CN113316574B - SHP2 inhibitor and application thereof - Google Patents
SHP2 inhibitor and application thereof Download PDFInfo
- Publication number
- CN113316574B CN113316574B CN202080008741.8A CN202080008741A CN113316574B CN 113316574 B CN113316574 B CN 113316574B CN 202080008741 A CN202080008741 A CN 202080008741A CN 113316574 B CN113316574 B CN 113316574B
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- Prior art keywords
- amino
- compound
- dihydrospiro
- piperidin
- thio
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The invention relates to a compound (shown as a formula I) applied as an Src homology region 2-containing protein tyrosine phosphatase 2 (SHP 2) inhibitor, a pharmaceutical composition, a preparation method and application thereof in treating SHP2 mediated diseases. The compounds of the present invention act by participating in a number of processes that regulate cell proliferation, apoptosis, migration, neovascularization, and the like.
Description
Technical Field
The invention relates to a series of compounds serving as Src homology region 2-containing protein tyrosine phosphatase 2 (Src homologyregion-containing protein tyrosine phosphatase 2, SHP 2) inhibitors, a preparation method thereof and a pharmaceutical composition thereof. The invention also relates to the use of the above compounds or pharmaceutical compositions thereof in the treatment of SHP2 mediated diseases.
Background
The Src homology 2-containing protein tyrosine phosphatase 2 (Src homologyregion 2-containing protein tyrosine phosphatase 2, SHP 2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, PTPN11 being the first proto-oncogene found to encode tyrosine kinases (Chan R J et al PTPN is the first identified proto-oncogene that encodes a tyrosine phosphatase Blood,2007, 109:862-867), encoding SHP2 proteins comprising an N-terminal SHP2 domain (N-SHP 2), a C-terminal SHP2 domain (C-SHP 2), a protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580), and a proline (Pro) -rich motif.
In recent years, the Ras/ERK pathway is mainly considered to be one of the most important Signal transduction pathways for SHP2 to function, and the mechanism (Dance M et al molecular functions of Shp in the RAS/mitogen-activated protein kinase (ERK 1/2) pathway.cell Signal,2008, 20:453-459) is approximately: upon activation of the growth factor receptor, its tyrosine residues autophosphorylate, providing a docking site for the phosphotyrosine binding region SH2 of Grb2 and SHP2 (SH 2 domain-containing adaptor protein). Binding of Grb2 to phosphorylated growth factor receptors results in aggregation of SOS proteins at the membrane. SOS, a guanine nucleotide exchange factor (guanine nucleotide exchange factor, GEF), catalyzes the conversion of the membrane-bound protein Ras from inactive Ras-GDP to active Ras-GTP. Ras-GTP is further connected with a downstream signal system, and Ser/Thr kinase Raf1 and the like are activated, so that ERK is activated under the action of regulating kinase MEK, and the ERK is directly acted on target molecules of cytoplasm after activation or transferred into nucleus to regulate gene transcription, so that cells proliferate or differentiate. This process may also be affected by SHP2 binding proteins and substrates (SHP substrate-1, SHPS-1), ras-GTPase activating proteins (Ras-GAP), and other Src members.
The SHP2 protein not only regulates Ras/ERK signal channels, but also regulates multiple signal channels of JAK-STAT3, NF-kappa B, PI K/Akt, RHO, NFAT and the like, thereby regulating physiological functions of cell proliferation, differentiation, migration, apoptosis and the like.
SHP2 has been shown to be associated with a variety of diseases, and Tartaglia et al (Tartaglia M et al Mutations in PTPN, encoding the protein tyrosine phosphatase SHP-2,cause Noonan syndrome Nat Genet,2001, 29:465-468) found that about 50% of noonan syndrome patients have missense mutations in PTPN 11. In addition, PTPN11 mutations have been found to be an important cause of the onset of JMML and a variety of leukemias (Tartaglia M et al Nat Genet,2003, 34:148-150;Loh ML et al.Blood,2004, 103:2325-2331;Tartaglia M et al.Br J Haematol,2005, 129:333-339;Xu R et al Blood,2005, 106:3142-3149.). As PTPN11/SHP2 was studied intensively, it was found that it was related to the occurrence of various cancers such as lung cancer, stomach cancer, colon cancer, melanoma, thyroid cancer, etc. (Tang Chunlan et Al J.Chinese lung cancer, 2010, 13:98-101;Higuchi M et al.Cancer Sci,2004, 95:442-447; bentires-Al j M et Al cancer Res,2004, 64:8816-8820;Martinelli S et al.Cancer Genet Cytogenet,2006, 166:124-129.).
Therefore, SHP2 inhibitors are gaining increasing attention as potential therapeutic approaches. There are a number of SHP2 inhibitors currently being developed, and TNO155 developed by nova entered phase I clinical trials for the treatment of solid tumors in 2017. JAB-3068 developed by the additive design entered phase I clinical trials for the treatment of solid tumors at month 4 of 2018. The RMC-4630 developed by Revolition was subjected to the first human clinical trial at 8 months of 2018. At present, the target is not seen in commercial varieties at home and abroad, so that a small molecular medicine capable of targeted inhibition of SHP2 activity is developed, and the target has important research significance for providing safer and more effective SHP2 inhibitors for patients.
Disclosure of Invention
The present invention relates to compounds useful as inhibitors of Src homology 2 containing protein tyrosine phosphatase 2 (SHP 2). The compound has a general structure shown in a formula I or pharmaceutically acceptable salts, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof,
wherein,
R 1 selected from hydrogen, hydroxy, C 1-8 Alkyl, C containing substituents 1-8 Alkyl, C 1-8 Alkoxy, C containing substituents 1-8 Alkoxy, C 2-8 Alkenyl, C containing substituents 2-8 Alkenyl, C 2-8 Alkynyl or substituted C 2-8 Alkynyl;
R 2 selected from hydrogen, C 1-4 Alkyl or C containing substituents 1-4 An alkyl group;
R 3 selected from hydrogen, amino, -C (O) NH 2 (C.ident.N, hydroxy, C) 1-8 Alkyl, C containing substituents 1-8 Alkyl, C 1-8 Alkoxy or C containing substituents 1-8 An alkoxy group;
R 4 selected from hydrogen, halogen, amino, amido, -C.ident.N, carboxyl, hydroxyl, hydroxymethyl, C 1-8 Alkyl, C containing substituents 1-8 Alkyl, C 1-8 Alkoxy, C containing substituents 1-8 Alkoxy, C 2-8 Alkenyl, C containing substituents 2-8 Alkenyl, C 2-8 Alkynyl or substituted C 2-8 Alkynyl;
A 1 optionally selected from CR 5 Or N;
A 2 optionally selected from CR 6 Or N;
A 3 optionally selected from CR 7 Or N;
u is optionally selected from C (R) 8 ) 2 O or NR 9 ;
Wherein R is 5 、R 6 、R 7 、R 8 Or R is 9 Independently selected from hydrogen, halogen, amino, C 1-8 Alkyl, C containing substituents 1-8 Alkyl, C 1-8 Alkoxy, C containing substituents 1-8 Alkoxy, C 2-8 Alkenyl, C containing substituents 2-8 Alkenyl, C 2-8 Alkynyl or substituted C 2-8 Alkynyl;
ring A is optionally selected from C 6-10 Aryl groupOr C 5-10 Heteroaryl, said C 5-10 Heteroaryl contains one or two N or S heteroatoms;
rx is optionally selected from hydrogen, halogen, amino, substituted amino, sulfonyl, C 1-8 Alkyl, C containing substituents 1-8 Alkyl, C 1-8 Alkoxy, C containing substituents 1-8 Alkoxy, C 3-8 Cycloalkyl or C containing substituents 3-8 Cycloalkyl;
n is 0, 1, 2, 3 or 4.
Preferably, A in formula I 3 Is N. Unexpectedly, when A 3 For N instead of CR 7 When the hERG is used, not only the SHP2 inhibition activity can be maintained, but also the hERG can be remarkably improved.
In some embodiments, R in formula I 1 Selected from C 1-3 An alkyl group.
In some embodiments, R in formula I 1 Is methyl.
In some embodiments, R in formula I 2 Selected from hydrogen or C 1-3 An alkyl group.
In some embodiments, R in formula I 2 Is hydrogen.
In some embodiments, R in formula I 3 Selected from hydrogen, amino or C 1-3 An alkyl group.
In some embodiments, R in formula I 3 Is hydrogen or amino.
In some embodiments, R in formula I 4 Selected from hydrogen, halogen, amino, C 1-3 Alkyl or C containing substituents 1-3 An alkyl group.
In some embodiments, R in formula I 4 Hydrogen, fluorine or chlorine.
In some embodiments, R in formula I 4 Is hydrogen or chlorine.
In some embodiments, A in formula I 1 Selected from CR 5 Or N, wherein R 5 Selected from halogen or halogen substituted C 1-3 An alkyl group.
In some embodiments, A in formula I 1 Selected from CR 5 Or N, wherein R 5 Selected from F, cl or trifluoromethylA base.
In some embodiments, A in formula I 1 Selected from CR 5 Or N, wherein R 5 Selected from Cl or trifluoromethyl.
In some embodiments, A in formula I 2 Selected from CR 6 Or N, wherein R 6 Selected from amino or C 1-3 An alkoxy group.
In some embodiments, A in formula I 2 Selected from CR 6 Or N, wherein R 6 Selected from amino or methoxy.
In some embodiments, A in formula I 3 Selected from CH or N.
In some embodiments, U in formula I is selected from CH 2 Or O.
In some embodiments, ring A in formula I is selected from phenyl or C 5-6 Heteroaryl, said C 5-10 Heteroaryl groups contain one or two N or S heteroatoms.
In some embodiments, ring A in formula I is selected from phenyl,
In some embodiments, a compound of formula IOptionally selected from->
In some embodiments, a compound of formula IOptionally selected from->
The invention further provides some preferred technical schemes of the compounds shown in the formula I. For example, the compounds of the present invention have the general structure shown in formula II or pharmaceutically acceptable salts, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof,
wherein,
R 1 selected from C 1-8 An alkyl group;
R 2 selected from hydrogen;
R 3 selected from H or amino;
R 4 selected from hydrogen, halogen;
A 1 selected from CR 5 ;
A 2 Selected from CR 6 ;
U is selected from C (R) 8 ) 2 ;
Wherein R is 5 、R 6 、R 8 Independently selected from hydrogen, halogen, C 1-8 Alkyl, C containing substituents 1-8 An alkyl group;
ring A is optionally selected from C 6-10 Aryl groups.
In some embodiments, the substituent-containing C 1-8 The alkyl group may be a halogenated C 1-8 Alkyl groups such as trifluoromethyl.
