CN115703783A - Pyrrolopyrimidine derivatives, and preparation method and application thereof - Google Patents
Pyrrolopyrimidine derivatives, and preparation method and application thereof Download PDFInfo
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- CN115703783A CN115703783A CN202210974369.7A CN202210974369A CN115703783A CN 115703783 A CN115703783 A CN 115703783A CN 202210974369 A CN202210974369 A CN 202210974369A CN 115703783 A CN115703783 A CN 115703783A
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- alkyl
- cycloalkyl
- aryl
- heteroaryl
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Abstract
The invention relates to a substituted pyrrolopyrimidine derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicines. Specifically, the invention relates to substituted pyrrolopyrimidine derivatives shown in a general formula (I), a preparation method thereof, pharmaceutically acceptable salts thereof, and application thereof as a therapeutic agent, particularly an SOS1 inhibitor, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.
Description
Technical Field
The present invention relates to substituted pyrrolopyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as SOS1 inhibitors.
Background
RAS genes are widely present in various eukaryotes such as mammals, drosophila, fungi, nematodes and yeasts, and have important physiological functions in various life systems, three members of the mammalian RAS gene family, H-RAS, K-RAS and N-RAS, respectively, and various RAS genes have similar structures, each consisting of four exons, and are distributed on about 30kb DNA. Their encoded product is a monomeric globular protein with a relative molecular mass of 21 kDa. The activated and inactivated state of RAS proteins has a major impact on cell growth, differentiation, proliferation and apoptosis. The protein is membrane-bound guanine nucleotide binding protein, has weak GTP enzyme activity, regulates the activity state of RAS through GTP enzyme activating protein (GAPs) and guanine nucleotide exchange factor (GEFs) in normal physiological activity, is in the activation state when RAS protein is combined with GTP to form RAS-GTP, and can ensure that RAS-GTP is dephosphorylated and converted into RAS-GDP through the GTP enzyme activating protein so as to be inactivated; the inactivated RAS-GDP is converted into active RAS-GTP under the action of guanine nucleotide exchange factors, so that a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR are activated.
The RAS gene is also closely related to various diseases of human beings, and particularly in cancer, RAS is an oncogene frequently mutated, in which KRAS subtype gene mutation accounts for 86% of the total RAS gene mutation, and about 90% of pancreatic cancer, 30% -40% of colon cancer, and 15-20% of lung cancer have different degrees of KRAS gene mutation. Given the prevalence of KRAS gene mutations, this target has been a direction of interest to drug developers. Starting with the publication of AMG-510 clinical results acting directly on the KRAS-G12C target, the studies on KRAS inhibitors have raised a hot tide at home and abroad.
SOS (Son of seven homology) protein was originally discovered in Drosophila studies and is a guanosine releasing protein encoded by the SOS gene. There are 2 SOS homologues, hSOS1 and hSOS2, both members of the guanine nucleotide exchange factor family, in humans, with 70% homology, although they are highly similar in structure and sequence, with some differences in their physiological functions. The hSOS1 protein is 150kDa in size, is a multi-structural protein domain consisting of 1333 amino acids, comprising an N-terminal protein domain (HD), multiple homeodomains, a Helical Linker (HL), a RAS exchange sequence (REM), and a proline-rich C-terminal domain. hSOS1 has 2 binding sites with RAS protein, which are catalytic site and allosteric site, the catalytic site combines with RAS protein on RAS-GDP complex to promote guanine nucleotide exchange, and the allosteric site combines with RAS protein on RAS-GTP complex to further enhance catalytic action, so as to participate and activate the signal transduction of RAS family protein. It has been shown that SOS1 inhibition not only results in complete inhibition of the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also results in a 50% reduction in phospho-ERK activity in mutated KRAS cell lines. Therefore, inhibition of SOS1 can also decrease the activity of RAS to treat various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, colorectal cancer, biliary tract cancer, gastric cancer, non-small cell lung cancer, etc.
In addition, alterations in SOS1 are also implicated in cancer. Studies have shown that SOS1 mutations are found in embryonal rhabdomyosarcoma, sertoli cell testicular tumor, diffuse large B cell lymphoma, neurofibroma, cutaneous granulocytic tumor, and lung adenocarcinoma. Meanwhile, studies have described overexpression of SOS1 in bladder and prostate cancer. In addition to cancer, inherited SOS1 mutations are implicated in the pathogenesis of RAS diseases such as Noonan Syndrome (NS), cardio-facial skin syndrome (CFC), and inherited gingival fibromas type i, among others.
