyclyl, heterocyclyl, and cycloalkyl;
R 5 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, hydroxyalkyl, aminoalkyl, hydroxyhaloalkyl, alkoxy, and cycloalkyl;
R 6 (ii) a group selected from dimethylphosphinyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocyclylheteraryl, optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, cycloalkylsulfonyl, heterocyclylacyl, heterocyclylsulfonyl, cycloalkylalkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups; or
R 6 is-n-R 6a N is selected from NH and O, R 6a Selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl, said aryl, heteroaryl, cycloalkyl, heterocyclyl and heterocycloheteroaryl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocycloyi, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groupsSubstituted with a group of (1); and
m is 1,2, 3 or 4.
2. The compound according to claim 1, wherein the general formula (I) has the structure of the following general formula (Ia) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And m has the meaning indicated above for formula (I), R 7 、R 8 Each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, haloalkylamino, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkanoyl, cycloalkylacyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylsulfonyl, heterocycloyl, heterocyclyloxy, cycloalkylamino, heterocyclylamino, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylsulfonyl, cycloalkylalkanoyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
3. The compound according to claim 1 or 2, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
wherein R is 1 Selected from hydrogen, C 1-3 Alkyl, halogen and halogeno C 1-3 An alkyl group; r 2 Selected from hydrogen, C 1-3 Alkyl, hydroxy C 1-3 Alkyl and halo C 1-3 An alkyl group; r 3 Each independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy radical,3-8 heterocyclic group and C 3-8 A cycloalkyl group.
4. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 4 Selected from hydrogen, halogen, hydroxy, carboxyl, cyano, amino, C 2-6 Alkenyl radical, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, hydroxy C 3-6 Cycloalkyl, hydroxy 3-6 A heterocyclic group, 3-6 Heterocyclyl and C 3-6 A cycloalkyl group; r 5 Selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxy-halogeno-C 1-6 Alkyl radical, C 1-6 Alkoxy and C 3-6 A cycloalkyl group.
5. The compound according to any one of claims 1, 3-4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 6 Selected from dimethylphosphinyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl, said C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclo 5-12 membered heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino radical, C 1-6 Alkylacylamino group, C 1-6 Alkyl acyl, C 1-6 Alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, di-C 1-6 Alkylamino radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo C 1-6 Alkyl acyl, hydroxy C 1-6 Alkyl acyl radical, C 3-12 Cycloalkyl acyl, C 3-12 Cycloalkylsulfonyl, 3-12 heterocycloyl, 3-12 heterocyclylsulfonyl, C 3-12 Cycloalkyl radical C 1-6 Alkyl acyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo.
6. The compound according to claim 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein R is 8 Selected from halogen, hydroxy, C 1-3 Alkyl, halo C 1-3 Alkyl, hydroxy C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halo C 1-3 Alkylamino radical, hydroxy radical C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino radical, C 1-3 Alkylacylamino group, C 1-3 Alkyl acyl radical, C 1-3 Alkylsulfonyl, aminoacyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-3 Alkyl acyl, hydroxy C 1-3 Alkyl acyl radical, C 3-8 Cycloalkyl acyl, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkyl radical C 1-3 Alkoxy radical, C 3-8 Cycloalkylsulfonyl, 3-8 membered heterocycloyl, 3-8 membered heterocyclyloxy, C 3-8 Cycloalkylamino, 3-8 membered heterocyclylamino C 1-3 Alkoxy, 3-to 8-membered heterocyclyl C 1-3 Alkylamino, 3-8 membered heterocyclylsulfonyl, C 3-8 Cycloalkyl radical C 1-3 Alkyl acyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl.
7. The compound according to any one of claims 1, 3-5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
wherein:
R 6 is selected from
8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound of any one of claims 1-8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition of claim 9 for the manufacture of a medicament for the treatment of a disease associated with SOS 1.
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| WO2023246837A1 (en) * | 2022-06-22 | 2023-12-28 | 上海海和药物研究开发股份有限公司 | Class of compounds having pyrimido-six-membered ring structure, pharmaceutical compositions comprising same, and use thereof |
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