In some embodiments, ring A in formula II is optionally substituted with hydrogen or C 1-8 Alkoxy substitution.
In some embodiments, ring a in formula II is optionally substituted with hydrogen or methoxy.
In some embodiments, R in formula II 1 Is methyl.
In some embodiments, R in formula II 4 Is hydrogen.
In some embodiments, U in formula II is selected from CH 2 。
In some embodimentsR in formula II 5 Selected from Cl.
In some embodiments, R in formula II 6 Selected from NH 2 。
In some embodiments, ring a in formula II is selected from phenyl.
The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(2) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(3) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(4) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((3-chloro-2-methoxypyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(5) (S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2, 3-dichlorophenyl) thio) -3-methylpyridin-4 (3H) -one;
(6) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methyl-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one;
(7) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((6-amino-3-chloropyridin-2-yl) thio) -3-methylpyridin-4 (3H) -one;
(8) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4-bromo-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(9) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6- (trifluoromethyl) -1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(10) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(11) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(12) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-5, 6-dimethoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(13) (S) -2- (4-amino-2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(14) (S) -2- (5-amino-2-methoxy-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(15) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2, 3-dichlorophenyl) thio) -3-methylpyridin-4 (3H) -one;
(16) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(17) (S) -6-amino-2- (1-amino-6-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2-aminopyrimidin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(18) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(19) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-5-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(20) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-7-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(24) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-fluoropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(25) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4, 7-difluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(26) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one; or (b)
(27) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-aminopyrimidin-4-yl) thio) -3-methylpyridin-4 (3H) -one.
Preferably, the present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(2) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(3) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(4) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((3-chloro-2-methoxypyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(8) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4-bromo-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(9) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6- (trifluoromethyl) -1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(10) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(11) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(12) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-5, 6-dimethoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(13) (S) -2- (4-amino-2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(14) (S) -2- (5-amino-2-methoxy-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(16) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(17) (S) -6-amino-2- (1-amino-6-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2-aminopyrimidin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(18) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(19) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-5-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(20) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-7-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(24) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-fluoropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(25) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4, 7-difluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(26) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one; or (b)
(27) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-aminopyrimidin-4-yl) thio) -3-methylpyridin-4 (3H) -one.
The invention also provides a pharmaceutical composition which is characterized by comprising a therapeutically effective amount of at least one compound shown as a formula I or a formula II and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition which is characterized in that the mass percentage of the compound shown in the structural formula I and pharmaceutically acceptable auxiliary materials is 0.0001:1-10.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula I in preparation of medicines.
The invention further provides a preferable technical scheme of the application:
Preferably, the use is for the manufacture of a medicament for the treatment, prevention, delay or prevention of cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
Preferably, the use is for the manufacture of a medicament for the treatment of a disorder mediated by SHP 2.
Preferably, the disease is cancer.
Preferably, the cancer is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, stomach cancer, pancreatic cancer, or a combination thereof.
Preferably, the use is for the preparation of an inhibitor of SHP 2.
The invention also provides a method of treating and/or preventing a disorder mediated by SHP2, comprising administering to a subject a therapeutically effective amount of at least one compound of formula I or a pharmaceutical composition.
Preferably, in the above method, the SHP2 mediated disease is cancer.
The invention also provides a method of treating cancer comprising administering to a subject a therapeutically effective amount of at least any one compound of formula I or pharmaceutical composition.
Preferably, in the above method, the cancer is Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, stomach cancer, pancreatic cancer, or a combination thereof.
Preferably, in the above method, the subject is a human.
Unless otherwise indicated, the terms used in the present invention have the following meanings:
the term "alkyl" includes straight, branched or cyclic saturated alkyl groups. For example, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-methylpentyl, and cyclohexyl and the like. Similarly, "C 1-8 "C in" alkyl 1-8 "refers to a group comprising 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a linear, branched, or cyclic fashion.
"alkenyl" and "alkynyl" include straight-chain, branched or cyclic alkenyl and alkynyl groups. Similarly, "C 2-8 Alkenyl groups "and" C 2-8 Alkynyl "refers to alkenyl or alkynyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight, branched or cyclic fashion.
The term "alkoxy" refers to the oxyether form of the aforementioned straight, branched or cyclic alkyl groups.
The term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group comprising carbon atoms. Preferably a 6 to 10 membered mono-or bicyclic aromatic group. Phenyl and naphthyl are preferred. Most preferred is phenyl.
The term "heteroaryl" refers to a monovalent heteroatom group formed by the removal of a hydrogen atom from a carbon atom of a parent heteroaromatic ring system. Heteroaryl groups include: 5-to 7-membered aromatic, monocyclic ring comprising at least one heteroatom selected from N, O or S, for example 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, the other atoms on the ring being carbon; the polyheteroaryl ring includes at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, the other atoms on the ring being carbon, and wherein at least one heteroatom is on an aromatic ring. Particularly preferred heteroaryl groups are C 3-10 Including, but not limited to, pyrrolyl, furanyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl, and the like.
However, in any event, the heteroaryl and aryl do not intersect or otherwise include each other. Thus, according to the definition above, if at least one all-carbon aromatic ring is fused to one heterocyclic group, a heteroaryl group is obtained instead of an aryl group.
"cycloalkyl" refers to a cyclic group that is saturated or unsaturated but not aromatic. The terms "cycloalkyl", "cycloalkenyl" or "cycloalkynyl" are used, respectively, depending on the particular level of saturation. Representative cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene and the like. Specifically, the cycloalkyl group may be C 3-10 Cycloalkyl groups of (c), such as: c (C) 3-6 Cycloalkyl groups.
"heterocyclyl" refers to a saturated or unsaturated, but not aromatic, cyclic group in which one or more carbon atoms (and the attached hydrogen atoms) may be replaced by the same or different heteroatoms and corresponding attached hydrogen atoms, respectively. Representative heteroatoms substituted for carbon atoms include, but are not limited to N, P, O, S and Si. When it is desired to describe a particular degree of saturation, the terms "heterocycloalkyl" or "heterocycloalkenyl", respectively, are employed. Representative heterocyclyl groups include, but are not limited to, epoxy, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, or tetrahydropyran, and the like. The substituent-containing heterocyclic group also comprises a ring system substituted with at least one oxygen-containing (=o) or oxide (-O-) substituent, such as: piperidine-nitrogen-oxide, morpholino-nitrogen-oxide, 1-oxo-1-thiomorpholino and 1-dioxo-1-thiomorpholino.
In any case, however, the heterocycloalkyl and cycloalkyl groups do not intersect or include each other. Thus, according to the above definition, if at least one full carbocycle is fused with a heterocycloalkyl to form a di-, poly-or spiro-ring, it will still be defined as heterocycloalkyl.
In addition, if a heteroaryl is fused to a heterocyclyl to form a di-, poly-or spiro-ring, it will be defined as heterocyclyl rather than heteroaryl.
"halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogens are fluorine, chlorine and bromine.
"halo" refers to fluoro, chloro, bromo or iodo groups. Preferred halo groups are fluoro and chloro.
"substituted" means that one or more hydrogen atoms in a group are each replaced by the same or different substituents. Representative substituents include, but are not limited to, halogen, amino, oxo, carbonyl, alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl. In some embodiments, substituents include, but are not limited to, halogen, amino, methyl, -CH 3 Trifluoromethyl, -CH 3 。
Whenever the term "alkyl" or "aryl" or its prefix root appears in a substituent name (e.g., aralkyl, or dialkylamino), the substituents are to be interpreted in a limiting sense as defined by the foregoing definition of "alkyl" and "aryl". Of a specified number of carbon atoms (e.g. C 1-6 ) Independently in an alkyl moiety or in aThe number of carbon atoms in the alkyl portion of the larger substituent (where alkyl is the prefix root).
The term "compound" as used herein includes compounds of formula I, as well as all pharmaceutically acceptable forms thereof. Such pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates or prodrugs thereof, or any mixture of all of the above.
By "pharmaceutically acceptable" is meant well known for use in animals, particularly humans.
The term "composition" as used herein includes products comprising specific amounts of specific components, as well as any products derived directly or indirectly from specific amounts of specific components. Thus, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and methods of preparing the compounds are within the scope of the present invention.
By "therapeutically effective amount" is meant that amount of a compound that, when administered to a subject being treated, treats and prevents and/or inhibits at least one clinical symptom of a disease, condition, symptom, indication, and/or disorder, is sufficient to effect treatment of the disease, condition, symptom, indication, or disorder. The specific "effective therapeutic dose" may vary depending on the compound, the route of administration, the age of the patient, the weight of the patient, the type of disease or disorder being treated, the symptoms and severity, and the like. Where possible, an appropriate dosage may be apparent to those skilled in the art or may be determined by routine experimentation.
The compounds provided herein may exist in the form of "pharmaceutically acceptable salts". In the aspect of pharmaceutical application, the salt of the compound provided by the invention refers to nontoxic pharmaceutically acceptable salt. Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anion or base/cation salts. Pharmaceutically acceptable acid/anion salts are generally present in the protonated form of basic nitrogen with inorganic or organic acids. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, alpha-ketoglutaric acid, hippuric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, salicylic acid, saccharinic acid or trifluoroacetic acid. Pharmaceutically acceptable base/cation salts include, but are not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts.
Prodrugs of the compounds of the present invention are included within the scope of the present invention. Typically, the prodrugs are functional derivatives that are readily convertible in vivo into the desired compounds. Thus, the term "administration" in reference to the methods of treatment provided herein includes administration of a compound disclosed herein, or treatment of a variety of diseases that, although not explicitly disclosed, are capable of being converted in vivo to a compound disclosed herein upon administration to a subject. Conventional methods for the selection and preparation of suitable prodrug derivatives have been described in, for example, the book "prodrug design" (Design of Prodrugs, ed.H. Bundgaard, elsevier, 1985).
Obviously, the definition of a variable at any substituent or particular position in one molecule is independent of the definition of a variable at any substituent or particular position in the other molecule. It will be readily appreciated that the compounds of the present invention may be prepared by selecting the appropriate substituents or substitution patterns in accordance with the current state of the art to provide compounds that are chemically stable and readily synthesized by the current state of the art or methods described herein.
When the compounds of formula I and pharmaceutically acceptable salts thereof are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like may be used.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds provided herein are acids, the corresponding salts thereof can be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc, and the like. In particular, salts of ammonium, calcium, magnesium, potassium and sodium are preferred. Nontoxic organic bases capable of derivatizing into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituent-containing amines, such as naturally occurring and synthetic substituent-containing amines. Other pharmaceutically acceptable non-toxic organic bases capable of salt formation include ion exchange resins as well as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, halamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compounds provided herein are bases, the corresponding salts thereof can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, alpha-ketoglutaric acid, hippuric acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Preferably, malic acid, citric acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably phosphoric acid, hydrochloric acid and malic acid. Since the compounds of formula I will be used as pharmaceuticals, it is preferred to use substantially pure forms, for example at least 60% pure, more suitably at least 75% pure, especially suitably at least 98% pure (% is by weight).