SOS1 is also a GEF for activation of the GTPase RAC1 (Ras-related botulinum C3 toxin substrate 1). Like RAS family proteins, RAC1 is involved in the pathogenesis of a variety of human cancers and other diseases.
No drug selectively targeting SOS1 has been marketed in the market, but a series of related patents have been published, including WO2018115380A1 by BI, WO2019122129A1, WO2019201848A1 by Bayer, WO2020180768A1 by Revolution, WO2020180768A1, WO2020180770A1, etc., and the drug currently in clinical trials is BI-1701963. However, these are far from sufficient for antitumor studies, and there is still a need to study and develop new selective SOS1 kinase inhibitors to address the unmet medical need.
Disclosure of Invention
In view of the above technical problems, the present invention provides a substituted pyrrolopyrimidine compound represented by general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein:
ring A is selected from C 6 -C 10 Aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclic group, or 9-10 membered fused ring;
x and Y are each independently selected from-CR a R b Or C = O;
l is selected from the group consisting of a bond, -C (O) -, -C (O) NH (CH) 2 )p-、-C(O)O-、-S(O) 2 -, -S (O) -or- (CH) 2 )q-;
R a 、R b Each independently selected from hydrogen atom, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl or C 6 -C 10 Aryl, wherein said C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl or C 6 -C 10 Aryl is optionally further substituted with one or more substituents selected from halo, alkyl, alkoxy, or hydroxy;
R 1 the same or different, each independently selected from hydrogen atom, alkyl groupHalogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with a substituent of (a);
L 1 Selected from the group consisting of a bond and C 1 -C 6 Alkylene, wherein said alkylene is optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, or hydroxy;
R A is selected from C 1 -C 6 Alkyl or C 1 -C 6 Cycloalkyl, wherein said alkyl or cycloalkyl is optionally further substituted with one or more halogen or hydroxy;
R B selected from halogen, cyano, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, -OR 8 or-NR 9 R 10 (ii) a Wherein said cycloalkyl OR heterocyclyl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 The substituent of (3) is taken;
R 3 、R 4 each independently selected from a hydrogen atom or C 1 -C 6 An alkyl group; and, R 3 、R 4 At least one of them is a hydrogen atom; wherein said alkyl is optionally further substituted with one or more halogen or hydroxy;
or, R 3 、R 4 Together with the atom to which they are attached form a C 3 -C 6 A cycloalkyl group;
R 5 selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, -OR 8 、-NR 9 R 10 or-C (O) NR 9 R 10 (ii) a Wherein said alkyl, cycloalkyl OR heterocyclyl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with a substituent of (a);
ring B is selected from 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, or 5-10 membered fused ring;
R 6 selected from the group consisting of hydrogen atoms, -L 2 -R C 、-C(O)-L 2 -R C or-C (O) -R D ;
L 2 Each independently selected from-C 1 -C 6 Alkylene, wherein said alkylene is optionally further substituted with one or more R E Substituted, R E Selected from halogen, alkyl, alkoxy or hydroxy; or, two R's attached to the same carbon atom E Together with the carbon atom to which they are attached form a cycloalkyl group; preferably cyclopropyl;
R C each independently selected from cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 or-S (O) r R 8 (ii) a Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
R D selected from deuterated alkyl, hydroxyalkyl, cycloalkyl, aryl, or heteroaryl; wherein said alkyl, cycloalkyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
R 7 selected from hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
the limiting conditions are as follows:
when R is 6 When selected from hydrogen atoms, X and Y are each independently selected from-CR a R b And R is a 、R b At least one selected from C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy and C 3 -C 6 A cycloalkyl group;
R 8 selected from the group consisting of hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted with one or more groups selected from the group consisting of deuterium atom, hydroxyl group, halogen, nitro group, cyano group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
R 9 and R 10 Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
or, R 9 And R 10 With itThe atoms to which they are attached together form a 4-to 8-membered heterocyclic group containing one or more of N, O or S (O) r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
R 11 、R 12 and R 13 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
r is selected from 0, 1 or 2;
m is selected from 1,2,3 or 4;
p is selected from 0 or 1;
q is selected from 1,2,3, 4, 5 or 6;
n is selected from 1,2 or 3;
k is selected from 0, 1,2 or 3.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein: ring A, X, Y, R 1 、R 5 、R A 、R B 、L、L 1 And m is as defined in formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein: ring A, X, Y, R 1 、R 5 、R 6 、R 7 L, m, n and k are as defined in formula (I).
