CN111295384B - Bicyclic derivative inhibitor, preparation method and application thereof - Google Patents

Bicyclic derivative inhibitor, preparation method and application thereof Download PDF

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CN111295384B
CN111295384B CN201980005251.XA CN201980005251A CN111295384B CN 111295384 B CN111295384 B CN 111295384B CN 201980005251 A CN201980005251 A CN 201980005251A CN 111295384 B CN111295384 B CN 111295384B
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amino
alkyl
hydrogen
pharmaceutically acceptable
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CN111295384A (en
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刘世强
鲍孟
袁逸达
王永升
周远锋
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Discloses a bicyclic derivative-containing inhibitor, a preparation method and application thereof. In particular, the invention discloses a compound shown in the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a protein tyrosine phosphatase SHP-2 inhibitor in treating diseases or symptoms such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer, colon cancer and the like, wherein each substituent in the general formula (I) is defined as the same as that in the specification.

Description

Bicyclic derivative inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a bicyclic derivative inhibitor and a preparation method and application thereof.
Background
SHP-2(Src homology-2 domain-associating phosphatase 2), also known as PTPN11 (type-protein phosphatase non-receptor type 11), is encoded by the PTPN11 gene and belongs to the family of Protein Tyrosine Phosphatases (PTPs). As downstream signal molecules of cytokines, growth factors and other extracellular stimulators, SHP-2 is widely expressed in various tissues and cells of the body, and is involved in cell signal transduction, regulation of cell growth, differentiation, migration, metabolism, gene transcription, immune response and the like.
SHP-2 has mainly 3 components: SH-2 domains (N-SH2 and C-SH2), PTP-active domains, the C-terminus (containing tyrosine phosphorylation sites). Among them, the SH2 domain is highly conserved, is a phosphotyrosine binding site, and mediates the binding of the PTP domain to its ligand.
SHP-2 has 2 main states in the body: and (4) inactivation and activation. In the inactivated state, the N-SH2 inside SHP-2 is combined with PTP domain mutually, and SHP-2 is inactivated because the PTP domain is occupied. When N-SH2 is specifically bound with the phosphorylated tyrosine residue ligand, the PTP domain is re-exposed, and the SHP-2 restores the activity. Recent studies have shown that SHP-2 is also able to form dimers in vivo, and that it also leads to inactivation of SHP-2.
SHP-2 mainly plays a role by regulating signal pathways such as ERK/MAPK, JAK-STAT, PI3K/AKT, Hippo, Wnt/beta-catenin and the like, thereby maintaining the development and homeostasis of organisms. Specific studies have shown that SHP-2 participates in activation of the ERK/MAPK pathway by directly binding to tyrosine kinase Receptors (RTKs) or scaffold. In addition, activated SHP-2 recruits GRB2/SOS, indirectly facilitating activation of the RAS signaling pathway. In addition, SHP-2 is also involved in suppressing signaling of immune responses, e.g., SHP-2 and SHP-1 are able to bind and activate immunosuppressive receptors (e.g., PD-1), blocking T cell activation.
As an important class of cell signaling factors, SHP-2 mutations are closely associated with a variety of diseases. The research finds that: SHP-2 mutations were found in neuroblastoma, AML (4%), breast cancer, NSCLC (10%), lung cancer (30%), melanoma, and gastric cancer.
The mutation site of SHP-2 mostly occurs in N-SH2 and PTP active region, thus releasing mutual inhibition of N-CH2/PTP structural domain, and generating high-activity SHP-2, wherein the SHP-2 activity is influenced by mutations such as Cys459Ser mutant, E76K mutant and the like. Research shows that the high-activity SHP-2 is closely related to inflammation, liver cirrhosis, toxin CagA secreted by helicobacter pylori and the like, can cause the regeneration and development of tumors, and is equivalent to protooncogenes. With the continuous and deep knowledge of SHP-2, SHP-2 has been used as a target for tumor therapy for drug development.
Several allosteric inhibitors of SHP-2 have been introduced into clinical research, such as TNO-155 developed by Novartis, RMC-4630 developed by Revolition Medicine, and JAB-3068 by Beijing plus Corse.
However, there is no SHP-2 inhibitor developed and marketed for the treatment of Noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer and colon cancer. Therefore, the development of SHP-2 inhibitor drugs with good pharmacy is urgently needed.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure GPA0000287746260000031
wherein:
l is selected from the group consisting of a bond, -S-, -O-, -NR aa -、-(CR aa R bb ) n1 -or- (C ═ O) -;
ring A is selected from 6-14 membered bicyclic; the bicyclic ring is preferably a heteroaryloaryl or heteroaryloaryl heterocyclic group;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb And- (CH) 2 ) n1 NR aa S(O) m1 R bb Is substituted with one or more substituents of (1);
ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb And- (CH) 2 ) n1 NR aa S(O) m1 R bb Is substituted with one or more substituents of (1);
R 1 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S＝O(R aa R bb )、-P(O)R aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
Or two R on the same carbon atom or on different carbon atoms 1 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl group being optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH, or C 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R 2 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, oxo, aldehyde, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S＝O(R aa R bb )、-P(O)R aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstitutedAlkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 3 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S＝O(R aa R bb )、-P(O)R aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted with one or more substituents selected from deuterium, alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
or two R on the same carbon atom or on different carbon atoms 3 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, saidThe cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further optionally substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH) 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted with one or more substituents of (1);
R aa 、R bb 、R cc and R dd Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted or unsubstituted with a substituent selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylSubstituted heteroaryl is substituted with one or more substituents;
or, R aa And R bb Linked to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
x is an integer of 0, 1, 2, 3 or 4;
y is an integer of 0, 1, 2, 3 or 4;
z is an integer of 0, 1, 2, 3 or 4;
m1 is an integer of 0, 1 or 2; and is
n1 is an integer of 0, 1, 2, 3, 4 or 5.
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (II):
Figure GPA0000287746260000061
wherein:
M 1 is S or NR aa ；
L is a bond, O, S or-CH 2 -；
Ring B is aryl or heteroaryl;
R 1 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
Or two R on the same carbon atom or on different carbon atoms 1 (ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups being optionally further substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, ester, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl and heteroaryl;
R 2 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, aldehyde, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa Or- (CH) 2 ) n1 OR aa ；
R 3 Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl, and heteroaryl;
or two R on the same carbon atom or on different carbon atoms 3 (ii) linked to form a cycloalkyl or heterocyclyl group, wherein said cycloalkyl and heterocyclyl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl and heteroaryl;
R aa and R bb Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
x is 0, 1, 2, 3 or 4;
z is 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
m1 is 0, 1 or 2; and is
n1 is 0, 1, 2, 3, 4 or 5.
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (III):
Figure GPA0000287746260000071
wherein:
ring B, L, R 1 、R 2 、R 3 X, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000287746260000072
wherein:
ring C is selected from aryl, cycloalkyl or heterocyclyl;
ring B, L, R 1 、R 2 、R 3 X and z are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by formula (IIA) and formula (IIB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000287746260000073
wherein:
ring B, M 1 、R 1 、R 2 、R 3 X, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (IIC):
Figure GPA0000287746260000081
wherein:
M 1 、R 1 、R 2 、R 3 x, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by general formula (IIIA) and general formula (IIIB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000287746260000082
wherein:
ring B, R 1 、R 2 、R 3 X, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (IIIC):
Figure GPA0000287746260000083
wherein:
R 1 、R 2 、R 3 x, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by general formula (IVA) and general formula (IVB):
Figure GPA0000287746260000084
wherein:
ring B, R 1 、R 2 、R 3 X, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (IVC):
Figure GPA0000287746260000091
wherein:
R 1 、R 2 、R 3 x, z and q are as described in formula (II).