The pharmaceutical composition provided by the invention comprises a compound (or pharmaceutically acceptable salt thereof) shown in a formula I as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular subject, nature of the subject and severity of the condition being administered, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently presented in unit dosage form well known in the art and prepared by any of the methods of manufacture well known in the pharmaceutical arts.
In fact, the compounds of formula I of the present invention, or prodrugs, or metabolites, or pharmaceutically acceptable salts thereof, may be combined as the active ingredient in admixture with a pharmaceutical carrier in accordance with conventional pharmaceutical compounding techniques to form pharmaceutical compositions. The pharmaceutical carrier may take a variety of forms depending on the mode of administration desired, for example, orally or by injection (including intravenous injection). Thus, the pharmaceutical compositions of the present invention may take the form of individual units suitable for oral administration, such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical compositions of the present invention may take the form of powders, granules, solutions, aqueous suspensions, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition, in addition to the usual dosage forms mentioned above, the compounds of formula I or pharmaceutically acceptable salts thereof may also be administered by means of controlled release and/or delivery means. The pharmaceutical compositions of the present invention may be prepared by any pharmaceutical method. Typically, such methods include the step of associating the active ingredient with a carrier that constitutes one or more of the necessary ingredients. Typically, the pharmaceutical compositions are prepared by intimate mixing of the active ingredient with a liquid carrier or finely divided solid carrier or a mixture of both. In addition, the product can be conveniently prepared to a desired appearance.
Accordingly, the pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier and a compound of formula I, or a pharmaceutically acceptable salt thereof. Also included in the pharmaceutical compositions of the invention are compounds of formula I, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, mannitol, sorbitol, microcrystalline cellulose, inorganic salts, starch, pregelatinized starch, powdered sugar, dextrin and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of the gas carrier include carbon dioxide and nitrogen. Any convenient pharmaceutically acceptable medium may be used in the preparation of the pharmaceutical oral formulation. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used in liquid preparations for oral administration such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used in the oral solid preparations such as powders, capsules and tablets. In view of ease of administration, the oral formulations are preferably tablets and capsules. Alternatively, tablet coatings may use standard aqueous or non-aqueous formulation techniques.
Tablets containing a compound or pharmaceutical composition of the invention may be prepared by mixing, compressing, or molding, optionally with one or more accessory ingredients or adjuvants. The active ingredient is mixed in a free-flowing form, such as a powder or granules, with a lubricant, inert diluent, surface active or dispersing agent, and compressed tablets may be made by compression in a suitable machine. Molded tablets may be made by impregnating the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine. Preferably, each tablet contains about 0.01mg to 5g of active ingredient and each sachet or capsule contains about 0.1mg to 0.5g of active ingredient. For example, a dosage form intended for oral administration to humans comprises from about 0.1mg to about 0.5g of the active ingredient, compounded with suitable and conveniently metered auxiliary materials, which constitute from about 5% to 99.99% of the total pharmaceutical composition. The unit dosage form generally contains from about 0.1mg to about 0.5g of the active ingredient, typically 0.1mg, 0.2mg, 0.5mg, 1mg, 2mg, 2.5mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg or 500mg.
The pharmaceutical compositions provided herein suitable for parenteral administration may be prepared as aqueous solutions or suspensions of the active ingredient in water. Suitable surfactants may be included such as sodium lauryl sulfate, polysorbate-80 (tween-80), polyoxyethylene hydrogenated castor oil, poloxamers. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.
The present invention provides pharmaceutical compositions suitable for injectable use, including sterile aqueous solutions or dispersions. Further, the above pharmaceutical composition may be prepared in the form of a sterile powder which can be used for the extemporaneous preparation of sterile injectable solutions. In any event, the final injection form must be sterile and must be readily flowable for ease of injection. Furthermore, the pharmaceutical composition must be stable during preparation and storage. Thus, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier may be a solvent or dispersion medium, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
The pharmaceutical compositions provided herein may be in a form suitable for topical administration, for example, an aerosol, emulsion, ointment, lotion, dusting powder, or other similar dosage form. Further, the pharmaceutical compositions provided herein may take a form suitable for use with transdermal drug delivery devices. These formulations can be prepared by conventional processing methods using the compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof. As an example, a cream or ointment may be prepared by adding a hydrophilic material and water to the above-described compounds (the total amount of both is about 5 to 50% by weight of the compound) to produce a cream or ointment having the desired consistency.
The pharmaceutical composition provided by the invention can be prepared into a form which takes a solid as a carrier and is suitable for rectal administration. The mixture is formed into a unit dose suppository, the most preferred dosage form. Suitable adjuvants include cocoa butter and other materials commonly used in the art. Suppositories may be conveniently prepared by first mixing the pharmaceutical composition with the softened or melted excipients and then cooling and molding the mixture.
In addition to the carrier components mentioned above, the above pharmaceutical formulations may include, where appropriate, one or more additional auxiliary components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. Further, other adjuvants may also include permeation enhancers that regulate the isotonic pressure of the drug and blood. Pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or concentrate.
Detailed Description
In order to make the above matters clearer and more obvious, the following examples are provided to further illustrate the technical aspects of the present invention. The following examples are presented only to illustrate specific embodiments of the invention so that those skilled in the art can understand the invention and are not intended to limit the scope of the invention. In the specific embodiment of the present invention, technical means, methods, and the like not specifically described are conventional technical means, methods, and the like in the art.
All parts and percentages herein are by weight and all temperatures are in degrees celsius unless otherwise indicated.
The following abbreviations are used in the examples:
ACE-Cl: 1-chloroethyl chloroformate;
(Boc) 2 o: di-tert-butyl dicarbonate;
BOP: benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate;
DBU:1, 8-diazabicyclo undec-7-ene;
DCE:1, 2-dichloroethane;
DCM: dichloromethane;
DIPEA or DIEA: n, N-diisopropylethylamine;
DMAc: n, N-dimethylacetamide;
DMF: n, N-dimethylformamide;
DMSO: dimethyl sulfoxide;
EA or EtOAc: ethyl acetate;
EGTA: ethylene glycol bis aminoethyl ether tetraacetic acid;
EtOH: ethanol;
EtONa: sodium ethoxide;
h. hr or hrs: hours;
hex: n-hexane;
HEPES:4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid;
LC-MS or LCMS: liquid chromatography-mass spectrometry;
LDA: lithium diisopropylamide;
MeCN: acetonitrile;
MeOH: methanol;
MeONa: sodium methoxide;
min or mins: minutes;
MsCl: methane sulfonyl chloride;
NEt 3 : triethylamine
NBS: n-bromosuccinimide;
NMP: n-methyl-2-pyrrolidone;
Pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium;
Pd(OAc) 2 : palladium (II) acetate;
PE: petroleum ether;
PPA: polyphosphoric acid;
RT or RT: room temperature;
TFA: trifluoroacetic acid;
THF: tetrahydrofuran;
Ti(OEt) 4 : tetraethyl titanate;
TLC: thin layer chromatography;
TMEDA: tetramethyl ethylenediamine; and
xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene.
Preparation of intermediate compound M1:
step 1: preparation of Compounds M1-3
15.00g of compound M1-1 and 7.08g of compound M1-2 were dissolved in 150mL of dioxane, and 198mg of Pd (OAc) was added 2 1.70g Xantphos and 15.00g DIEA. The reaction was stirred for 12hrs at 85℃under nitrogen blanket with three nitrogen substitutions. TLC was used to check completion of the reaction, the reaction solution was filtered, the filter cake was washed with DCM (50 mL. Times.2), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 20.00g of Compound M1-3.
Step 2: preparation of Compound M1
20.00g of Compound M1-3 was dissolved in 200mL of THF, etONa (35 mL,20% EtOH) was added dropwise at-30℃and the reaction was stirred at RT for 3hrs. TLC detection of completion of the reaction was complete, concentration under reduced pressure, stirring for 30mins with 200mL of DCM was added, the reaction solution was filtered, and the filter cake was washed with DCM (50 mL. Times.2) to give 15.00g of compound M1 as a solid.
Preparation of intermediate compound M2:
step 1: preparation of Compound M2-2
1.00g of Compound M2-1 was dissolved in 10mL of DMSO, meONa in MeOH (15 mL, 0.5M) was added, and then reacted at 70℃for 1hr. TLC was used to determine completion of the reaction, the reaction mixture was poured into 30mL of water, etOAc was added thereto for extraction (40 mL. Times.3), the organic phases were combined, washed with 50mL of saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.10g of Compound M2-2 as a pale yellow oil.
Step 2: preparation of Compound M2-3
Compound 1.10g M2-2 was dissolved in 15mL dioxane, 491mg of Compound M1-2, 46mg Xantphos,35mg Pd (OAc) was added 2 1.05g DIEA, the mixture was replaced 3 times with nitrogen and heatedThe reaction was carried out at 90℃for 5hrs. TLC was used to check completion of the reaction, the reaction solution was cooled to room temperature, filtered, the cake was washed with EtOAc (5 mL. Times.3), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.03g of pale yellow solid M2-3.
Step 3: preparation of Compound M2
1.03g of Compound M2-3 was dissolved in 10mL of anhydrous THF, cooled to-30℃and EtOH solution (2 mL, 20%) of EtONa was slowly added dropwise to the above solution, and the reaction was stirred at-30℃for 30mins, slowly warmed to room temperature and stirred for 2hrs. TLC showed complete reaction, the reaction was concentrated under reduced pressure, the residue was slurried with 20mL of DCM for 30min, filtered, the filter cake washed with DCM (5 mL. Times.3), and the filter cake was taken and dried in vacuo to yield 990mg of brown solid M2.
Preparation of intermediate compound M3:
step 1: preparation of Compound M3-2
3.00g of compound M3-1 and 1.60g of compound M1-2 were dissolved in 30mL of dioxane, and 243mg of Pd was added 2 (dba) 3 384g Xantphos and 3.40g DIPEA were replaced three times with nitrogen, and the reaction mixture was warmed to 110℃and stirred for 3hrs. TLC was used to check completion of the reaction, the reaction solution was filtered, the filter cake was washed with DCM (30 mL. Times.2), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 4.80g of Compound M3-2.