In a preferred embodiment of the present invention, a compound represented by the general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, whereinSelected from the following structures:
wherein: r 1 And m is as defined in formula (I).
In a preferred embodiment of the present invention, a compound represented by the general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, whereinIs selected from
In a preferred embodiment of the present invention, the compound is represented by the general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is-C (O) -.
In a preferred embodiment of the present invention, a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R is A Is methyl.
In a preferred embodiment of the present invention, a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
L 1 is selected from C 1 -C 6 Alkylene, preferably methylene or- (CH) 2 ) 2 -;
R B Is selected from-OR 8 or-NR 9 R 10 ;
R 8 、R 9 、R 10 Each independently selected from alkyl groups, preferably methyl groups.
In a preferred embodiment of the present invention, a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein L 1 Is a bond;
In a preferred embodiment of the present invention, a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring B is selected from 5-10 membered heterocyclyl, preferably piperazinyl, piperidinyl, morpholinyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl.
In a preferred embodiment of the present invention, a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 6 is selected from-L 2 -R C or-C (O) -L 2 -R C ;
R C Each independently selected from cyano, heterocyclyl or-NR 9 R 10 ;
R 9 、R 10 Independently selected from a hydrogen atom or C 1 -C 6 An alkyl group; r 9 、R 10 Preferably methyl.
In a preferred embodiment of the present invention, a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 6 selected from-C (O) -R D ;
R D Selected from deuterated alkyl;
R D deuterated methyl is preferred.
In a preferred embodiment of the present invention, a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 7 is selected from C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
R 7 preferably methyl or methoxy.
In a preferred embodiment of the present invention, a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, whereinSelected from the following groups:
in a preferred embodiment of the present invention, a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, whereinSelected from the following groups:
in a preferred embodiment of the present invention, the compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen, C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, preferably chlorine, iodine, methyl or methoxy.
In a preferred embodiment of the invention, the compound of formula (I) is selected from:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note: if there is a difference between a drawn structure and a given name for that structure, the drawn structure will be given more weight.
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing an SOS1 inhibitor.
The invention also provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease mediated by SOS1, wherein the disease mediated by SOS1 is preferably a RAS family protein signaling pathway dependent related cancer, a SOS1 mutation induced cancer or a SOS1 mutation induced genetic disease; wherein said SOS 1-mediated disease is preferably lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, noonan syndrome, cardio-facial skin syndrome, type I hereditary gingival fibroma, embryonal rhabdomyosarcoma, seltorit cell testicular tumor, or cutaneous granulomatosis.
The invention further provides an application of the compound of the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating RAS family protein signal transduction pathway dependence related cancers, cancers caused by SOS1 mutation or genetic diseases caused by SOS1 mutation.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostatic cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, noonan syndrome, cardio-facio-cutaneous syndrome, type I hereditary gingival fibroma, embryonal rhabdomyosarcoma, sellergliomas or skin granulomatosis.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"bond" means that the indicated substituent is absent and the two end portions of the substituent are directly connected to form a bond.
"alkyl" when taken as a group or part of a group means including C 1 -C 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures wherein the individual rings share a common carbon atom (called the spiro atom) and may contain 1 or more double bonds within the ring, but none of the rings have a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cyclic alkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decahydronaphthyl or tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s, 4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s, 5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r, 5r) -bicyclo [3.3.2] decyl.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, polycyclic, fused, bridged, and spiro rings. Preferably having a 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic ring which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-onyl, piperazinyl, hexahydropyrimidyl,
monocyclic heterocyclyl groups may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which may contain 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]]Nonyl, 7-oxaspiro [3.5]]Nonyl, 5-oxaspiro [2.4]]A heptyl radical,
The spiroheterocyclic group may be substituted or unsubstituted.
"fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c ] s]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines).
"bridged heterocyclic radical"refers to a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated π electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2] rings]Octyl, 2-azabicyclo [3.3.2]A decyl group,
The bridged heterocyclic groups may be substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridonyl,
Heteroaryl groups may be substituted or unsubstituted.
"fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a completely conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14, more preferably 8 to 10. Examples of "fused rings" include, but are not limited to:
the fused rings may be substituted or unsubstituted.
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C 1 -C 6 Alkoxy groups of (2) are preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"haloalkyl" refers to an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.
"hydroxyalkyl" refers to a group wherein the alkyl group is optionally further substituted with one or more hydroxyl groups, wherein alkyl is as defined herein.