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Figure GPA0000287746260000092
wherein:
M 1 is-S-or-NH-;
M 2 selected from the group consisting of CR 5 Or N;
R 4 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
Or two R on the same carbon atom or on different carbon atoms 4 Are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Ester group, C 2-6 Amide group, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 3 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl or C 1-6 An alkylamino group;
R 5 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
Or, R 4 And R 5 Are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Ester group, C 2-6 Amide group, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 6 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
s is 0, 1, 2, 3 or 4;
z-1 is 0, 1, 2 or 3.
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (VI):
Figure GPA0000287746260000101
wherein:
M 3 selected from the group consisting of CR 8 Or N;
R 7 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
Or, the same carbon atom or different carbonsTwo R on the atom 7 Are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Ester group, C 2-6 Amide group, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 8 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
When M is 3 Is CR 8 When is, optionally, R 7 And R 8 Are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogenAmino, oxo, thio, nitro, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Ester group, C 2-6 Amide group, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 9 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
t is 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3; and is
z-1 is 0, 1, 2 or 3.
In a preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, according to any one of the preceding claims, wherein ring a is selected from the group consisting of:
Figure GPA0000287746260000111
Figure GPA0000287746260000112
in a preferred embodiment of the present invention, any one of the compounds represented by the respective formulae, stereoisomers thereof or pharmaceutically acceptable salts thereof, is characterized in that:
ring B is selected from the following groups:
Figure GPA0000287746260000113
in a further preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, according to any one of the preceding claims, wherein ring B is selected from the group consisting of:
Figure GPA0000287746260000114
in a preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, according to any one of the preceding claims, wherein ring C is selected from the group consisting of:
Figure GPA0000287746260000121
in a further preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, according to any one of the preceding claims, wherein ring C is selected from the group consisting of:
Figure GPA0000287746260000122
in a preferred embodiment of the present invention, each of the formulae of any one or more, its stereoisomers or a pharmaceutically acceptable salt thereof, is characterized in that,
R 1 selected from hydrogen, cyano, amino, halogen, C 1-6 Alkyl, - (CH) 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 C(O)OR aa Or a 3-8 membered heterocyclic group;
R 2 selected from hydrogen, - (CH) 2 ) n1 OR aa Or 5-6 heteroaryl;
R 3 selected from hydrogen, C 1-6 Alkyl, amino or- (CH) 2 ) n1 NR aa R bb Wherein said C 1-6 Alkyl, optionally further substituted with one or more substituents selected from hydrogen, halogen, amino, cyano and hydroxy.
In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (VI-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000287746260000131
the invention also relates to a method for preparing the compound shown in the general formula (V) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:
Figure GPA0000287746260000132
deprotection is carried out on the general formula (V-a) to obtain a compound shown as the general formula (V) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
pg is an amino protecting group selected from tert-butylsulfinyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; tert-butyloxycarbonyl is preferred.
The invention also relates to a method for preparing the compound shown in the general formula (V-a) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000133
the general formula (V-b) is subjected to reduction reaction to obtain the compound shown in the general formula (V-a) or a stereoisomer and pharmaceutically acceptable salts thereof.
The invention also relates to a method for preparing the compound shown in the general formula (V-b) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000134
reacting the general formula (V-c) with the general formula (V-d) to obtain a compound shown as the general formula (V-b) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein:
X 1 is halogen, preferably fluorine, chlorine, bromine, iodine; more preferably chlorine.
The invention also relates to a method for preparing the compound shown in the general formula (V-c) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000141
the general formula (V-e) reacts to obtain the compound shown in the general formula (V-c) or the stereoisomer and the pharmaceutically acceptable salt thereof.
The invention also relates to a method for preparing the compound shown in the general formula (V) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000142
the invention also relates to a method for preparing the compound shown in the general formula (VI) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000143
deprotection is carried out on the general formula (VI-a) to obtain a compound shown as the general formula (VI) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
pg' is an amino protecting group selected from tert-butylsulfinyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; tert-butoxycarbonyl is preferred.
The invention also relates to a method for preparing the compound shown in the general formula (VI) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000151
carrying out coupling reaction on the general formula (VI-b) and the general formula (VI-c) to obtain a compound shown in the general formula (VI-a) or a stereoisomer and pharmaceutically acceptable salt thereof;
wherein:
X 2 selected from halogen, preferably fluorine, chlorine, bromine or iodine; bromine is more preferred.
The invention also relates to a method for preparing the compound shown in the general formula (VI) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
Figure GPA0000287746260000152
the invention further relates to any one of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or application of the pharmaceutical composition in preparation of SHP-2 inhibitor drugs.
The invention also relates to a method for the treatment, prevention and/or treatment of a condition mediated by a SHP-2 inhibitor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, the compounds and compositions of the present invention are useful for the treatment of diseases or disorders that are characterized by noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer, and colon cancer thereof.
The compounds and compositions of the invention are useful in methods for treating diseases or disorders in the preparation of a medicament for treating noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, lung cancer, and colon cancer thereof.
In some embodiments, the invention provides a method of treating a cancer disorder comprising administering a compound or composition of the invention to a patient having a cancer disorder.
In some embodiments, the cancer treated by the compounds or compositions of the present invention is noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer and colon cancer thereof, wherein said leukemia is preferably AML and lung cancer is preferably NSCLC.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include 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. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen of an alkyl group is further substituted, for example: "methylene" means-CH 2 -, "ethylene" means- (CH) 2 ) 2 -, "propylene" means- (CH) 2 ) 3 -, "butylene" means- (CH) 2 ) 4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like,Heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl groups, more preferably cyclopropyl and cyclobutyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure GPA0000287746260000171
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure GPA0000287746260000172
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure GPA0000287746260000173
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure GPA0000287746260000181
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, boron, phosphorus, S (O) m (wherein m is an integer of 0 to 2) or P (O) n (wherein n is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. More preferably an oxetanyl group. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 3 to 20 membered polycyclic heterocyclic group in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are nitrogen, oxygen, boron, phosphorus, s (o) m (where m is an integer from 0 to 2) or p (o) n (where n is an integer from 0 to 2) are heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic 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 preferably a 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:
Figure GPA0000287746260000182
Figure GPA0000287746260000191
Figure GPA0000287746260000192
and the like.
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or s (o) m (where m is an integer from 0 to 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 3-to 5-membered, 4-to 5-membered or 5-to 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure GPA0000287746260000193
and the like.
The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or s (o) m (where m is an integer from 0 to 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:
Figure GPA0000287746260000194
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure GPA0000287746260000201
Figure GPA0000287746260000202
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure GPA0000287746260000203
Figure GPA0000287746260000204
and the like.
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl and the like, preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; and further selected from oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure GPA0000287746260000211
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" means-CN.
"nitro" means-NO 2 。
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "means diethyl ether.
"DCE" refers to 1, 2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2 (dba) 3 "refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
The hydrogen described herein may be replaced by deuterium, which is an isotope thereof, and any hydrogen in the compounds of the examples to which the invention relates may also be replaced by deuterium.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more hydrogens, preferably up to 5, more preferably 1 to 3 hydrogens in the 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, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically 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.
"pharmaceutically acceptable salts" 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.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by 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 the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000231
The first step is as follows: preparation of tert-butyl (5-bromo-1, 3, 4-thiadiazol-2-yl) carbamate
Figure GPA0000287746260000232
5-bromo-1, 3, 4-thiadiazol-2-amine (5.0g, 27.78mmol), di-tert-butyldicarbonate (7.3g, 33.34mmol) and DMAP (339mg, 2.78mmol) were dissolved in 150mL of dichloromethane and stirred at room temperature until the reaction was complete. The organic phase was concentrated to give the crude product which was purified by column chromatography (PE/EA ═ 10: 1) to give the desired product tert-butyl (5-bromo-1, 3, 4-thiadiazol-2-yl) carbamate (6.6g, 83% yield) as a white solid.