Step 2: preparation of Compound M3
4.80g of compound M3-2 were dissolved in 50ml of THF, etONa (7.4 mL,20% EtOH) was added dropwise at-30℃and the reaction was stirred at RT for 2hrs. TLC detection of completion of the reaction was complete, concentrated under reduced pressure, 50mL of DCM was added and stirred for 30min, the reaction solution was filtered, the filter cake was washed with DCM (10 mL. Times.2) and dried by suction to give 3.60g of Compound M3.
Preparation of intermediate compound M4:
step 1: preparation of Compound M4-3
300mg of compound M4-1 and 174mg of compound M4-2 were dissolved in 10mL of dioxane, and 4mg of Pd (OAc) was added 2 34mg Xantphos and 300mg DIEA. The reaction was stirred for 12hrs at 85℃under nitrogen blanket with three nitrogen substitutions. TLC was used to check completion of the reaction, the reaction solution was filtered, the filter cake was washed with DCM (10 mL. Times.2), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 266mg of Compound M4-3.
Step 2: preparation of Compound M4
266mg of compound M4-3 was dissolved in 5mL of THF, etONa (0.47 mL,20% EtOH) was added dropwise at-30℃and the reaction was stirred at RT for 3hrs. TLC detection of completion of the reaction was complete, concentration under reduced pressure, stirring for 30mins with 15mL of DCM was added, the reaction solution was filtered, and the filter cake was washed with DCM (20 mL. Times.2) to give 182mg of compound M4 as a solid.
Preparation of intermediate compound M5:
Step 1: preparation of Compound M5-3
Under the protection of nitrogen, 25.00g of compound M5-1 is dissolved in 200mL of DMF, the temperature is reduced to 0 ℃, 22.70g of NaH is added in batches, the temperature is kept at 0 ℃ for 1hr, then 54.96g of compound M5-2 is slowly added into the reaction liquid in a dropwise manner, the reaction is carried out for 1hr at 0 ℃ after the dropwise is finished, and the temperature is increased to 60 ℃ for continuing the reaction for 1hr. The reaction mixture was cooled to 0deg.C, quenched with 500mL of ice water, extracted with EtOAc (500 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography to give 29.00g of brown oil M5-3.
Step 2: preparation of Compound M5-5
29.00g of Compound M5-3 were dissolved in 50mL of Ti (OEt) 4 34.99g of Compound M5-4 was added thereto, followed by heating to 90℃for reaction for 12hrs. TCL detection reaction was complete, the reaction mixture was poured into 500mL of ice water, 300mL of EtOAc was added and stirred for 1hr, extracted with EtOAc (300 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL. Times.4), dried over anhydrous sodium sulfate, and concentrated under reduced pressureConcentration gave 39.00g of crude brown oil M5-5.
Step 3: preparation of Compounds M5-6
48.00g of Compound M5-5 are dissolved in 500mL of anhydrous THF under nitrogen protection, cooled to-20℃and 6.73g of NaHB are slowly added 4 Then naturally warmed to RT and stirred for 2hrs. After the completion of the reaction, the reaction mixture was cooled to 0℃and quenched with 300mL of water, extracted with EtOAc (300 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 25.40g of Compound M5-6 as a brown oil.
Step 4: preparation of Compound M5
10.00g of Compound M5-6 was dissolved in 100mL of DCM solution, 28.04g of TFA solution was added dropwise, and then reacted at RT for 1hr. The reaction mixture was cooled to 0deg.C and quenched with 100mL saturated NaHCO 3 The aqueous solution was quenched, extracted with EtOAc: thf=3:1 (100 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7.64g of a brown solid, crude compound M5, which was used directly in the next reaction.
1 H NMR(500MHz,DMSO-d 6 ):δ7.26-7.16(m,4H),5.50(d,J=10.0Hz,1H),4.30(d,J=10.0Hz,1H),3.04(d,J=16.0Hz,1H),2.87-2.80(m,2H),2.67-2.58(m,3H),1.88-1.82(m,1H),1.59-1.53(m,1H),1.37-1.34(m,1H),1.21(s,9H),1.12-1.09(m,1H)。
Preparation of intermediate compound M6:
step 1: preparation of Compound M6-3
10.00g of compound M6-1 and 19.50g of compound M6-2 were dissolved in 100mL of MeCN and 26.20g K was added 2 CO 3 . The reaction was raised to 90℃and stirred for 3hrs. TLC was used to check completion of the reaction, the reaction solution was filtered, the cake was washed with EtOAc (50 mL. Times.2), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 5.90g of compound M6-3.
Step 2: preparation of Compound M6-4
1.50g of Compound M6-3 was dissolved in 15mL of toluene, and 1.1mL of PBr was added dropwise 3 The reaction mixture was stirred at 105℃for 12hrs. TLC detection was complete, concentrated under reduced pressure, added 15mL of water, adjusted to ph=9 with NaOH solution, extracted with EtOAc (30 ml×3), the combined organic phases dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.50g of compound M6-4.
Step 3: preparation of Compound M6-6
450mg of compound M6-5 was dissolved in 6mL of DMF, 271mg of NaH was added in portions at 0℃under nitrogen protection, and after stirring at 60℃for 1hr, 1.20g of compound M6-4 was added and stirring at 60℃for 1hr. TLC was used to check completion of the reaction, 30mL of water was added to quench the reaction, extraction was performed with EtOAc (25 mL. Times.2) and water (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 160mg of compound M6-6.
Step 4: preparation of Compound M6-7
160mg of Compound M6-6 was dissolved in 2mL of DCE at 0deg.C, 155mg of ACE-Cl was added dropwise and the reaction was stirred at RT for 2hrs. TLC checked for completion, concentrated under reduced pressure, 4mL MeOH was added and the reaction was raised to 80 ℃ and stirred for 3hrs. TLC detection of completion of the reaction, concentration under reduced pressure, addition of 4mL of DCM,242mg (B) OC ) 2 O and 239mg DIEA, RT were stirred for 12hrs. TLC detection reaction is complete, concentration under reduced pressure, and purification of the residue by column chromatography gives 25mg of Compound M6-7.
Step 5: preparation of Compound M6
The procedure for the preparation of compound M6 from compound M6-7 was similar to that from compound M5-3 to compound M5.
Preparation of intermediate compound M7:
step 1: preparation of Compound M7-3
4.00g of compound M7-1 are dissolved in 50mL of anhydrous THF, replaced by nitrogen for three times, cooled to-78 ℃, and LDA is slowly added dropwise into the THF solutionA solution (11.70 mL, 2.0M) was then reacted at-78deg.C for 1hr, and a solution of Compound M7-2 in THF (10 mL) was slowly added dropwise to the above reaction solution, and reacted at-78deg.C for 30mins and slowly warmed to room temperature for 2hrs. TLC detection of completion of reaction was performed with 30mL of saturated NH 4 The reaction was quenched with Cl solution, extracted with 50mL of water, added EtOAc (60 mL. Times.3), the combined organic phases were washed with 50mL of saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 4.30g of M7-3 as a colorless oil.
Step 2: preparation of Compound M7-4
4.30g of Compound M7-3 was dissolved in THF/MeOH (40 mL/40 mL), aqueous NaOH (20 mL, 2.4N) was added and the mixture was heated to 80℃for 18hrs. TLC detection reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was distilled off under reduced pressure, the residue was adjusted to pH 3-4 with concentrated hydrochloric acid, filtered, the cake was washed with water (10 mL. Times.3), and the cake was dried under vacuum to give 3.40g of compound M7-4 as a white solid.
Step 3: preparation of Compound M7-5
3.40g of Compound M7-4 was dissolved in 40ml of LPPA and reacted at 120℃for 2hrs. TLC detection of completion of the reaction was completed, the reaction solution was slowly dropped into 200mL of crushed ice, the pH was adjusted to 9-10 with 2.4N aqueous NaOH solution, and 4.40g (B) OC ) 2 O, RT was stirred for 18hrs. TLC was used to check completion of the reaction, etOAc extraction (100 mL. Times.3) was added, the organic phases were combined, washed with 100mL saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 2.40g of white solid M7-5.
Step 4: preparation of Compound M7
The procedure for the preparation of compound M7 from compound M7-5 was similar to that from compound M5-3 to compound M5.
Preparation of intermediate compound M8:
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step 1: preparation of Compound M8-2
10.00g of Compound M8-1 was dissolved in 100mL of MeOH, 2.0mL of concentrated sulfuric acid was added thereto, and the mixture was heated to 70℃to react 3hrs. After the reaction, the solvent was dried by spin drying, 20mL of water was added, and the mixture was washed with saturated Na 2 CO 3 The aqueous solution was adjusted to ph=9, extracted with etoac (100 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 9.23g of a white solid, compound M8-2.
Step 2: preparation of Compound M8-3
9.23g of Compound M8-2 are dissolved in 150mL of MeOH, cooled to 0℃in an ice bath, and 6.97g of NaHB are added in portions 4 Naturally heating to RT for 5hrs. After the reaction was completed, 20mL of saturated NH was added 4 Cl solution, spin-dry solvent, add EtOAc (100 mL. Times.3) extract, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to give 6.40g of colorless liquid, compound M8-3.
Step 3: preparation of Compound M8-4
3.00g of compound M8-3 is dissolved in 50mL of dichloromethane under the protection of nitrogen, the reaction solution is cooled to-15 ℃, and 2.81mL of NEt is added 3 Then 1.04mL of MsCl solution was added dropwise, and after the completion of the dropwise addition, the temperature was raised to 0℃for reaction for 1hr. After the completion of the reaction, a water layer was added, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 4.05g of Compound M8-4 as a white solid.
Step 4: preparation of Compound M8-6
3.39g of compound M8-5 is dissolved in 20mL of anhydrous THF under the protection of nitrogen, the temperature is reduced to-50 ℃, 1.71g of LDA solution is added dropwise, and the reaction is carried out at-50 ℃ for 1hr after the dropwise addition. 3.00g of a solution of Compound M8-4 in anhydrous THF (10 mL) was added dropwise, and the mixture was allowed to react at RT for 1hr. After the reaction was completed, 50mL of saline solution was added, etOAc (50 mL. Times.3) was extracted, the organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 4.61g of compound M8-6 as a white solid.
Step 5: preparation of Compound M8-7
4.61g of Compound M8-6 were dissolved in 8mL of water and 40mL of MeOH, and 2.07g of NaOH was added. The temperature was raised to 65℃and stirred overnight. After the reaction was completed, 30mL of water was added, the solvent methanol was dried with a screw, the concentrate was adjusted to ph=6 with 2N hydrochloric acid, etoac (50 ml×3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 3.98g of a white solid, namely, compound M8-7.