"deuterated alkyl" refers to an alkyl group optionally further substituted with one or more deuterium atoms, wherein alkyl is as defined herein.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"Nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" refers to-C (O) OH.
"carboxylate" means-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"Boc" refers to tert-butoxycarbonyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyAlkyl, carboxyl, carboxylate group, = O, -C (O) R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
R 8 selected from the group consisting of hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted by one or more groups selected from deuterium atom, hydroxyl group, halogen, nitro group, cyano group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
R 9 and R 10 Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
or, R 9 And R 10 Together with the atoms to which they are attached form a 4-to 8-membered heterocyclic group containing one or more of N, O or S (O) r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl,Cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
R 11 、R 12 and R 13 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
r is selected from 0, 1 or 2;
the compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, all isomers (e.g., diastereomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms; e.g., R and S configurations at each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers) of the structures are also encompassed by the structures described herein.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds of formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.
Synthesis of Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which process comprises:
a compound of the general formula (IIIC) obtained by condensation reaction of a compound of the general formula (IIIA) and a compound of the general formula (IIIB), and optionally further deprotection reaction, the compound of the general formula (IIIC) and one or more R 6 -X 2 Carrying out substitution reaction; optionally further carrying out nitro reduction reaction to obtain a compound of a general formula (III);
wherein:
X 1 、X 2 is a leaving group, preferably hydroxy or halogen;
ring A, X, Y, R 1 、R 5 、R 6 、R 7 L, m, n or k are as defined in formula (III).
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds of formula (I) and associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention. 1 The H NMR spectrum was obtained using a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Use fourMethylsilane internal standard (0.00 ppm). 1 Method for H NMR expression: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. When coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of Futai Huanghai silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, the starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials or reagents are used without further purification, unless otherwise indicated, and commercially available manufacturers include, but are not limited to, shanghai haohnhong reagent limited, shanghai beth medicine technology limited, shanghai kaider chemical technology (shanghai) limited, and shanghai ling kaiki medicine technology limited.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Purifying the compound using an eluent system for column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol system, wherein the volume ratio of the solvent is different according to the polarity of the compound, and small amount of acidic or alkaline reagent such as acetic acid or triethylamine can be added for carrying out the conditions.
Room temperature: 20-30 ℃.
Example 1
(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxy-1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methanone
(4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone
First step of
tert-butyl(R)-2-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate
(R) -2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester
Tert-butyl 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate 1a (500mg, 1.72mmol, prepared according to published patent WO 2021058018A 1), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine 1b (524.61mg, 2.24mmol, prepared according to published patent WO 2021105960) and N, N-diisopropylethylamine (1.111g, 8.62mmol) were added in that order to 1, 4-dioxane (15 mL) and the mixture was heated to 100 ℃ with stirring for 24 hours. Extraction with ethyl acetate (30 mL), washing of the organic phase with saturated sodium chloride solution (30 mL × 2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the residue by thin layer chromatography (developer: system a) gave (R) -tert-butyl 2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate 1c (600mg, 1.23mmol), yield: 71.37 percent.
MS m/z(ESI):488.9[M+H] +
Second step of
(R)-2-chloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine
(R) -2-chloro-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-amine
(R) -2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester 1c (500mg, 1.02mmol) and concentrated hydrochloric acid (186.84mg, 5.12mmol) were added in succession to 1, 4-dioxane (10 mL) and stirring continued at room temperature for 4 hours. Direct concentration gave (R) -2-chloro-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-amine 1d (380mg, 0.98mmol), yield: 95.62 percent.
MS m/z(ESI):388.3[M+H] +
The third step
tert-butyl(R)-4-(2-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-methoxypiperidine-1-carboxylate
(R) -4- (2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine-6-carbonyl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester
(R) -2-chloro-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-amine 1d (400mg, 1.03mmol), 1- (tert-butoxycarbonyl) -4-methoxypiperidine-4-carboxylic acid 1e (401.24mg, 1.55mmol, prepared according to published patent WO 2020175968A 1) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (197.76mg, 1.03mmol) were added in this order to dichloromethane (10 mL) and stirring was continued at room temperature for 4 hours. The reaction solution was added with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system a) to give (R) -tert-butyl 4- (2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine-6-carbonyl) -4-methoxypiperidine-1-carboxylate 1f (450mg, 0.72mmol), yield: 70 percent.