1 H NMR(400MHz，CDCl 3 )δ1.56(s，9H).
MS m/z(ESI)：280.1[M+H] + ，282.3[M+2+H] +
The second step is that: preparation of 2- (5-bromo-2- ((tert-butoxycarbonyl) imino) -1, 3, 4-thiadiazol-3 (2H) -yl) acetic acid
Figure GPA0000287746260000241
Tert-butyl (5-bromo-1, 3, 4-thiadiazol-2-yl) carbamate (840mg, 3.00mmol), bromoacetic acid (2.1g, 0.14mmol) were dissolved in anhydrous tetrahydrofuran (150mL), and sodium hydride (1.2g, 30.00mmol, 60% in oil, in three portions, one for each half hour) was added in an ice-water bath under nitrogen. After the addition was complete, the mixture was stirred at room temperature for about 72 hours. After the reaction was completed, the reaction solution was added dropwise to 100mL of water, stirred for 30 minutes, extracted with ethyl acetate (200mL), the aqueous layer was adjusted to pH 3 to 4 with dilute hydrochloric acid, the organic phase was extracted with dichloromethane (150mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain a crude product without purification to obtain the objective compound, 2- (5-bromo-2- ((tert-butoxycarbonyl) imino) -1, 3, 4-thiadiazol-3 (2H) -yl) acetic acid (467mg, yield 46%) as a pale yellow liquid.
MS m/z(ESI)：337.9[M+H] + ，340.0[M+2+H] + 。
The third step: preparation of 2-bromo-6-chloroimidazo [2, 1-b ] [1, 3, 4] thiadiazole
Figure GPA0000287746260000242
2- (5-bromo-2- ((tert-butoxycarbonyl) imino) -1, 3, 4-thiadiazol-3 (2H) -yl) acetic acid (467mg, 1.38mmol) was dissolved in anhydrous acetonitrile (50mL), triethylamine (0.80mL, 5.52mmol, d ═ 0.726g/mL) was added dropwise in an ice-water bath under nitrogen protection, after completion of the addition, the mixture was stirred at room temperature for 10 minutes, phosphorus oxychloride (0.77mL, 8.28mmol, d ═ 1.65g/mL) was added dropwise, and the reaction mixture was heated to 80 ℃ and stirred for 3 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature, added dropwise to stirred water (100mL), adjusted to pH 9-10 with saturated sodium carbonate solution, extracted three times with ethyl acetate (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (PE/EA ═ 5: 1) to give the desired product 2-bromo-6-chloroimidazo [2, 1-b ] [1, 3, 4] thiadiazole (143mg, yield 43%) as a white solid.
1 H NMR(400MHz，CDCl3)δ7.69(s，1H).
MS m/z(ESI)：237.9[M+H] + ，239.8[M+2+H] + 。
The fourth step: preparation of 6-chloro-2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole
Figure GPA0000287746260000251
2-bromo-6-chloroimidazo [2, 1-b)][1，3，4]Thiadiazole (121mg, 0.51mmol), (2, 3-dichlorophenyl) boronic acid (243mg, 1.28mmol), sodium carbonate (162mg, 1.53mmol) and cesium fluoride (87mg, 0.51mmol) were dissolved in dioxane (15mL) and water (5mL), Pd (dppf) Cl was added under nitrogen protection 2 (73mg, 0.1 mmol). Heated to 60 ℃ and stirred for 1 hour. After the reaction is finished, the solvent is removed, ethyl acetate (50mL) is used for extraction for three times, an organic phase is dried by anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, and the crude product is purified by column chromatography (PE/EA is 3: 1) to obtain the target product 6-chloro-2- (2, 3-dichlorophenyl) imidazo [2, 1-b][1，3，4]Thiadiazole (46mg, yield 30%) as a white solid.
MS m/z(ESI)：303.9[M+H] + ，305.9[M+2+H] +
The fifth step: preparation of 6-chloro-2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole-5-carbaldehyde
Figure GPA0000287746260000252
Phosphorus oxychloride (1mL) was added dropwise to anhydrous DMF (5mL) in an ice water bath, heated to 60 ℃ and stirred for 30 min, the substrate 6-chloro-2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole (46mg, 0.15mmol) was added, stirring was continued, and TLC monitoring was performed until the starting material was completely consumed. The reaction was cooled to room temperature, added dropwise to water, adjusted to pH 9-10 with saturated sodium carbonate solution, extracted three times with ethyl acetate (80mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, and purified by column chromatography (PE/EA ═ 2: 1) to give the desired product 6-chloro-2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole-5-carbaldehyde (28mg, 56% yield) as a white solid.
1 H NMR(400MHz，CDCl 3 )δ10.01(s，1H)，8.07(dd，J＝8.0，1.5Hz，1H)，7.71(dd，J＝8.0，1.5Hz，1H)，7.42(t，J＝8.0Hz，1H).
MS m/z(ESI)：331.9[M+H] + ，333.9[M+2+H] + 。
And a sixth step: (1- (2- (2, 3-dichlorophenyl) -5-formylimidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
Figure GPA0000287746260000253
6-chloro-2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole-5-carbaldehyde (28mg, 0.08mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (180mg, 0.80mmol) and diisopropylethylamine (20mg, 0.16mmol) were dissolved in dioxane (3mL), heated to 120 ℃ under nitrogen, and stirred for 20 hours. After the reaction was completed, the reaction solution was poured into water, extracted three times with ethyl acetate (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to give a crude product, which was purified by preparative HPLC to give tert-butyl 1- (2- (2, 3-dichlorophenyl) -5-formylimidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamate (10mg, yield 23%) as a white solid.
MS m/z(ESI)：510.1[M+H] + ，512.1[M+2+H] + 。
The seventh step: preparation of tert-butyl (1- (2- (2, 3-dichlorophenyl) -5- (hydroxymethyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamate
Figure GPA0000287746260000261
Tert-butyl (1- (2- (2, 3-dichlorophenyl) -5-formylimidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamate (10mg, 0.02mmol) was dissolved in ethanol (3.0mL), and sodium borohydride (0.4mg, 0.10mmol) was added under an ice-water bath and nitrogen atmosphere. Stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was dropped into a saturated ammonium chloride solution, extracted three times with dichloromethane (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to give a crude product, which was purified by preparative HPLC to give the target product tert-butyl 1- (2- (2, 3-dichlorophenyl) -5- (hydroxymethyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamate (7.2mg, yield 70%) as a white solid.
MS m/z(ESI)：512.0[M+H] + ，514.1[M+2+H] + 。
Eighth step: preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000262
Tert-butyl (1- (2- (2, 3-dichlorophenyl) -5- (hydroxymethyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamate (7.2mg, 0.01mmol) was dissolved in dichloromethane (3mL), and trifluoroacetic acid (1mL) was added and stirred at room temperature for 2 hours. The solvent was removed to give a crude product, which was purified by preparative HPLC to give the title compound (6- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol (1.8mg, 33% yield).
1 H NMR(500MHz，CDCl 3 )δ7.78(s，1H)，7.59(s，1H)，7.33(s，1H)，5.37(s，2H)，4.43(s，2H)，3.89(s，2H)，2.41(s，1H)，1.83(s，2H)，1.61(s，2H)，1.22(s，2H)，1.12(s，2H).
MS m/z(ESI)：412.1[M+H] + ，414.1[M+2+H] + 。
Example 2
Preparation of 6- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole-5-carbaldehyde
Figure GPA0000287746260000271
The first step is as follows: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole-5-carbaldehyde
Figure GPA0000287746260000272
Tert-butyl (1- (2- (2, 3-dichlorophenyl) -5-formylimidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-yl) carbamate (20mg, 0.04mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (1mL) was added to the solution in an ice-water bath and stirred for 30 minutes. The reaction was added dropwise to a saturated aqueous sodium bicarbonate solution, extracted three times with dichloromethane (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to give a crude product which was purified by preparative HPLC to give the desired product 6- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazole-5-carbaldehyde (3.5mg, yield: 22%).