Step 6: preparation of Compound M8-8
3.98g of compound M8-7 is dissolved in 20mL of anhydrous THF under the protection of nitrogen, the temperature of the reaction solution is reduced to minus 15 ℃, naH (60 percent, 0.42 g) is added in batches, then the reaction is carried out at minus 15 ℃ for 1hr, then the temperature is reduced to minus 60 ℃, n-butyllithium (1.6M, 7.8 mL) is added dropwise, and the reaction is carried out at the temperature for 1hr. After completion of the reaction, 50mL of water was added, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 2.36g of a pale yellow solid, namely, compound M8-8.
Step 7: preparation of Compound M8
The procedure for the preparation of compound M8 from compound M8-8 was similar to that from compound M5-3 to compound M5.
Preparation of intermediate compound M9:
step 1: preparation of Compound M9-3
2.83g of Compound M9-2 are dissolved in 50mL of anhydrous THF under nitrogen, cooled to-78deg.C and LDA (2M, 6 mL) in THF/Hex is added dropwise. The reaction was incubated at-78deg.C for 1hr, then 1.69g of a solution of Compound M9-1 in THF (3 mL) was slowly added dropwise to the reaction solution, and the reaction was carried out at-78deg.C for 1hr after completion of the dropwise addition. The reaction mixture was quenched with 50mL of saturated brine, extracted with EtOAc (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.44g of Compound M9-3 as a pale yellow oil.
Step 2: preparation of Compound M9-4
900mg of Compound M9-3 was dissolved in 50mL of anhydrous THF under nitrogen, and cooled to-78 ℃. A solution of LDA (2M, 3 mL) in THF/Hex was added dropwise. The reaction was incubated at-78deg.C for 1hr. The reaction mixture was quenched with 50mL of saturated brine, extracted with EtOAc (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound M9-4 as a pale yellow solid, 300 mg.
Step 3: preparation of Compound M9
The procedure for the preparation of compound M9 from compound M9-4 was similar to that from compound M5-3 to compound M5.
Intermediate compounds M10-M14 of table 1 were prepared in a similar manner to the previously described intermediates 5-9 via different reaction starting materials and suitable reagents, for example 6-methoxy-1-indanone as starting material for the synthesis of M11.
TABLE 1
Example 1: preparation of the Compound (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one
Step 1: preparation of Compounds 1-2
2.00g of Compound 1-1 was dissolved in 40mL of THF, naOH (30 mL, 1N) was added, and then the reaction was performed at RT for 2hrs. TLC was used to check completion of the reaction, the reaction mixture was poured into 100mL of water, pH was adjusted to 4-5 with 6N HCl, etOAc was added to extract (100 mL. Times.4), the organic phases were combined, washed with 50mL of saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was slurried with N-hexane to give 1.67g of pale yellow solid 1-2.
Step 2: preparation of Compounds 1-3
1.28g of Compound 1-2 was dissolved in 13mL of DMF, cooled to 0deg.C, and 3.26g of Cs was added 2 CO 3 Then 2.13g of CH are added dropwise 3 I, heating to 10 ℃ after dripping, and reacting for 1hr. TLC detection reaction is complete, and the reaction solution is cooled to 0 DEG C20mL of EtOAc and 20mL of water were added, the organic phase was separated, the aqueous phase was continued to be extracted with 20mL of EtOAc, the organic phases were combined, washed with saturated NaCl (5X 4 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 635mg of compound 1-3.
Step 3: preparation of Compounds 1-5
359mg of Compound 1-3 and 448mg of Compound M5 were dissolved in 6mL of DMAc, 860mg of DIPEA was added, the mixture was replaced with nitrogen gas three times, and the mixture was reacted at 120℃for 1hr under microwave conditions. TLC was used to check completion of the reaction, the reaction solution was cooled to room temperature, 20mL of water was added, etOAc (20 mL. Times.3) was added, the organic phases were combined, washed with saturated NaCl (5 mL. Times.4), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 290mg of compound 1-5.
Step 4: preparation of Compounds 1-6
250mg of Compounds 1-5 and 127mg of Compound M1 were dissolved in 8mL of dioxane, and 18mg CuI,22mg TMEDA and 293mg of K were added 3 PO 4 The mixture was reacted by nitrogen displacement three times, heated to 100℃for 48hrs. The reaction was cooled to room temperature, filtered, the filter cake was washed with EtOAc (10 mL. Times.3), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 153mg of compounds 1-6.
Step 5: preparation of Compound 1
29mg of compounds 1-6 were dissolved in 0.5mL EtOAc and 0.5mL MeOH, 0.1mL 2N HCl in MeOH was added and the reaction was allowed to proceed for 2hrs at RT. TLC detection reaction is complete, vacuum concentration, naHCO addition 3 The pH was adjusted to 7-8, extracted with EtOAc (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 11.9mg of Compound 1.
[M+H + ]=469.16。
1 H NMR(500MHz,DMSO-d 6 ):δ8.12(s,1H),7.65(d,J=5.5Hz,1H),7.32-7.31(m,1H),7.20-7.15(m,3H),6.27(s,2H),6.02(d,J=5.5Hz,1H),3.87(s,1H),3.71-3.65(m,2H),3.41(s,3H),3.21-3.11(m,2H),3.04(d,J=15.5Hz,1H),2.63(d,J=15.5Hz,1H),1.92-1.87(m,1H),1.83-1.78(m,1H),1.56-1.54(m,1H),1.17-1.14(m,1H)。
Example 2: preparation of the Compound (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one
Step 1: preparation of Compound 2-1
To a solution of 205mg of Compound M11 and 150mg of Compounds 1-3 in dioxane (2 mL) was added 215mg of DIEA and the mixture was stirred at 60℃for 2hrs. The reaction was distilled off under reduced pressure to remove the organic solvent, and the crude product was isolated and purified by Pre-TLC (PE: etOAc=1:1) to give 180mg of compound 2-1.
[M+H + ]:571.10。
Step 2: preparation of Compound 2-2
To 160mg of Compound 2-1 and 61mg of Compound M1 in DMSO (2 mL) under nitrogen are added 179mg of K 3 PO 4 11mg of CuI and 13mg of TMEDA were replaced with nitrogen three times and stirred at 100℃for 12hrs. The reaction was diluted with 20mL of water, extracted with EtOAc (20 mL. Times.3), the organic phases were combined, washed with saturated NaCl water, dried over anhydrous sodium sulfate and concentrated, and the crude product was isolated and purified by Pre-TLC (DCM: meOH=20:1) to give 70mg of compound 2-2.
[M+H + ]=603.28。
Step 3: preparation of Compound 2
To a solution of 70mg of Compound 2-2 in dioxane (3 mL) was added dropwise a solution of hydrochloric acid in methanol (2M, 0.5 mL) at 0deg.C, and the mixture was stirred at 25deg.C for 1hr. Saturated NaHCO was used as the reaction solution 3 The aqueous solution was adjusted to pH 8-9, the reaction was quenched, extracted with EtOAc: thf=5:1 (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-TLC (DCM: meoh=20:1) followed by Pre-HPLC (basic) to give 12mg of compound 2.
[M+H+]=499.17
1 H NMR(500MHz,DMSO-d6)δ:8.12(s,1H),7.65(d,J=5.5Hz,1H),7.08(d,J=8.0Hz,1H),6.90(d,J=2.5Hz,1H),6.70(dd,J=8.0,2.5Hz,1H),6.27(s,2H),6.02(d,J=5.5Hz,1H),3.82(s,1H),3.73(s,3H),3.70-3.62(m,2H),3.40(s,3H),3.21-3.07(m,2H),2.96(d,J=15.0Hz,1H),2.53(d,J=15.0Hz,1H),1.93-1.87(m,1H),1.82-1.76(m,1H),1.56-1.53(m,1H),1.14-1.12(m,1H)
Example 3: preparation of the Compound (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one
Step 1: preparation of Compound 3-1
To a solution of 150mg of Compound M10 and 208mg of Compounds 1-3 in dioxane (2 mL) was added 215mg of DIEA and the mixture was stirred at 60℃for 2hrs. The reaction was distilled off under reduced pressure to remove the organic solvent, and the crude product was purified by Pre-TLC (PE: etOAc=1:1) to give 200mg of compound 3-1.
[M+H + ]:575.08。
Step 2: preparation of Compound 3-2
200mg of Compound 3-1 and 76.23mg of Compound M1 were dissolved in DMSO (2 mL) under nitrogen, and 221.53mg of K was added 3 PO 4 13.25mg of CuI and 16.17mg of TMEDA were replaced with nitrogen three times and stirred at 100deg.C for 12hrs. The reaction was diluted with 20mL of water, extracted with EtOAc (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was isolated and purified by Pre-TLC (DCM: meoh=20:1) to give 95mg of compound 3-2 as a brown solid.
[M+H + ]=607.21。
Step 3: preparation of Compound 3
To a solution of 95mg of Compound 3-2 in dioxane (3 mL) was added dropwise a solution of hydrochloric acid in methanol (2M, 0.5 mL) at 0deg.C, and the mixture was stirred at 25deg.C for 1hr. Saturated NaHCO was used as the reaction solution 3 The reaction was quenched by adjusting the pH to 8-9 with EA: THF=5:1 (10ml×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by Pre-TLC (DCM: meoh=20:1) followed by Pre-HPLC (basic) to give 11mg of compound 3.
[M+H + ]:503.13。
Compounds 4-14, 24 of Table 2 were prepared in a similar manner to examples 1-3 above, via different reaction starting materials and appropriate reagents.