MS m/z(ESI):574.3[M-55] +
The fourth step
(R)-(2-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxypiperidin-4-yl)methanone
(R) - (2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxypyridin-4-yl) methanone
(R) -4- (2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine-6-carbonyl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester 1f (500mg, 0.79mmol), concentrated hydrochloric acid (28.98mg, 0.79mmol) were added in this order to 1, 4-dioxane (10 mL) and stirring was continued at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give 1g (400mg, 0.76mmol) of (R) - (2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxypyridin-4-yl) methanone, yield: 95.14 percent.
MS m/z(ESI):530.1[M+H] +
The fifth step
(2-chloro-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxy-1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methanone
(2-chloro-4- (((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone
1g (300mg, 0.57mmol) of (R) - (2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxypyridin-4-yl) methanone, 2- (bromomethyl) tetrahydrofuran (187.21mg, 1.13mmol) and sodium carbonate (120.24mg, 1.13mmol) were added in that order to acetonitrile (15 mL) and stirring was continued for 36H at 85 ℃. The reaction solution was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system B) to give the product (2-chloro-4- (((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone 1H (200mg, 0.65mmol), 58% yield.
MS m/z(ESI):614.3[M+H] +
The sixth step
(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxy-1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methanone
(4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone
Reacting (2-chloro-4- (((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3, 4-d)]Pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone 1h (100mg, 0.16mmol), iron powder (18.22mg, 0.32mmol) and 1M aqueous hydrochloric acid (3 mL) were added in that order to ethanol (5 mL), warmed to 100 ℃ for 4 hours with stirring, extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: b system) to obtain (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-5, 7-dihydro-6H-pyrrolo [3, 4-d)]Pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone 1 (76mg, 0.13mmol), yield: 80 percent. MS m/z (ESI): 583.2[ M ] +H] +
Example 2 and example 3
(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxy-1-(((S)-tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methanone
(4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- (((S) -tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone 2
(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxy-1-(((R)-tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methanone
(4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- (((R) -tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone 3
(4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxy-1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methanone 1 (170mg, 0.29mmol) was resolved by SFC chiral resolution (column model: superchiral S-IC (Chiralway), 2.1cm I.D.. 25cm Length,5um; mobile phase: hexane/EtOH/DEA =70/30/0.05 (v/v/v); column pressure: 100bar; flow rate: 15mL/min; detection wavelength: 220nm; column temperature: 35 ℃ C.) to give a single configuration compound (shorter retention time) and a single configuration compound (longer retention time). Single configuration compound (shorter retention time):
71mg; retention time 5.313 min, chiral purity 99.84% ee.
MS m/z(ESI):583.2[M+1] +
1 H NMR(400MHz,DMSO-d6)δ8.24(dd,J=8.0,3.4Hz,1H),6.84(s,1H),6.78(s,1H),6.71(d,J=4.7Hz,1H),5.56(d,J=3.2Hz,2H),5.20(t,J=7.5Hz,1H),4.80(d,J=22.5Hz,2H),4.52(d,J=22.7Hz,2H),3.91(q,J=6.4Hz,1H),3.73(q,J=7.2Hz,1H),3.60(q,J=7.4Hz,1H),3.12(d,J=14.1Hz,3H),2.77-2.60(m,2H),2.42-2.25(m,4H),1.98-1.75(m,7H),1.45(t,J=7.0Hz,4H).
Single configuration compound (longer retention time):
75mg; retention time 5.990 minutes, chiral purity 99.32% ee.
MS m/z(ESI):583.3[M+1]+
1 H NMR(400MHz,DMSO-d6)δ8.24(dd,J=8.2,3.5Hz,1H),6.84(s,1H),6.78(s,1H),6.71(d,J=4.8Hz,1H),5.56(d,J=3.4Hz,2H),5.21(m,J=10.8,5.3Hz,1H),4.80(d,J=22.3Hz,2H),4.52(d,J=22.8Hz,2H),3.92(q,J=6.4Hz,1H),3.73(q,J=7.2Hz,1H),3.60(q,J=7.5Hz,1H),3.13(d,J=14.0Hz,3H),2.81-2.58(m,2H),2.43-2.23(m,4H),1.97-1.68(m,7H),1.45(t,J=6.9Hz,4H)
Biological evaluation
Test example 1 test for blocking binding of SOS1 to KRAS G12C protein by Compounds of the invention
The following method was used to determine the ability of the compounds of the invention to block the interaction of SOS1 with KRAS G12C protein under in vitro conditions. The method uses KRAS-G12C/SOS1 BINDING ASSAY KITS kit (product number 63ADK000CB16 PEG) of Cisbio company, and the detailed experimental operation can refer to the kit instruction.