1 H NMR(400MHz，CDCl 3 )δ9.75(s，1H)，7.78(s，1H)，7.59(s，1H)，7.33(s，1H)，4.31(s，2H)，4.17(s，2H)，1.87(s，2H)，1.54(s，2H)，1.22(s，3H)，1.06(s，2H).
MS m/z(ESI)：409.1[M+H] + ，411.1[M+2+H] + 。
Example 3
Preparation of (5- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) -3-methyl-3H-imidazo [1, 2-b ] [1, 2, 4] triazol-6-yl) methanol
Figure GPA0000287746260000273
The preparation of example 3 refers to the experimental protocol of example 1.
MS m/z(ESI)：409.1[M+H] + ，411.1[M+2+H] + 。
Example 4
Preparation of (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000274
The procedure for the preparation of example 4 is as described in the experimental protocol of example 1.
MS m/z(ESI)：468.1[M+H] + ，470.1[M+2+H] + 。
Example 5
Preparation of (R) - (6- (1-amino-8-azaspiro [4.5] decan-8-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000281
The procedure of example 5 is as described in example 1.
MS m/z(ESI)：452.1[M+H] + ，454.1[M+2+H] + 。
Example 6
Preparation of (6- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000282
The procedure for the preparation of example 6 refers to the experimental protocol of example 1.
MS m/z(ESI)：396.1[M+H] + ，398.1[M+2+H] + 。
Example 7
Preparation of (6- (5-aminohexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000283
The procedure for the preparation of example 7 refers to the experimental protocol of example 1.
MS m/z(ESI)：424.1[M+H] + ，426.1[M+2+H] + 。
Example 8
Preparation of (6- (3-aminopiperidin-1-yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000284
The procedure for the preparation of example 8 is as in example 1.
MS m/z(ESI)：398.1[M+H] + ，400.1[M+2+H] + 。
Example 9
Preparation of (6- ((2R) -2-aminospiro [ bicyclo [3.1.0] hexane-3, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorophenyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000291
The procedure for the preparation of example 9 is as in example 1.
MS m/z(ESI)：464.1[M+H] + ，466.1[M+2+H] + 。
Example 10
Preparation of 1- (2- (2, 3-dichlorophenyl) -5- (1, 3, 4-oxadiazol-2-yl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000292
Example 10 the procedure was as in example 1.
MS m/z(ESI)：450.1[M+H] + ，452.1[M+2+H] + 。
Example 11
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- (1-methyl-1H-benzo [ d ] imidazol-6-yl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000293
The procedure for the preparation of example 11 is as in example 1.
MS m/z(ESI)：398.1[M+H] + 。
Example 12
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- (benzo [ d ] [1, 3] dioxazol-5-yl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000294
Example 12 the procedure was as in example 1.
MS m/z(ESI)：388.1[M+H] + 。
Example 13
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- (quinolin-7-yl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000301
The procedure for the preparation of example 13 is as in example 1.
MS m/z(ESI)：395.1[M+H] + 。
Example 14
Preparation of ethyl 6- (6- (4-amino-4-methylpiperidin-1-yl) -5- (hydroxymethyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-2-yl) -2-naphthoate
Figure GPA0000287746260000302
Example 14 the procedure was as in example 1.
MS m/z(ESI)：466.1[M+H] + 。
Example 15
Preparation of 3- (6- (4-amino-4-methylpiperidin-1-yl) -5- (hydroxymethyl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-2-yl) -N-methylbenzamide
Figure GPA0000287746260000303
Example 15 the procedure was as in example 1.
MS m/z(ESI)：401.1[M+H] + 。
Example 16
Preparation of (2- ((2-amino-3-chloropyridin-4-yl) thio) -6- (4-amino-4-methylpiperidin-1-yl) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000304
Example 16 the procedure was as in example 1.
MS m/z(ESI)：426.1[M+H] + ，428.1[M+2+H] + 。
Example 17
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- ((2, 3-dichloropyridin-4-yl) thio) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000311
The procedure for the preparation of example 17 refers to the experimental protocol of example 1.
MS m/z(ESI)：445.1[M+H] + ，447.1[M+2+H] + 。
Example 18
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- ((2, 3-dichlorophenyl) thio) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000312
Example 18 the procedure was as in example 1.
MS m/z(ESI)：444.1[M+H] + ，446.1[M+2+H] + 。
Example 19
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -2- ((3-chloro-2-morpholinopyridin-4-yl) thio) imidazo [2, 1-b ] [1, 3, 4] thiadiazol-5-yl) methanol
Figure GPA0000287746260000313
Example 19 the procedure was as in example 1.
MS m/z(ESI)：496.1[M+H] + ，498.1[M+2+H] + 。
Example 20
Preparation of (5- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) -3-methyl-3H-imidazo [1, 2-b ] [1, 2, 4] triazol-6-yl) methanol
Figure GPA0000287746260000314
Example 20 the procedure was as in example 1.
MS m/z(ESI)：409.1[M+H] + ，411.1[M+2+H] + 。
Example 21
Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- (2, 3-dichlorophenyl) -6- (hydroxymethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000321
The first step is as follows: preparation of ethyl 4-cyano-2- (2, 3-dichlorophenyl) -6-methyl nicotinate
Figure GPA0000287746260000322
Ethyl 2-chloro-4-cyano-6-methyl nicotinate (5.0g, 22.32mmol), 2, 3-dichlorophenylboronic acid (5.1g, 26.84mmol) and potassium carbonate (9.2g, 66.67mmol) were dissolved in 100mL tetrahydrofuran and 10mL water, Pd (dppf) Cl was added 2 (7.27g, 2.23mmol), nitrogen substitution. Microwave reaction at 90 deg.c for 13 hr. Concentrating to remove solvent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain crude product, and purifying by column chromatography to obtain target product ethyl 4-cyano-2- (2, 3-dichlorophenyl) -6-methyl nicotinate (5.6g, yield 75%).
MS m/z(ESI)：335.1[M+H] + ，337.1[M+2+H] + 。
The second step is that: preparation of 4- (2, 3-dichlorophenyl) -6-methyl-1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000323
Adding anhydrous InCl into a dry round-bottom flask 3 (2.0g，9.05mmol)，NaBH 4 (1.02g, 26.94mmol), and anhydrous THF (50mL) was added to dissolve the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. A solution of ethyl 4-cyano-2- (2, 3-dichlorophenyl) -6-methyl nicotinate (3.0g, 8.98mmol) in dry THF (20mL) was added dropwise at room temperature and stirred at room temperature overnight. Quenching with 3M hydrochloric acid (10mL), stirring at room temperature for 30 min, adjusting to neutral with NaOH aqueous solution, adding water and ethyl acetate, extracting, washing organic phase with water and sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and purifying with column chromatography to obtain 4- (2, 3-dichlorophenyl) -6-methyl-1, 2-dihydro-3H-pyrrolo [3, 4-c ] product]Pyridin-3-one (1.1g, 42% yield).
MS m/z(ESI)：293.1[M+H] + ，295.1[M+2+H] + 。
The third step: preparation of 7-bromo-4- (2, 3-dichlorophenyl) -6-methyl-1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000331
4- (2, 3-dichlorophenyl) -6-methyl-1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one (1.0g, 3.42mmol) was dissolved in DMF (30mL), NBS (730mg, 4.11mmol) was added, KOH (383mg, 6.84mmol) was added, and the mixture was stirred at room temperature for 13 hours. Adding water (100mL), stirring for 30 minutes, filtering, washing with water, and drying to obtain a solid crude product. The filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the resulting solid was concentrated and purified by column chromatography together with the dried solid to give the product 7-bromo-4- (2, 3-dichlorophenyl) -6-methyl-1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one (510mg, 40% yield).