TABLE 2
The nuclear magnetic data for compounds 6,8,9, 10, 12 and 24 are as follows:
1 H NMR(500MHz,DMSO-d 6 ): delta 8.46 (d, j=4.4 hz, 1H), 8.17 (s, 1H), 7.60 (d, j=8.2 hz, 1H), 7.53 (dd, j=8.2, 4.5hz, 1H), 7.33 (m, 1H), 7.20-7.15 (m, 3H), 3.90 (s, 1H), 3.75-3.60 (m, 2H), 3.39 (s, 3H), 3.22-3.13 (m, 3H), 3.05 (d, j=15.6 hz, 1H), 2.65 (d, j=15.5 hz, 1H), 1.92-1.87 (m, 1H), 1.83-1.79 (m, 1H), 1.57-1.54 (m, 1H), 1.20-1.17 (m, 1H). (Compound 6)
1 H NMR(500MHz,CDCl 3 ): delta 8.11 (s, 1H), 7.72 (d, j=5.5 hz, 1H), 7.39 (d, j=8.0 hz, 1H), 7.27 (d, j=7.5 hz, 1H), 7.13 (t, j=7.5 hz, 1H), 6.14 (d, j=5.5 hz, 1H), 4.85 (s, 2H), 4.08 (s, 1H), 3.67-3.61 (m, 2H), 3.55 (s, 3H), 3.28-3.22 (m, 2H), 3.11 (d, j=16.0 hz, 1H), 2.73 (d, j=16.0 hz, 1H), 2.03-1.97 (m, 1H), 1.93-1.87 (m, 1H), 1.70-1.68 (m, 1H), 1.43-1.40 (m, 1H). (Compound 8)
1 H NMR(500MHz,CDCl 3 ):δ8.10(s,1H),7.74(d,J=5.4Hz,1H),7.60(s,1H) 7.49 (d, j=7.8 hz, 1H), 7.32 (d, j=7.8 hz, 1H), 6.18 (d, j=5.4 hz, 1H), 4.08 (s, 1H), 3.71-3.60 (m, 2H), 3.54 (s, 3H), 3.2-3.17 (m, 2H), 3.13 (d, j=16.0 hz, 1H), 2.76 (d, j=16.0 hz, 1H), 2.03-1.99 (m, 1H), 1.89-1.87 (m, 1H), 1.69-1.67 (m, 1H), 1.38-1.34 (m, 1H). (Compound 9)
1 H NMR(500MHz,CDCl 3 ): delta 8.11 (s, 1H), 7.72 (d, j=5.5 hz, 1H), 7.24 (t, j=8.0 hz, 1H), 6.95 (d, j=7.5 hz, 1H), 6.76 (d, j=8.0 hz, 1H), 6.15 (d, j=5.5 hz, 1H), 4.85 (s, 2H), 4.00 (s, 1H), 3.84 (s, 3H), 3.66-3.61 (m, 2H), 3.54 (s, 3H), 3.28-3.19 (m, 2H), 3.05 (d, j=16.0 hz, 1H), 2.64 (d, j=16.0 hz, 1H), 2.00-1.94 (m, 1H), 1.93-1.88 (m, 1H), 1.69-1.66 (m, 1H), 1.45-1.43 (m, 1H). (Compound 10)
1 H NMR(500MHz,DMSO-d 6 ): delta 8.12 (s, 1H), 7.65 (d, j=5.5 hz, 1H), 6.93 (s, 1H), 6.80 (s, 1H), 6.28 (s, 2H), 6.02 (d, j=5.0 hz, 1H), 3.79 (s, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.68-3.65 (m, 2H), 3.41 (s, 3H), 3.20-3.12 (m, 2H), 2.93 (d, j=15.5 hz, 1H), 2.56 (d, j=15.5 hz, 1H), 1.88-1.79 (m, 2H), 1.54-1.52 (m, 1H), 1.23-1.20 (m, 1H). (Compound 12)
1 H NMR(500MHz,DMSO-d 6 ) Delta 8.12 (s, 1H), 7.52 (d, j=5.3 hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.16 (m, 3H), 6.16 (s, 2H), 6.05 (t, j=5.1 hz, 1H), 3.93 (s, 1H), 3.68-3.64 (m, 2H), 3.40 (s, 3H), 3.20-3.11 (m, 2H), 3.05 (d, j=15.6 hz, 1H), 2.66 (d, j=15.7 hz, 1H), 1.92-1.78 (m, 2H), 1.56-1.53 (m, 1H), 1.21-1.18 (m, 1H), (compound 24)
Example 15: preparation of the Compound (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2, 3-dichlorophenyl) thio) -3-methylpyrimidin-4 (3H) -one
Step 1: preparation of Compound 15-2
1.50g of Compound 15-1 was dissolved in 10mL of anhydrous DMF, 2.36g of NBS was added to the above solution in portions under ice bath, and the reaction was slowly raised to RT for 4hrs. LC-MS detection reaction was complete, the reaction solution was poured into 100mL of water, stirred for 30mins, filtered, the filter cake was washed with water (15 mL. Times.3), and the filter cake was dried to give 1.57g of a white solid 15-2.
Step 2: preparation of Compound 15-4
1.57g of Compound 15-2 and 2.56g of Compound 15-3 were added to 20mL of dioxane, 0.27g CuI,0.33g TMEDA and 4.54. 4.54g K 3 PO 4 The mixture was replaced with nitrogen three times and heated to 100deg.C for 12hrs. The reaction was cooled to room temperature, 50mL of MeOH was added, the filter cake was washed with MeOH (10 mL. Times.5), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 0.50g of a white solid 15-4.
Step 3: preparation of Compound 15-5
200mg of compound 15-4 and 288mg of compound M5 were dissolved in 5mL of DMF, and 832mg BOP,480mg DBU,RT was added thereto and the reaction was stirred for 4hrs. TLC was used to determine completion of the reaction, the reaction mixture was added to 20mL of water, etOAc (20 mL. Times.3) was added to extract, the organic phases were combined, washed with saturated NaCl (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 69mg of compound 15-5.
Step 4: preparation of Compound 15
69mg of compound 15-5 was dissolved in 2mL of MeOH, 0.2mL of 2N HCl in methanol was added and the reaction was allowed to proceed for 2hrs at RT. TLC detection reaction is complete, vacuum concentration, saturated NaHCO addition 3 The aqueous solution was adjusted to pH 7-8, extracted with EtOAc (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 44mg of compound 15.
[M+H + ]:502.10。
1 H NMR(500MHz,DMSO-d 6 ):δ7.35-7.1(m,2H),7.22-7.15(m,4H),6.72-6.70(m,1H),3.89(s,1H),3.57-3.51(m,2H),3.29(s,3H),3.09-2.99(m,2H),2.64(d,J=15.0Hz,1H),2.53(d,J=15.0Hz,1H),1.89-1.86(m,1H),1.81-1.76(m,1H),1.55-1.52(m,1H),1.17-1.14(m,1H)。
Example 16: preparation of the compound (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one:
step 1: preparation of Compound 16-2
0.50g of Compound 16-1 and 1.19g of Compound M5 were dissolved in 15ML of anhydrous N, N-dimethylformamide, 3.13g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 3.78g of DBU were sequentially added under an ice bath, and the reaction was stirred at room temperature for 18 hours. LCMS checked for completion, 25mL of water was added, extracted with DCM (20 ml×3), the organic layers combined, washed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, desolventized and purified by column chromatography (DCM: meoh=95% -92%) to give 0.59g of compound 16-2.
Step 2: preparation of Compound 16-3
Under nitrogen protection, 0.59g of Compound 16-2 was dissolved in 10mL of anhydrous N, N-dimethylformamide, and 0.39. 0.39g N-iodosuccinimide was added to the reaction solution under an ice bath. TLC detection of completion of the reaction was performed by adding 15mL of water, extraction with DCM (20 mL. Times.3) was performed, the organic layers were combined, washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, desolventized, and purified by column chromatography (DCM: meOH=95% -92%) to give 0.42g of compound 16-3.
Step 3: preparation of Compound 16-4
300mg of Compound 16-3 and 198mg of Compound M1 were dissolved in 5mL of 1, 4-dioxane in this order, and 25mg TMEDA,344mg K was added 3 PO 4 And 21mg of CuI, under nitrogen at 95℃for 24hrs. LCMS detected completion of the reaction, the reaction was filtered, concentrated under reduced pressure, and the residue was purified using prep. plates to yield 77mg of compound 16-4 as a white solid.
Step 4: preparation of Compound 16
77mg of compound 16-4 was dissolved in 3mL dioxane, and hydrochloric acid methanol solution (2N, 0.3 mL) was added dropwise, followed by TLC. After the reaction was completed, the solvent was removed under reduced pressure, and after solidification with a small amount of n-hexane, n-hexane was poured off, 2.0mL of water was added to dissolve the solid, and then saturated aqueous sodium bicarbonate solution was added dropwise to adjust ph=9 to 10, whereby a solid was precipitated. After filtration, the filter cake was washed with a small amount of water and dried in vacuo to give 33.6mg of compound 16 as a white solid.
[M+H + ]=484.17。
1 H NMR(500MHz,DMSO-d6)δ7.62(d,J=5.4Hz,1H),7.31(d,J=6.9Hz,1H),7.19-7.13(m,3H),6.15(s,2H),5.97(d,J=5.4Hz,1H),3.86(s,1H),3.56-3.49(m,2H),3.25(s,3H),3.10-2.98(m,3H),2.61(d,J=15.6Hz,1H),1.91-1.81(m,1H),1.82-1.76(m,1H),1.54-1.52(m,1H),1.19-1.12(m,1H)。
Example 17: preparation of compound 17:
step 1: preparation of Compound 17-2
7.30g of Compound 17-1 and 6.77g of Compound M1-2 were dissolved in 100mL of dioxane under nitrogen, and 1.55g of Pd was added 2 (dba) 3 1.95g Xantphos and 14.57g DIEA were reacted at 100℃for 16hrs. TLC detection of completion of the reaction, concentration of the reaction solution, addition of 100mL of ethyl acetate and 50mL of water for separation of an organic phase, further extraction of the aqueous phase with 50mL of ethyl acetate, combination of the organic phases, drying over anhydrous sodium sulfate, concentration under reduced pressure, and beating of the residue 50mL (PE: EA=4:1) to give 8.5g of compound 17-2 as a pale yellow solid, which is used directly in the next step.
Step 2: preparation of Compound 17-3
8.5g of compound 17-2 was dissolved in 30mL of dichloromethane and EtONa (16.27 g,20% EtOH) was added dropwise at RT and the reaction was stirred at RT for 0.5hrs. TLC detection of completion of the reaction was completed, concentration under reduced pressure was performed, 10mL of methylene chloride was added and stirred for 30mins, the reaction solution was filtered, and the cake was washed with methylene chloride (15 mL. Times.2), to give 4g of compound 17-3 as an off-white solid, which was used directly in the next step.
Step 3: preparation of Compound 17-4
44mg of compound 18-2 and 23mg of compound 17-3 were dissolved in 2mL of dioxane under nitrogen, and 5.8mg CuI,7.1mg TMEDA and 48.8mg of K were added 3 PO 4 The temperature was raised to 100℃and the reaction was carried out for 48hrs. TLC detection was complete, concentrated, and the residue was purified by preparative thin layer chromatography to give 8.5mg of white compound 17-4.
Step 3: preparation of Compound 17
8.5mg of Compound 17-4 was dissolved in 1.5mL of dioxane and 0.5mL of MeOH under nitrogen, methanol hydrochloride (2N, 0.3 mL) was added, the reaction was stirred at RT for 1hrs, TLC was complete, and the reaction solution was concentrated under reduced pressure. Residue addition H 2 O (2 mL) was dissolved with saturated NaHCO 3 Adjusting the solution to ph=8, precipitating solids, filtering, and filtering cake with H 2 O (2 mL) was washed, and the filter cake was dried under vacuum to give 2.8mg of compound 17 as an off-white solid.