The experimental procedure is briefly described as follows: the solution concentrations of Tag1-SOS1 and Tag2-KRAS-G12C protein at 5X were prepared using a differential buffer (cat # 62 DLBDDF) for use. Test compounds were dissolved in DMSO to prepare 10mM stock solutions, which were then diluted with a diluent buffer for use. Firstly, adding 2 mu L of tested compound (the final concentration of a reaction system is 10000nM-0.1 nM) into a hole, then adding 4 mu L of working solution of Tag1-SOS 1X and 4 mu L of working solution of Tag2-KRAS-G12C5X, centrifuging and uniformly mixing, and standing for 15 minutes; then 10 mu.L of premixed anti-Tag1-Tb is added 3+ And anti-Tag2-XL665, and incubating for 2 hours at room temperature; finally, the fluorescence intensity of each well at an excitation wavelength of 304nM, which is measured in TF-FRET mode using a microplate reader, is 620nM and 665nM, and the ratio of 665/620 fluorescence intensity of each well is calculated. The percent inhibition of the test compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the IC of the compound was obtained by nonlinear regression analysis of the value-inhibition at the test compound concentration using GraphPad Prism5 software 50 Values, results are given in the following table.
TABLE 1 Table of Activity of Compounds of the invention to Block binding of SOS1 to KRAS G12C protein
And (4) conclusion: the compound has stronger blocking effect on interaction of SOS1 and KRAS G12C protein, and IC of the compound 50 <1 μ M, IC of preferred compounds 50 <100nM。
Test example 2 inhibition of OCI-AML5 cell proliferation by the Compound of the present invention
The following methods were used to determine the effect of the compounds of the present invention on proliferation of OCI-AML5 cells. OCI-AML5 cells (containing the SOS 1N 233Y mutation) were purchased from Nanjing Ke Bai Biotech, inc. and cultured in MEM α medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. Cell viability byThe Luminescent Cell Viability Assay kit (Promega, cat # G7573) was used for the Assay.
The experimental method is operated according to the steps of the kit specification, and is briefly as follows: test compounds were first dissolved in DMSO to prepare 10mM stock solutions, which were then diluted with medium to prepare test samples at a final concentration of compound in the range of 10000nM to 0.15nM. Inoculating cells in logarithmic growth phase into 96-well cell culture plates at a density of 1000 cells per well, at 37 deg.C, 5% 2 The incubation in the incubator is carried out overnight, followed by a further 120 hours after addition of the test compound. After the incubation was completed, 50uL volume of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then Luminescence values of each well of the sample were read on a microplate reader using Luminescence mode. The percentage inhibition of the compounds at each concentration point was calculated by comparison with the values of the control (0.3% DMSO), after which non-linear regression analysis was performed in GraphPad Prism5 software at the log-inhibition of the compound concentration, to obtain the IC of the compounds for inhibition of cell proliferation 50 Values, results are given in the table below.
TABLE 2 inhibitory Activity of the Compounds of the present invention on OCI-AML5 cell proliferation
And (4) conclusion: the compound has better inhibition effect on the proliferation of OCI-AML5 cells.
Test example 3 measurement of p-ERK1/2 inhibitory Activity of the Compound of the present invention in DLD-1 cells
The following method was used to determine the p-ERK1/2 inhibitory activity of the compounds of the present invention in DLD-1 cells. The method uses Advanced phosphor-ERK 1/2 (Thr 202/tyr 204) kit (cat. 64 AERPEH) of Cisbio company, and the detailed experimental operation can refer to the kit instruction. DLD-1 cells (containing KRAS G13D mutation) were purchased from cell resource center of Shanghai Life science research institute of Chinese academy of sciences.