MS m/z(ESI)：371.1[M+H] + ，373.1[M+2+H] + 。
The fourth step: preparation of tert-butyl (1- (4- (2, 3-dichlorophenyl) -6-methyl-3-oxo-2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridin-7-yl) -4-methylpiperidin-4-yl) carbamate
Figure GPA0000287746260000332
7-bromo-4- (2, 3-dichlorophenyl) -6-methyl-1, 2-dihydro-3H-pyrrolo [3, 4-c)]Pyridin-3-one (500mg, 1.35mmol), tert-butyl (4-methylpiperidin-4-yl) carbamate (578mg, 2.70mmol), Pd 2 (dba) 3 (247mg, 0.27mmol), XantPhos (185mg, 0.32mmol) and cesium carbonate (1.3g, 4.05mmol) were dissolved in anhydrous dioxane (50mL), purged with nitrogen, and heated to 100 ℃ for 13 hours. Cooling to room temperature, concentrating to remove solvent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain crude product, and purifying by column chromatography to obtain product (1- (4- (2, 3-dichlorophenyl) -6-methyl-3-oxo-2, 3-dihydro-1H-pyrrole [3, 4-c)]Pyridin-7-yl) -4-methylpiperidine-4-yl) carbamic acid tert-butyl ester (150mg, 22% yield).
MS m/z(ESI)：505.1[M+H] + ，507.1[M+2+H] + 。
The fifth step: preparation of tert-butyl (1- (4- (2, 3-dichlorophenyl) -6-bromomethyl-3-oxo-2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridin-7-yl) -4-methylpiperidin-4-yl) carbamate
Figure GPA0000287746260000333
(1- (4- (2, 3-dichlorophenyl) -6-methyl-3-oxo-2, 3-dihydro-1H-pyrrolo [3, 4-c)]Pyridin-7-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (140mg, 0.28mmol) was added to CCl 4 Adding NBS (54mg, 0.31mmol) and AIBN (10mg, 0.06mmol) into the mixture (20mL), replacing the mixture with nitrogen, heating and refluxing for 2 hours, cooling to room temperature, filtering the reaction solution, washing filter residues twice with carbon tetrachloride, concentrating the filtrate to obtain a crude product, and purifying by column chromatography to obtain a product (1- (4- (2, 3-dichlorophenyl) -6-bromomethyl-3-oxo-2, 3-dihydro-1H-pyrrole [3, 4-c)]Pyridin-7-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (45mg, yield 28%).
MS m/z(ESI)：583.1[M+H] + ，585.1[M+2+H] + 。
And a sixth step: preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- (2, 3-dichlorophenyl) -6- (hydroxymethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000341
Tert-butyl (1- (4- (2, 3-dichlorophenyl) -6-bromomethyl-3-oxo-2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridin-7-yl) -4-methylpiperidin-4-yl) carbamate (45mg, 0.08mmol) was dissolved in THF (10mL), diluted hydrochloric acid (2M, 5mL) was added at room temperature, stirred for 3H, water was added, the pH was adjusted to 10 with NaOH solution, dichloromethane was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, the crude product was purified by preparative HPLC to give 7- (4-amino-4-methylpiperidin-1-yl) -4- (2, 3-dichlorophenyl) -6- (hydroxymethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one (7mg, 22% yield).
1 H NMR(400MHz，d-DMSO)δ：8.43(s，1H)，7.85(d，J＝8Hz，1H)，7.80(d，J＝7.6Hz，1H)，7.35(t，J＝7.2Hz，1H)，5.54(s，2H)，4.42(s，1H)，3.51(m，2H)，3.44(s，2H)，3.16(m，2H)，3.04(m，2H)，1.85(m，2H)，1.76(m，2H)，1.23(s，3H).
MS m/z(ESI)：421.1[M+H] + ，423.1[M+2+H] + 。
Example 22
Preparation of (R) -7- (1-amino-8-azaspiro [4.5] decan-8-yl) -4- (2, 3-dichlorophenyl) -6- (hydroxymethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000342
The preparation of example 22 refers to the experimental protocol of example 21.
MS m/z(ESI)：461.1[M+H] + ，463.1[M+2+H] + 。
Example 23
Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -4- (2, 3-dichlorophenyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000351
Example 23 the procedure was as in example 21.
MS m/z(ESI)：447.1[M+H] + ，449.1[M+2+H] + 。
Example 24
Preparation of 7- (3-aminopiperidin-1-yl) -4- (2, 3-dichlorophenyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000352
Example 24 the procedure was as in example 21.
MS m/z(ESI)：377.1[M+H] + ，379.1[M+2+H] + 。
Example 25
Preparation of 7- (5-aminohexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -4- (2, 3-dichlorophenyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000353
The procedure for the preparation of example 25 is as described in the experimental protocol of example 21.
MS m/z(ESI)：403.1[M+H] + ，405.1[M+2+H] + 。
Example 26
Preparation of 7- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -4- (2, 3-dichlorophenyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000354
Example 26 the procedure was as in example 21.
MS m/z(ESI)：375.1[M+H] + ，377.1[M+2+H] + 。
Example 27
Preparation of 4- (2, 3-dichlorophenyl) -7- (hexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000361
Example 27 the procedure was as in example 21.
MS m/z(ESI)：389.1[M+H] + ，391.1[M+2+H] + 。
Example 28
Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- (1-methyl-1H-benzo [ d ] imidazol-6-yl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000362
Example 28 the procedure was as in example 21.
MS m/z(ESI)：377.1[M+H] + 。
Example 29
Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- (benzo [ d ] [1, 3] dioxazol-5-yl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000363
The preparation of example 29 refers to the experimental protocol of example 21.
MS m/z(ESI)：367.1[M+H] + 。
Example 30
Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- (quinolin-7-yl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000371
The procedure for the preparation of example 30 is as described in the experimental protocol of example 21.
MS m/z(ESI)：374.1[M+H] + 。
Example 31
Preparation of 3- (7- (4-amino-4-methylpiperidin-1-yl) -3-carbonyl-2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridin-4-yl) -N-methylbenzamide
Figure GPA0000287746260000372
Example 31 the procedure was as in example 21.
MS m/z(ESI)：380.1[M+H] + 。
Example 32
Preparation of 4- ((2-amino-3-chloropyridin-4-yl) thio) -7- (4-amino-4-methylpiperidin-1-yl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000373
Example 32 the procedure was as in example 21.
MS m/z(ESI)：405.1[M+H] + ，407.1[M+2+H] + 。
Example 33
Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- ((3-chloro-2-morpholinopyridin-4-yl) thio) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000374
The procedure for the preparation of example 33 is as described in the experimental protocol of example 21.
MS m/z(ESI)：475.1[M+H] + ，477.1[M+2+H] + 。
Example 34
Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -4- (2, 3-dichlorophenyl) -6- (hydroxymethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000381
Example 34 reference is made to the experimental protocol of example 21.
MS m/z(ESI)：421.1[M+H] + ，423.1[M+2+H] + 。
Example 35
Preparation of 4- ((2-amino-3-chloropyridin-4-yl) thio) -7- (4-amino-4-methylpiperidin-1-yl) -6- (hydroxymethyl) -1, 2-dihydro-3H-pyrrolo [3, 4-c ] pyridin-3-one
Figure GPA0000287746260000382
The procedure for the preparation of example 35 refers to the experimental protocol of example 21.