[M+H + ]=469.25。
1 H NMR(500MHz,DMSO-d 6 )δ7.88(d,J=5.4Hz,1H),7.21-7.18(m,1H),7.10(d,J=9.0Hz,1H),6.97-6.94(m,1H),6.54(s,2H),6.04(d,J=5.4Hz,1H),3.88(s,1H),3.56-3.46(m,2H),3.28(s,3H),3.07-2.93(m,3H),2.63(d,J=15.6Hz,1H),1.92-1.87(m,1H),1.80-1.75(m,1H)1.56-1.51(m,1H),1.14-1.12(m,1H).
Preparation of intermediate compound 18-2:
a method for preparing a synthetic reference compound 16-3 of a compound 18-2.
Preparation of intermediate compound 19-6:
step 1: preparation of Compound 19-3
33.00g of Compound 19-1 was dissolved in 400mL of anhydrous THF, replaced with nitrogen three times, cooled to-78deg.C, and LDA in THF (64.00 mL, 2.0M) was slowly added dropwise, followed by reaction at-78deg.C for 1hr, and 19-2 in THF (50 mL) was slowly added dropwise to the above reaction solution, followed by reaction at-78deg.C for 30mins, and slowly warmed to room temperature for 18hrs. TLC was used to check completion of the reaction, the reaction was quenched with 200mL of saturated NH4C1 solution, 150mL of water was added, etOAc was added to extract (200 mL. Times.3), the organic phases were combined, washed with 200mL of saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 34.31g of colorless oil 19-3.
Step 2: preparation of Compound 19-4
34.31g of compound 19-3 was dissolved in dioxane/MeOH (400 mL/160 mL), aqueous NaOH (80 mL, 6N) was added, and the mixture was heated to 100deg.C for 18hrs. TLC detection reaction was complete, the reaction solution was cooled to room temperature, the organic solvent was distilled off under reduced pressure, the residue was adjusted to pH 3-4 with concentrated hydrochloric acid, filtered, the cake was washed with water (80 mL. Times.3), and the cake was dried under vacuum to give 28.00g of compound 19-4 as a white solid.
Step 3: preparation of Compound 19-5
28.00g of compound 19-4 was dissolved in 200mL PPA and heated to 120℃for 0.5hrs. TLC was used to check completion of the reaction, the reaction mixture was slowly added dropwise to 400mL of crushed ice, the pH was adjusted to 9-10 with 2.4N aqueous NaOH solution, and 23.30g (Boc) was added 2 O, RT was stirred for 1hrs. TLC was used to check completion of the reaction, etOAc extraction (150 mL. Times.3) was added, the organic phases were combined, washed with 200mL saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 8.50g of a white solid 19-5 and 900mg of a white solid 20-1.
Step 4: preparation of Compound 19-6
The procedure for the preparation of compound 19-6 from compound 19-5 was similar to that from compound M5-3 to compound M5.
The procedure for the preparation of compound 20-2 from compound 20-1 is similar to that from compound M5-3 to compound M5
Compound 18-compound 20, compound 25-compound 27 in table 4 were prepared by a similar method to that of example 16 described previously, via different reaction starting materials and appropriate reagents.
TABLE 4 Table 4
The nuclear magnetic data of compound 18-20 and compound 25-27 are as follows:
1 h NMR (500 MHz, DMSO-d 6) delta 7.62 (d, J=5.4 Hz, 1H), 7.22-7.19 (m, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.99-6.95 (m, 1H), 6.15 (s, 2H), 5.97 (d, J=5.4 Hz, 1H), 3.91 (s, 1H), 3.57-3.50 (m, 2H), 3.28 (s, 3H), 3.03-2.97 (m, 3H), 2.60 (d, J=15.6 Hz, 1H), 1.92-1.88 (m, 1H), 1.80-1.76 (m 1H), 1.56-1.54 (m, 1H), 1.16-1.14 (m, 1H), (Compound 18)
1 H NMR (500 MHz, DMSO-d 6) delta 7.62 (d, J=5.4 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.02-6.96 (m, 2H), 6.15 (s, 2H), 5.97 (d, J=5.4 Hz, 1H), 3.82 (s, 1H), 3.55-3.49 (m, 2H), 3.28 (s, 3H), 3.06-2.97 (m, 3H), 2.61 (d, J=16.1 Hz, 1H), 1.89-1.83 (m, 1H), 1.81-1.76 (m, 1H), 1.55-1.52 (m, 1H), 1.16-1.13 (m, 1H), (Compound 19)
1 H NMR (500 MHz, DMSO-d 6) delta 7.63 (d, J=5.2 Hz, 1H), 7.22 (d, J=7.0 Hz, 1H), 7.05-7.03 (m, 1H), 6.96-6.93 (m, 1H), 6.16 (s, 2H), 5.97 (d, J=5.2 Hz, 1H), 4.08 (s, 1H), 3.49-3.39 (m, 2H), 3.28 (s, 3H), 3.19-3.08 (m, 3H), 2.76 (d, J=16.0 Hz, 1H), 2.02-1.90 (m, 2H), 1.62-1.59 (m, 1H), 1.44-1.41 (m, 1H), (Compound 20)
1 H NMR (500 MHz, DMSO-d 6) delta 7.62 (d, J=5.4 Hz, 1H), 7.08-7.02 (m, 2H), 5.97 (d, J=5.4 Hz, 1H), 4.10 (s, 1H), 3.51-3.38 (m, 2H), 3.28 (s, 3H), 3.20-3.12 (m, 2H), 2.94 (d, J=15.6 Hz, 1H), 2.80 (d, J=15.6 Hz, 1H), 2.03-1.88 (m, 1H), 1.62-1.57 (m, 1H), 1.47-1.44 (m, 1H), 1.24-1.19 (m, 1H), (Compound 25)
1 H NMR(500MHz,DMSO-d6)δ7.62(d,J=5.3Hz,1H),7.33(s,1H),7.21-7.17(m,2H),6.14(s,2H),5.97(d,J=5.3Hz,1H),3.87(s,1H),3.56-3.49(m,2H),3.28(s,3H),3.06-2.96(m, 3H), 2.58 (d, j=15.7hz, 1H), 1.92-1.87 (m, 1H), 1.79-1.74 (m, 1H), 1.56-1.53 (m, 1H), 1.12-1.09 (m, 1H), (compound 26)
1 H NMR(500MHz,DMSO-d 6 ) Delta 7.88 (d, j=5.2 hz, 1H), 7.32 (d, j=6.9 hz, 1H), 7.19-7.13 (m, 3H), 6.53 (s, 2H), 6.05 (d, j=5.3 hz, 1H), 3.87 (s, 1H), 3.55-3.51 (m, 2H), 3.29 (s, 3H), 3.09-2.96 (m, 3H), 2.61 (d, j=15.7 hz, 1H), 1.91-1.86 (m, 1H), 1.81-1.76 (m, 1H), 1.54-1.52 (m, 1H), 1.16-1.13 (m, 1H), (compound 27)
Comparative example
The following control was prepared according to the method described in EXAMPLE 48 of WO 2018172984.
Pharmacological test
Example a: SHP2 allosteric inhibition enzyme activity assay
SHP2 is allosterically activated by binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH 2) domain. This subsequent activation step results in release of the auto-inhibitory interface of SHP2, which in turn activates the SHP2 Protein Tyrosine Phosphatase (PTP) and is useful for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored in a rapid fluorometric format using the surrogate difmeup.
The test steps are as follows:
(1) Compound preparation:
the final test concentrations of the compounds of the invention (10 mM stock solution) were 10. Mu.M, 3.3333. Mu.M, 1.1111. Mu.M, 0.3704. Mu.M, 0.1235. Mu.M, 0.0412. Mu.M, 0.0137. Mu.M, 0.0046. Mu.M, 0.0015. Mu.M, 0.00. Mu.M, diluted with 100% DMSO to appropriate fold;
(2) Preparing an enzyme reaction working solution:
phosphatase enzyme activity assays were performed in 96-well black polystyrene plates (flat bottom, low flange, non-binding surface) (PE, cat# 6005270) at room temperature using 50 μl of final reaction volume and the following assay buffer conditions: 60mM HEPES,75mM NaCl,75mM KCl,0.05%BRIJ-35,1mM EDTA,5mM DTT.
(3) Enzyme-catalyzed reaction and data monitoring:
mu.L of the compound of the present invention was added to the corresponding 96-well plate, and a blank test well was prepared without adding the compound and with adding only the buffer to the enzyme. SHP2 Activating Peptide (irs1_py1172 (dPEG 8) pY 1222) was thawed on ice, 25uM was added to each well, and then 0.2ng of SHP2 protein sample was added to the corresponding well plate and incubated for 1 hour at room temperature. Addition of alternative substrate DiFMUP (Invitrogen, cat#D6567) the reaction was added and after 2 hours at room temperature. Fluorescence signals were monitored using an enzyme-labeled instrument (Envision, perki Elmer) using excitation and emission wavelengths of 340nm and 450nm, respectively.
(4) Data analysis:
the calculation formula is as follows:
inhibition% _sample -Conversion _min )/(Conversion _max -Conversion _min )]×100%
Wherein: conversion_sample is the Conversion reading of the sample; convertion_min is a blank Kong Junzhi, representing a Conversion reading without enzyme wells; convertion_max is the mean of positive control Kong Bizhi, representing the Conversion reading without compound inhibition wells. Log (inhibitor) vs. response-Variable slope fit response curve using analytical software GraphPad Prism and calculating the IC of the compound for enzyme activity 50 Values.
IC of some embodiments 50 The data are shown in table 3.
TABLE 3 Table 3
The compounds of the invention have allosteric inhibition on SHP2 phosphatase.
Example B: cell proliferation assay
The effect of the compounds of the present invention on proliferation of KYSE-520 cells and MV-4-11 cells, which are lung squamous carcinoma cells, was evaluated using an in vitro cell assay. The detection method used in the assay was CELL TITER-GLO (CTG) luminescence, which allows the number of living cells to be detected by quantitative determination of ATP. Because ATP participates in various enzymatic reactions in living organisms and is an index of metabolism of living cells, the content of ATP directly reflects the quantity and the state of the cells, cellTiter-GloTM reagent is added into a cell culture medium in the experimental process, and the luminescence value is measured and is directly proportional to the quantity of ATP, and the ATP is directly related to the quantity of living cells, so that the activity of the cells can be examined by detecting the content of ATP.
The test steps are as follows:
(1) Cell plating:
taking a bottle of KYSE-520 cells in logarithmic phase, digesting and re-suspending the cells, counting, adjusting cell density, inoculating into 96-well plate, inoculating 1000 cells into each well, placing the well plate into 37 ℃ and 5% CO 2 After 24hrs in the incubator of (2) the compound of the present invention was added for treatment;
taking a bottle of MV-4-11 cells in logarithmic growth phase, counting after digesting and re-suspending the cells, adjusting the cell density, inoculating into 96-well plates, inoculating 4000 cells into each well, placing the well plates at 37 ℃ and 5% CO 2 After 24hrs of incubation in an incubator, the compounds of the invention were added for treatment.