The experimental procedure is briefly described as follows: DLD-1 cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. 30000 cells per well of DLD-1 were plated in a 96-well plate as a complete medium, and cultured overnight at 37 ℃ in a 5% CO2 incubator. Test compounds were dissolved in DMSO to prepare a 10mM stock solution, which was then diluted with RPMI 1640 basic medium, to which 90uL of RPMI 1640 basic medium containing the test compound at the corresponding concentration was added per well, the final concentration of the test compound in the reaction system ranged from 10000nM to 0.15nM, and the cells were cultured in a cell culture chamber for 3 hours and 40 minutes. Then 10uL of hEGF (purchased from Roche under the trademark 11376454001) prepared in RPMI 1640 basic medium was added to a final concentration of 5nM and incubated in an incubator for 20 minutes. Cell supernatants were discarded, cells were washed with ice-bath PBS, after which 45. Mu.l of 1 xcell phosphor/total protein lysis buffer (Advanced phosphor-ERK 1/2 kit component) was added per well for lysis, 96-well plates were placed on ice for lysis for half an hour, and lysates were then assayed according to the instructions of the Advanced phosphor-ERK 1/2 (Thr 202/tyr 204) kit. Finally, the fluorescence intensity of each well with the emission wavelength of 620nM and 665nM under the excitation wavelength of 304nM is measured on a microplate reader in TF-FRET mode, and the fluorescence intensity of each well 665/620 is calculatedAnd (4) a degree ratio. The percent inhibition of the test compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the IC of the compound was obtained by nonlinear regression analysis of the value-inhibition at the test compound concentration using GraphPad Prism5 software 50 Values, results are given in the table below.
TABLE 3 inhibition of p-ERK1/2 in DLD-1 cells by Compounds of the invention
And (4) conclusion: the compound has a good inhibition effect on ERK phosphorylation of DLD-1 cells.
Test example 4 measurement of inhibition of NCI-H358 cell proliferation by the Compound of the present invention
The following method was used to determine the effect of the compounds of the invention on cell proliferation of NCI-H358 cells under three-dimensional (3D) non-anchorage conditions. NCI-H358 cells (containing KRAS G12C mutation) were purchased from the cell resource center of Shanghai Life sciences institute of Chinese academy of sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. Cell viability by3D Cell Viability Assay kit (Promega, cat # G9683).
The experimental method is operated according to the steps of the kit specification and is briefly described as follows: test compounds were first prepared as 10mM stock solutions dissolved in DMSO and then diluted with culture medium to prepare test samples, with the final concentration of compound ranging from 10000nM to 0.15nM. Cells in logarithmic growth phase were seeded at a density of 2000 cells per well in ultra-low adsorption 384-well cell culture plates (PerkinElmer, # 3830) and cultured for an additional 120 hours after addition of test compound. After the incubation was completed, 30uL volume of CellTiter-Glo 3D detection solution was added to each well, shaken for 30 minutes and then allowed to stand for 120 minutes, and then Luminescence values of each well of the sample were read on a microplate reader using a Luminescence mode. By passing withComparison of the values of the control group (0.1% DMSO) the percent inhibition of the compound at each concentration point was calculated, after which non-linear regression analysis was performed in GraphPad Prism5 software at the compound concentration log-inhibition to obtain the IC of the compound for inhibiting cell proliferation 50 Values, results are given in the table below.
TABLE 4 inhibitory Activity of the Compounds of the present invention on NCI-H358 cell proliferation
And (4) conclusion: the compound has better inhibition effect on H358 cell proliferation.
Claims (21)
1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
ring A is selected from C 6 -C 10 Aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered fused ring;
x and Y are each independently selected from-CR a R b Or C = O;
l is selected from the group consisting of a bond, -C (O) -, -C (O) NH (CH) 2 )p-、-C(O)O-、-S(O) 2 -, -S (O) -or- (CH) 2 )q-;
R a 、R b Each independently selected from hydrogen atom, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl or C 6 -C 10 Aryl, wherein said C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl or C 6 -C 10 Aryl is optionally further substituted with one or more substituents selected from halo, alkyl, alkoxy, or hydroxy;
R 1 the same OR different, each independently selected from hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with a substituent of (a);
L 1 Selected from a bond or C 1 -C 6 Alkylene, wherein said alkylene is optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, or hydroxy;
R A is selected from C 1 -C 6 Alkyl or C 1 -C 6 Cycloalkyl, wherein said alkyl or cycloalkyl is optionally further substituted with one or more halogen or hydroxy;
R B selected from halogen, cyano, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, -OR 8 or-NR 9 R 10 (ii) a Wherein said cycloalkyl OR heterocyclyl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 The substituent(s) is taken;