MS m/z(ESI)：435.1[M+H] + ，437.1[M+2+H] + 。
Example 36
Preparation of 1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidine-4-amine
Figure GPA0000287746260000383
The first step is as follows: preparation of 6-bromo-1-trityl-1H-pyrazolo [4, 3-b ] pyridine
Figure GPA0000287746260000384
6-bromo-1H-pyrazolo [4, 3-b ] pyridine (1.00g, 5mmol), triphenylchloromethane (1.67g, 6mmol), cesium carbonate (4.86g, 15mmol) were stirred in N, N-dimethylformamide (20mL) at room temperature for 18 hours. To the reaction mixture was added ethyl acetate (100mL), washed with water (50mL × 2), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated to give a crude product, slurried with ethanol (8mL), and filtered to give tert-butyl (4-methyl-1- (1-trityl-1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine) carbamate (2.00g, yield 90%) as a white solid.
MS m/z(ESI)：440.1[M+H] + ，442.1[M+2+H] +
The second step is that: preparation of tert-butyl (4-methyl-1- (1-trityl-1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine) carbamate
Figure GPA0000287746260000391
6-bromo-1-trityl-1H-pyrazolo [4, 3-b]Pyridine (1g, 2.27mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (728mg, 3.4mmol), Pd 2 (dba) 3 (208mg, 0.023mmol), XantPhos (262mg, 0.45mmol) and sodium tert-butoxide (436mg, 4.54mmol) were reacted in dioxane at 120 ℃ for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to complete column chromatography [ eluent: petroleum Ether-Petroleum Ether/Ethyl acetate (50: 50)]Purifying to obtain (4-methyl-1- (1-trityl-1H-pyrazolo [4, 3-b)]Pyridin-6-yl) piperidin-4-amine) carbamic acid tert-butyl ester (1.3g, 100% yield) as a gray solid.
MS m/z(ESI)：574.3[M+H] +
The third step: preparation of 4-methyl-1- (1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine
Figure GPA0000287746260000392
To a solution of tert-butyl (4-methyl-1- (1-trityl-1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine) carbamate (1.3g, 2.26mmol) and triethylsilane (394mg, 3.4mmol) in dichloromethane (5mL) was added trifluoroacetic acid (6mL) and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated to give a crude product of 4-methyl-1- (1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine (1.9g) as a red-black solid.
MS m/z(ESI)：232.1[M+H] +
The fourth step: preparation of 1- (3-bromo-1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidine-4-amine
Figure GPA0000287746260000393
Add slowly N-bromosuccinimide (392mg, 2.2mmol) in DMF (20mL) of 4-methyl-1- (1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine (1.8g, 2.2mmol) and potassium hydroxide (1.2g, 22mmol) followed by stirring for 10 minutes and LCMS to detect the remaining 10% of starting material which is used directly in the next reaction.
MS m/z(ESI)：310.0[M+H] + ，312.1[M+2+H] +
The fifth step: preparation of tert-butyl 3-bromo-6- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -1H-pyrazolo [4, 3-b ] pyridine-1-carboxylate
Figure GPA0000287746260000401
Di-tert-butyl dicarbonate (1.2g, 5.5mmol) was added to the reaction mixture in the previous step, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, di-tert-butyl dicarbonate (0.96g, 4.4mmol) was added and the mixture was stirred at room temperature for 3 hours. Water (100mL) was added to the reaction solution, extracted with ethyl acetate (80mL × 2), and the organic phase was concentrated and subjected to column chromatography [ eluent: petroleum ether-Petroleum ether/ethyl acetate (75: 25) ] to give tert-butyl 3-bromo-6- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -1H-pyrazolo [4, 3-b ] pyridine-1-carboxylate (300mg, 26% yield in three steps) as a pale yellow solid.
MS m/z(ESI)：510.1[M+H] + ，512.1[M+2+H] +
And a sixth step: preparation of tert-butyl 6- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridine-1-carboxylate
Figure GPA0000287746260000402
After stirring 3-bromo-6- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -1H-pyrazolo [4, 3-b ] pyridine-1-carboxylic acid tert-butyl ester (200mg, 0.39mmol), (2, 3-dichlorophenyl) boronic acid (112mg, 0.59mmol), sodium carbonate (124mg, 1.17mmol), tetratriphenylphosphine palladium (45mg, 0.039mmol) in dioxane (15mL) and water (1mL) at 100 ℃ for 16 hours, the reaction was concentrated to give a crude product, column chromatography [ eluent: petroleum ether-Petroleum ether/ethyl acetate (70: 30) ] to give tert-butyl 6- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridine-1-carboxylate (50mg, 22% yield) as a white solid.
MS m/z(ESI)：576.2[M+H] + ，578.2[M+2+H] +
The seventh step: preparation of 1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000403
To a solution of tert-butyl 6- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridine-1-carboxylate (15mg, 0.026mmol) in dichloromethane (10mL) was added trifluoroacetic acid (2mL), and after stirring at room temperature for 4 hours, the reaction was concentrated to give 1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine (10mg, yield 100%) as a yellow oil.
1 H NMR(400MHz，MeOD)δ8.80(s，1H)，8.18(s，1H)，8.05-7.95(m，1H)，7.79(d，J＝8Hz，1H)，7.66-7.58(m，1H)，7.56-7.47(m，1H)，3.94-3.83(m，2H)，3.50-3.43(m，2H)，2.10-1.96(m，4H)，1.53(s，3H).
MS m/z(ESI)：376.1[M+H] + ，378.1[M+2+H] + 。
Examples 37-60 were prepared with reference to the above experimental protocol.
Example 37
Preparation of 1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -N, 4-dimethylpiperidin-4-amine
Figure GPA0000287746260000411
Example 37 the procedure was as in example 36.
MS m/z(ESI)：390.1[M+H] + ，392.1[M+2+H] + 。
Example 38
Preparation of 1- (3- (3-chlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidine-4-amine
Figure GPA0000287746260000412
Example 38 reference is made to the experimental protocol of example 36.
1 H NMR(500MHz，CDCl 3 )δ8.04(d，J＝2.9Hz，1H)，7.97(dd，J＝3.5，1.9Hz，1H)，7.77-7.68(m，1H)，7.48-7.42(m，2H)，7.36(d，J＝2.9Hz，1H)，3.44(dt，J＝24.7，11.1Hz，2H)，3.23(dt，J＝24.7，11.1Hz，2H)，1.88(dt，J＝24.8，11.1Hz，2H)，1.66(dt，J＝24.8，11.1Hz，2H)，1.22(s，3H)，1.15(s，2H).
MS m/z(ESI)：342.1[M+H] + ，344.1[M+2+H] + 。
Example 39
Preparation of (R) -8- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -8-azaspiro [4.5] decan-1-amine
Figure GPA0000287746260000421
Example 39 the procedure was as in example 36.
MS m/z(ESI)：416.1[M+H] + ，418.1[M+2+H] + 。
Example 40
Preparation of (3S, 4S) -8- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure GPA0000287746260000422
Example 40 the procedure was as in example 36.
MS m/z(ESI)：432.1[M+H] + ，434.1[M+2+H] + 。
EXAMPLE 41
Preparation of 3- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -3-azabicyclo [3.1.0] hexane-6-amine
Figure GPA0000287746260000423
Example 41 reference is made to the experimental protocol of example 36.
MS m/z(ESI)：360.1[M+H] + ，362.1[M+2+H] + 。
Example 42
Preparation of 2- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) octahydrocyclopenta [ c ] pyrrol-5-amine
Figure GPA0000287746260000431
Example 42 reference example 36 protocol was used for the preparation of the same.
MS m/z(ESI)：388.1[M+H] + ，390.1[M+2+H] + 。
Example 43
Preparation of (1R) -2- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) cyclopentan-1-amine
Figure GPA0000287746260000432
Example 43 the procedure was as in example 36.
MS m/z(ESI)：347.1[M+H] + ，349.1[M+2+H] + 。
Example 44
Preparation of (1R) -3- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) cyclopentan-1-amine
Figure GPA0000287746260000433
Example 44 the procedure was as in example 36.
MS m/z(ESI)：347.1[M+H] + ，349.1[M+2+H] + 。
Example 45
Preparation of (R) -1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-3-amine
Figure GPA0000287746260000441
Example 45 the procedure was as in example 36.
MS m/z(ESI)：362.1[M+H] + ，364.1[M+2+H] + 。
Example 46
Preparation of N-cyclopropyl-1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000442
Example 46 the procedure is as in example 36.
MS m/z(ESI)：416.1[M+H] + ，418.1[M+2+H] + 。
Example 47
Preparation of 4-methyl-1- (3- (1-methyl-1H-benzo [ d ] imidazol-6-yl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine
Figure GPA0000287746260000443
Example 47 the procedure was as in example 36.
MS m/z(ESI)：362.1[M+H] + 。
Example 48
Preparation of 1- (3- (benzo [ d ] [1, 3] dioxazol-5-yl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000451
Example 48 the procedure was as described in example 36.
MS m/z(ESI)：352.1[M+H] + 。
Example 49
Preparation of 4-methyl-1- (3- (quinolin-7-yl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) piperidin-4-amine
Figure GPA0000287746260000452
Example 49 the procedure is as in example 36.
MS m/z(ESI)：359.1[M+H] + 。
Example 50
Preparation of 3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [4, 3-b ] pyridin-3-yl) -N, N-dimethylbenzamide
Figure GPA0000287746260000453
Example 50 was prepared according to the protocol of example 36.
MS m/z(ESI)：379.1[M+H] + 。
Example 51
Preparation of 4- ((6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [4, 3-b ] pyridin-3-yl) thio) -3-chloropyridin-2-amine
Figure GPA0000287746260000461
Example 51 the procedure was as in example 36.
MS m/z(ESI)：390.1[M+H] + ，392.1[M+2+H] + 。
Example 52
Preparation of 1- (3- ((2, 3-dichloropyridin-4-yl) thio) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000462
Example 52 the procedure was as in example 36.
MS m/z(ESI)：409.1[M+H] + ，411.1[M+2+H] + 。
Example 53
Preparation of 4- ((6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [4, 3-b ] pyridin-3-yl) thio) -3-chlorocyanopyridine
Figure GPA0000287746260000463
Example 53 the procedure is as in example 36.
MS m/z(ESI)：400.1[M+H] + ，402.1[M+2+H] + 。
Example 54
Preparation of 1- (3- ((2, 3-dichlorophenyl) thio) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000471
Example 54 the procedure was as in example 36.
MS m/z(ESI)：408.1[M+H] + ，410.1[M+2+H] + 。
Example 55
Preparation of 1- (3- ((3-chloro-2-morpholinopyridin-4-yl) thio) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -4-methylpiperidin-4-amine
Figure GPA0000287746260000472
Example 55 the procedure was as in example 36.
MS m/z(ESI)：460.1[M+H] + ，462.1[M+2+H] + 。
Example 56
Preparation of (3- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) phenyl) methylamine
Figure GPA0000287746260000473
Example 56 the procedure is as in example 36.
MS m/z(ESI)：369.1[M+H] + ，371.1[M+2+H] + 。
Example 57
Preparation of 1- (3- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) phenyl) ethane-1-amine
Figure GPA0000287746260000481
Example 57 the procedure was as in example 1.
MS m/z(ESI)：383.1[M+H] + ，385.1[M+2+H] + 。
Example 58
Preparation of 3- (2, 3-dichlorophenyl) -6- (isoindolin-5-yl) -1H-pyrazolo [4, 3-b ] pyridine
Figure GPA0000287746260000482
The procedure for the preparation of example 58 is as described in example 36.
MS m/z(ESI)：381.1[M+H] + ，383.1[M+2+H] + 。
Example 59
Preparation of 5- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-6-yl) -2-methyl-2, 3-dihydro-1H-indene-2-amine
Figure GPA0000287746260000483
The procedure for the preparation of example 59 is as described in example 36.
MS m/z(ESI)：409.1[M+H] + ，411.1[M+2+H] + 。
Example 60
Preparation of (6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [4, 3-b ] pyridin-5-yl) methanol
Figure GPA0000287746260000491
Example 60 the procedure was as in example 36.
MS m/z(ESI)：406.1[M+H] + ，408.1[M+2+H] + 。
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 determination of the SHP-2 kinase Activity inhibitory Effect of the Compound of the present invention
The purpose of this test was to measure the inhibitory ability of compounds on the allosteric activity of the full-length SHP-2 protein.
An experimental instrument: the centrifuge (5810R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: in vitro SHP-2 activity assays were performed using the Homogeneous Full Length SHP-2 Assay Kit (BPS Bioscience, # 79330). 18 μ L of Master Mix, i.e. 0.5 μ M SHP-2 activating Peptide and 5mM DTT in a final concentration of 1 × reaction buffer, was first added to a 96-well low adsorption microplate (NUNC, #267342), 5 μ L of test compound/DMSO per well (final DMSO content 1%, V/V, test compound dissolved in DMSO to 1mM, three-fold serial dilutions were performed, 10 concentrations, reaction system final concentrations ranged from 1 μ M to 0.05nM) was added after centrifugation, SHP-2 was diluted to a final concentration of 0.06nM in 1 × reaction buffer, 2 μ L per well was added to the reaction microplate, full activity control (compound plus DMSO only) and full inhibition control (no SHP-2) were placed on the reaction plate, the reaction mixture was incubated at room temperature for 60 min after centrifugation.
After the incubation was complete, 25. mu.L of Substrate solution containing Substrate at a final concentration of 10. mu.M and 5mM DTT was added to each well and incubation continued for 30 minutes at room temperature after centrifugation. After the reaction is finished, the excitation wavelength is set to be 340nM, the emission wavelength is set to be 455nM, and the gain value is set to be 75 for reading on a Synergy H1 full-function microplate reader (Biotek).
The experimental data processing method comprises the following steps:
percentage inhibition ratio data {% inhibition ratio {% inhibition 100- [ (test compound-Min average)/(Max average-Min average) for wells treated with compound was calculated from the values of total activity control and total inhibition control as Max and Min by positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate]X 100 }. IC of test compounds was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
And (4) experimental conclusion:
it was concluded from the above protocol that the compounds of the examples shown in the present invention show the biological activities in the SHP-2 kinase activity assay as shown in table 1 below,
table 1: relative IC of compound for SHP-2 kinase activity inhibition 50 Value of
Figure GPA0000287746260000501
Test example 2 measurement of mouse pharmacokinetics
2.1. The research aims are as follows:
the pharmacokinetic behavior of the compounds example 1, example 36 and example 38, orally administered in vivo (plasma) in mice, was studied using Balb/c mice as test animals.
2.2. Test protocol
2.2.1 test drugs:
example 1, example 36 and example 38 of the present invention, homemade;
2.2.2 test animals:
balb/c mice, male, purchased from Shanghai Jitsie laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013-.
2.2.3 preparation of the medicine:
5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps) was weighed, dissolved in 1000mL of purified water, and 10g of Tween80 was added. Mix well to get a clear solution.
The sample was weighed 1.2mg separately, added to a 4-mL glass vial, 2.4mL of this solution was added, and sonicated for 10 minutes to give a colorless clear solution at a concentration of 0.5 mg/mL.
2.2.4 dosing:
balb/c mice, male; PO was administered overnight after fasting at a dose of 5mg/kg and at a volume of 10 mL/kg.
2.2.5 sample Collection:
collecting blood before administration and after administration for 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h, placing the blood in EDTA-2K test tube, centrifuging at 4 deg.C and 6000rpm for 6min to separate blood plasma, and storing at minus 80 deg.C; food was consumed 4h after dosing.