R 3 、R 4 each independently selected from a hydrogen atom or C 1 -C 6 An alkyl group; and, R 3 、R 4 At least one of them is a hydrogen atom; wherein said alkyl is optionally further substituted with one or more halogen or hydroxy;
or, R 3 、R 4 Together with the atom to which they are attached form a C 3 -C 6 A cycloalkyl group;
R 5 selected from hydrogen atom, halogen, nitro, cyano, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, -OR 8 、-NR 9 R 10 or-C (O) NR 9 R 10 (ii) a Wherein said alkyl, cycloalkyl OR heterocyclyl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
ring B is selected from 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, or 5-10 membered fused ring;
R 6 selected from the group consisting of a hydrogen atom, -L 2 -R C 、-C(O)-L 2 -R C or-C (O) -R D ;
L 2 Each independently selected from-C 1 -C 6 Alkylene, wherein said alkylene is optionally further substituted with one or more R E Substituted, R E Selected from halogen, alkyl, alkoxy or hydroxy; or, two R's attached to the same carbon atom E Together with the carbon atom to which they are attached formA cycloalkyl group; preferably a cyclopropyl group;
R C each independently selected from cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 or-S (O) r R 8 (ii) a Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
R D selected from deuterated alkyl, hydroxyalkyl, cycloalkyl, aryl, or heteroaryl; wherein said alkyl, cycloalkyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
R 7 selected from hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more alkyl, halo, nitro, cyano, ringAlkyl, heterocyclyl, aryl, heteroaryl, = O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH 2 NHC(O)OR 8 、-CH 2 NR 9 R 10 or-S (O) r R 8 Substituted with the substituent(s);
the limiting conditions are as follows:
when R is 6 When selected from hydrogen atoms, X and Y are each independently selected from-CR a R b And R is a 、R b At least one selected from C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy and C 3 -C 6 A cycloalkyl group;
R 8 selected from the group consisting of hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted with one or more groups selected from the group consisting of deuterium atom, hydroxyl group, halogen, nitro group, cyano group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with a substituent of (a);
R 9 and R 10 Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with a substituent of (a);
or, R 9 And R 10 Together with the atoms to which they are attached form a 4-to 8-membered heterocyclic group in which the 4-to 8-membered heterocyclic group contains one or more of N, O or S (O) r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or-NR 12 C(O)R 13 Substituted with the substituent(s);
R 11 、R 12 and R 13 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
r is selected from 0, 1 or 2;
m is selected from 1,2,3 or 4;
p is selected from 0 or 1;
q is selected from 1,2,3, 4, 5 or 6;
n is selected from 1,2 or 3;
k is selected from 0, 1,2 or 3.
2. The compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein: ring A, X, Y, R 1 、R 5 、R A 、R B 、L、L 1 And m is as defined in claim 1.
3. The compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein: ring A, X, Y, R 1 、R 5 、R 6 、R 7 L, m, n and k are as defined in claim 1.
6. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein L is-C (O) -.
7. The compound of claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R A Is a methyl group.
8. A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
L 1 is selected from C 1 -C 6 Alkylene, preferably methylene or- (CH) 2 ) 2 -;
R B Is selected from-OR 8 or-NR 9 R 10 ;
R 8 、R 9 、R 10 Each independently selected from alkyl groups, preferably methyl groups.
10. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
ring B is selected from 5-10 membered heterocyclyl, preferably piperazinyl, piperidinyl, morpholinyl, tetrahydropyranyl, azetidinyl or pyrrolidinyl.
11. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 6 is selected from-L 2 -R C or-C (O) -L 2 -R C ;
R C Each independently selected from cyano, heterocyclyl or-NR 9 R 10 ;
R 9 、R 10 Independently selected from a hydrogen atom or C 1 -C 6 An alkyl group; r 9 、R 10 Preferably methyl.
12. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 6 selected from-C (O) -R D ;
R D Selected from deuterated alkyl;
R D deuterated methyl is preferred.
13. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 7 is selected from C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
R 7 preferably methyl or methoxy.
16. a compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen, C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, preferably chlorine, iodine, methyl or methoxy.
18. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
19. Use of a compound according to any one of claims 1 to 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the preparation of an SOS1 inhibitor.
20. Use of a compound according to any one of claims 1 to 17 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment of a disease mediated by SOS1, preferably a cancer mediated by SOS1, which is dependent on the RAS family protein signalling pathway, a cancer caused by a SOS1 mutation or a genetic disease caused by a SOS1 mutation.
21. The use of claim 20, wherein the disease mediated by SOS1 is selected from lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibromatosis, noonan syndrome, cardio-facial skin syndrome, hereditary gingival fibroma type i, embryonal rhabdomyosarcoma, sertoli cell testicular tumor, or skin granulomatosis.
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