2.2.6 assay results:
the final measurement results obtained by applying LCMS/MS method are shown in Table 2
Table 2: mouse pharmacokinetic parameters of Compounds
Figure GPA0000287746260000502
Figure GPA0000287746260000511
The above data show that: at a dose of 5mg/kg, the compounds of the examples of the present invention showed good metabolic activity.
Test example 3 inhibition experiment of tumor in MiaPaca2 transplanted tumor model
3.1 purpose of experiment:
BALB/c nude mice are used as tested animals, and in vivo efficacy experiments are carried out by adopting a human pancreatic cancer cell MiaPaca2 xenograft tumor (CDX) model to evaluate the anti-tumor effect of tested compounds.
3.2 laboratory instruments and reagents:
3.2.1 Instrument:
super clean bench (BSC-1300II A2, Shanghai Bocheng industry Co., Ltd.)
CO 2 Incubator (Thermo-311, Thermo)
Centrifuge (Centrifuge 5720R, Eppendorf)
Full-automatic cell counter (Countess II, Life Technologies)
Pipettor (10-20 μ L, Eppendorf)
Microscope (Ts 2, Nikang)
Slide measure (CD-6' AX, Japan Sanfeng)
Cell culture bottles (T25/T75/T225, Corning)
Constant temperature water tank (HWS12, Shanghai-Heng science)
3.2.2 reagents:
DMEM(11995-065，Gibco)
fetal Bovine Serum (FBS) (10091-148, Gibco)
0.25% trypsin (25200-056, Gibco)
Penicillin streptomycin double antibody (P/S) (SV30010, GE)
Phosphate Buffered Saline (PBS) (10010-023, Gibco)
Matrigel(356234，Corning)
Gln(25030-081，Gibco)
3.3 Experimental procedures:
removing MiaPaca2 cells from cell bank, adding DMEM medium (containing 10% FBS, 1% Glu and 1% P/S) after recovery, and placing in CO 2 Culturing in incubator (incubator temperature 37 deg.C, CO) 2 Concentration 5%). After the cells are spread to 80-90% of the bottom of the culture bottlePassage, after passage, the cells are continuously placed in CO 2 Culturing in an incubator. Repeating the process until the cell number meets the in vivo drug effect inoculation demand, collecting cells in logarithmic growth phase, counting with a full-automatic cell counter, re-suspending the cells with PBS and Matrigel (volume ratio of 1: 1) according to the counting result, and making into cell suspension (density of 8 × 10) 7 Ml) and put in an ice box for standby.
Animals used were BALB/c nude mice, female, 6-8 weeks old, and approximately 18-22 grams in weight. Mice were kept in a special pathogen free environment and in a single ventilated cage, 5 mice per cage. All cages, bedding and water were sterilized prior to use and all animals were free to obtain standard certified commercial laboratory diets. The nude mice were marked with disposable universal ear tags for both small and large mice before the start of the experiment, the skin of the inoculated part was disinfected with 75% medical alcohol before the inoculation, and each mouse was subcutaneously inoculated with 0.1ml (containing 8 x 10) of the right back 6 Individual cells) MiaPaca2 tumor cells. When the average tumor volume reaches 100- 3 The grouped administration is started. The tested compounds were administered via oral gavage daily, and the dose, frequency of administration and the drug effect at the end of the experiment are shown in table 3. Tumor volume (mm) was measured twice weekly using a vernier caliper 3 ) The calculation formula is as follows: v0.5 x D, wherein D and D are the long and short diameters of the tumor, respectively. The anti-tumor efficacy was determined by dividing the mean tumor gain volume of compound-treated animals by the mean tumor gain volume of untreated animals. The tumor inhibition rate is calculated by the formula: TGI (%) ═ 1- [ (Vt-V0) administration group/(Vt-V0) solvent control group]100%. All animals were euthanized at the end of the experiment.
3.4 Experimental results:
table 3: transplanted tumor of compound mouse pharmacodynamic parameters
Figure GPA0000287746260000521
And (4) experimental conclusion: the above data show that the compounds of the examples of the invention significantly inhibited the growth of MiaPaca2 nude mice transplanted tumors after 21 days of oral continuous administration.

Claims (12)

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof:
Figure FDA0003624568130000011
wherein:
M 1 is S or NR aa ；
L is a bond or S;
ring B is selected from the following groups:
Figure FDA0003624568130000012
R 1 selected from hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, halogen, amino, hydroxy, cyano, 3-8 membered heterocyclyl, - (CH) 2 ) n1 C(O)OR aa Or- (CH) 2 ) n1 C(O)NR aa R bb ；
R 2 Selected from hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, halogen, amino, hydroxy, cyano, aldehyde, 5-6 membered heteroaryl or- (CH) 2 ) n1 OR aa ；
R 3 Selected from hydrogen, deuterium, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, halogen, amino or- (CH) 2 ) n1 NR aa R bb Said C is 1-6 Alkyl radical, C 1-6 Deuterated alkyl and amino optionally further substituted with one or more substituents selected from hydrogen, halogen, amino, cyano, and hydroxy;
or two R on the same carbon atom or on different carbon atoms 3 Linked to form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally further substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, amino, cyano or hydroxy;
R aa and R bb Each independently selected from hydrogen, deuterium, C 1-6 Alkyl or C 1-6 A deuterated alkyl group;
x is 0, 1, 2 or 3;
z is 0, 1, 2 or 3;
q is 0 or 1; and is
n1 is 0 or 1.
2. The compound of formula (II), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein formula (II) is further represented by formula (IIA) and formula (IIB):
Figure FDA0003624568130000021
wherein:
ring B, M 1 、R 1 、R 2 、R 3 X, z and q are as defined in claim 1.
3. The compound of formula (II), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein formula (II) is further represented by formula (IIC):
Figure FDA0003624568130000022
wherein:
M 1 、R 1 、R 2 、R 3 x, z and q are as defined in claim 1.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (II) is further represented by formula (VI):
Figure FDA0003624568130000023
wherein:
M 3 selected from the group consisting of CR 8 Or N;
ring a is selected from the group:
Figure FDA0003624568130000024
R 7 selected from hydrogen, deuterium, halogen, amino, 6-membered heterocyclic group or- (CH) 2 ) n1 C(O)NR aa R bb ；
R 8 Selected from hydrogen, deuterium or halogen;
R 9 selected from hydrogen or C 1-6 An alkyl group;
t is 0, 1, 2 or 3;
q is 0 or 1; and is
z-1 is 1, 2 or 3.
5. A compound of each formula or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 2, wherein:
ring B and substituent R thereof 1 I.e. by
Figure FDA0003624568130000031
Further selected from the group consisting of:
Figure FDA0003624568130000032
6. the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof,
R 1 selected from hydrogen, cyano, amino, halogen, C 1-6 Alkyl or 3-8 membered heterocyclyl;
R 2 selected from hydrogen or- (CH) 2 ) n1 OR aa ；
R 3 Selected from hydrogen, C 1-6 Alkyl or amino- (CH) 2 ) n1 NR aa R bb 。
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (II) is further represented by formula (V):
Figure FDA0003624568130000033
wherein:
M 1 is-S-;
M 2 selected from the group consisting of CR 5 Or N;
R 4 selected from hydrogen, deuterium, halogen or amino;
R 5 selected from hydrogen, deuterium or halogen;
R 3 selected from hydrogen, deuterium, amino or C 1-6 An alkyl group;
R 6 selected from hydrogen;
s is 1 or 2;
z-1 is 1 or 2.
8. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure FDA0003624568130000041
9. a process for the preparation of a compound of formula (V) according to claim 7 and pharmaceutically acceptable salts thereof, comprising the steps of:
Figure FDA0003624568130000042
wherein:
X 1 fluorine, chlorine, bromine, iodine;
pg is tert-butyloxycarbonyl.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II) as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
11. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a SHP-2 inhibitor medicament.
12. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the treatment of noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer, and colon cancer diseases or disorders thereof.
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