(2) Treatment with a cell compound:
a proper amount of the compound is prepared for cell treatment, the final concentration of the compound is 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, 0.1524nM and 0nM in sequence from top to bottom, the orifice plate is placed in 37 ℃ and 5% CO 2 The incubator was incubated for 120hrs. The cell holes which are only added with the culture medium and not added with the culture medium are set as zeroing groups; the compound concentration of 0nM group is blank group.
(3) CTG detection:
after 120hrs of cell culture 50. Mu.L of each well was addedLuminescent Cell Viability Assand (3) the ay solution is gently shaken for 2mins, incubation is continued for 10mins at room temperature, and detection values of all the holes are read on a multifunctional enzyme-labeled instrument.
(4) Data analysis:
the inhibition rate is calculated from the luminescence value readings,
inhibition% = (1- (dosing-zeroing)/(blank-zeroing) ×100
Log (inhibitor) vs. response-Variable slope of GraphPad Prism fit efficacy curves and calculate IC for compounds that inhibit cell proliferation 50 . The experimental data for some of the example compounds are shown in table 5.
TABLE 5
The compound has good inhibition effect on proliferation of KYSE-520 cells and proliferation of MV-4-11 cells. Example C: inhibition assay of hERG Potassium ion channel
The blocking effect of the test compound on the hERG channel is detected by adopting a whole-cell patch clamp technology.
Cell culture
HEK293 cell line with stable expression of hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 at 37℃and carbon dioxide concentration of 5%.
Cell passage: the old medium was removed and washed once with PBS, then 1mL of TrypLE was added TM Express solution, incubated at 37℃for 0.5 min. When the cells were detached from the bottom of the dish, 5mL of complete medium, pre-warmed at 37℃was added. The cell suspension was gently swirled with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 5 minutes to collect the cells. Cells were seeded in 6 cm cell culture dishes, each with an amount of 2.5 x 105cells (final volume: 5 mL).
To maintain the cell's electrophysiological activity, the cell density must not exceed 80%.
Patch clamp detection, realTrypLE for pre-assay cells TM Express separation, 3 x 103 cells were plated onto coverslips, incubated in 24 well plates (final volume: 500 μl), and after 18 hours, experimental assays were performed.
Intracellular and extracellular fluids
Extracellular fluid: 140mM NaCl,3.5mM KCl,1mM MgCl 2 ·6H 2 O,2mM CaCl 2 10mM D-glucose, 10mM HEPES,1.25mM NaH 2 PO 4 NaOH adjusts ph=7.4.
Intracellular fluid: 20mM KCl,115mM K-Aspartic,1mM MgCl 2 ·6H 2 O,5mM EGTA,10mM HEPES,2mM Na 2 ATP, KOH adjusts ph=7.2.
Preparation of the Compounds
The stock solution of the compound to be tested is diluted with extracellular fluid to prepare 10 mu M working solution or is diluted in a gradient manner to 0.3 mu M,1 mu M,3 mu M,10 mu M and 30 mu M solution.
The solubility of the test compound was visually examined, and the test compound was completely dissolved without macroscopic precipitation.
Cisapride (positive control)
A10 mM stock solution was prepared from the weighed 1.2mg of cisapride using 243. Mu.L of DMSO.
Cisapride stock was diluted sequentially with DMSO at 10 fold dilutions from high to low to 10 μm dilution.
10nM working solution was prepared by diluting 10. Mu.M cisapride with extracellular fluid.
The solubility of cisapride was visually examined, and cisapride was completely dissolved without macroscopic precipitation.
The experimental method is as follows:
the voltage stimulation protocol for whole cell patch clamp recording whole cell hERG potassium current is as follows: the cell membrane voltage was clamped at-80 mV after the whole cell seal was formed. The clamp voltage is divided from-80 mV to-50 mV for 0.5 seconds, then is stepped to 30mV for 2.5 seconds, and then is quickly restored to-50 mV for 4 seconds, so that the tail current of the hERG channel can be excited. Data were collected repeatedly every 10 seconds and the effect of the drug on hERG tail current was observed. Leakage current was measured at-50 mV stimulation for 0.5 seconds. Experimental data was collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
The capillary glass tube was drawn into a recording electrode using a microelectrode drawing instrument. And operating the microelectrode operator under an inverted microscope to contact the recording electrode on the cell, and giving negative pressure suction to form the GΩ seal. After forming G omega sealing, carrying out rapid capacitance compensation, then continuing to give negative pressure, sucking and breaking cell membranes, and forming a whole cell recording mode. Then compensating the slow capacitance and recording the film capacitance and the series resistance. No leakage compensation is given.
Administration was started after hERG current recorded by whole cells stabilized, and each drug concentration was applied for 5 minutes (or current to steady). The coverslip with cells laid thereon was placed in a recording bath in an inverted microscope, and the test compound and the external liquid containing no compound were sequentially flowed through the recording bath by gravity perfusion to act on the cells, and liquid exchange was performed in the recording using a vacuum pump. The current detected by each cell in the compound-free external fluid served as its own control. Multiple cells were independently and repeatedly tested. All electrophysiological experiments were performed at room temperature.
Data quality standard
The following criteria are used to determine whether the data is acceptable:
(1) Series resistance is less than or equal to 20MΩ
(2) The sealing resistance is more than or equal to 1G omega
(3) The peak value of the initial tail current is more than or equal to 400pA
(4) The peak value of the initial tail current is larger than that of the activation current
(5) There was no significant spontaneous decay in tail current (spontaneous decay less than 5% in 5 minutes)
(6) No obvious leakage current (leakage current is less than or equal to 100 pA) at film potential of-80 mV
Data analysis
The current after each drug concentration was first normalized to the current for the blankThen calculating the inhibition rate corresponding to each drug concentration>
Average and standard errors were calculated for each concentration and the semi-inhibitory concentration for each compound was calculated using the following equation:
a non-linear fit was made to the dose-dependent effect using the equation above, where c represents drug concentration, IC50 is half-inhibitory concentration, and h represents the hill coefficient. Curve fitting and IC 50 Is done using IGOR software.
Results of the hERG test for the compounds of the examples are shown in table 6.
TABLE 6
Numbering device | Inhibition ratio @ 10. Mu.M | IC 50 |
Comparative example | 95.12% | 1.94μM |
Compound 1 | 73.30% | 5μM |
Compound 2 | 65.08% | 6.9μM |
Compound 3 | 84.54% | / |
Compound 5 | 99.87% | / |
Compound 9 | 36.41% | / |
Compound 10 | 48.50% | / |
Compound 11 | 20.53% | / |
Compound 13 | 42.63% | / |
Compound 15 | 88.92% | / |
Compound 16 | 25.53% | >30μM |
Compound 24 | 54.50% | 13.6μM |
Note that: "/" indicates no test.
Unexpectedly, it has been found that the compounds of the invention, while generally having better inhibitory activity against SHP2, are useful in the treatment of the general formula I, A 3 Where N is a position other than C, for example, in embodiments of the invention, compound 1, compound 2, compound 3, compound 9, compound 10, compound 11, compound 13, compound 16, compound 24 have a significant improvement in hERG.
While the present invention has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such variations and modifications are intended to be included within the scope of the appended claims.
Claims (20)
1. A compound shown in a formula I, or pharmaceutically acceptable salts and tautomers thereof,
wherein,
R 1 selected from C 1-8 An alkyl group;
R 2 selected from hydrogen;
R 3 selected from hydrogen or amino;
R 4 selected from hydrogen;
A 1 selected from CR 5 ;
A 2 Selected from CR 6 ;
A 3 Selected from N;
u is selected from C (R) 8 ) 2 ;
R 5 、R 6 Independently selected from halogen, amino, C 1-8 Alkyl, C 1-8 Alkoxy, halogen substituted C 1-8 An alkyl group;
R 8 selected from hydrogen;
ring A is selected from phenyl,
Rx is selected from hydrogen, halogen, amino, C 1-8 Alkyl, halogen substituted C 1-8 Alkyl or C 1-8 An alkoxy group;
n is 0, 1, 2 or 3.
2. A compound according to claim 1, wherein R 1 Selected from C 1-3 An alkyl group.
3. A compound according to claim 1, wherein R 1 Is methyl.
4. A compound according to claim 1, wherein a 1 Selected from CR 5 Wherein R is 5 Selected from halogen or halogen substituted C 1-3 An alkyl group.
5. A compound according to claim 1, wherein a 1 Selected from CR 5 Wherein R is 5 Selected from F, cl or trifluoromethyl.
6. A compound according to claim 1, wherein a 1 Selected from CR 5 Wherein R is 5 Selected from Cl or trifluoromethyl.
7. A compound according to claim 1, wherein a 2 Selected from CR 6 Wherein R is 6 Selected from amino or C 1-3 An alkoxy group.
8. A compound according to claim 1, wherein a 2 Selected from CR 6 Wherein R is 6 Selected from amino or methoxy.
9. A compound according to claim 1, wherein,selected from->
10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer thereof, wherein the compound has the structure of formula II,
wherein,
R 1 selected from C 1-8 An alkyl group;
R 2 selected from hydrogen;
R 3 selected from H or amino;
R 4 selected from hydrogen;
A 1 selected from CR 5 ;
A 2 Selected from CR 6 ;
U is selected from C (R) 8 ) 2 ;
R 5 、R 6 Independently selected from NH 2 Halogen, C 1-8 Alkyl, halogen substituted C 1-8 An alkyl group;
R 8 selected from hydrogen;
ring a is selected from phenyl.
11. The compound of claim 10, wherein R 1 Is methyl.
12. The compound of claim 10, wherein R 5 Selected from Cl.
13. The compound of claim 10, wherein R 6 Selected from NH 2 。
14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(2) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(3) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(4) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((3-chloro-2-methoxypyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(8) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4-bromo-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(9) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6- (trifluoromethyl) -1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(10) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4-methoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(11) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(12) (S) -5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-5, 6-dimethoxy-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(13) (S) -2- (4-amino-2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(14) (S) -2- (5-amino-2-methoxy-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(16) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(17) (S) -6-amino-2- (1-amino-6-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- ((2-aminopyrimidin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(18) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(19) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-5-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(20) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-7-fluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(24) (S) -2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-amino-3-fluoropyridin-4-yl) thio) -3-methylpyridin-4 (3H) -one;
(25) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-4, 7-difluoro-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one;
(26) (S) -6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -2- (1-amino-6-chloro-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methylpyridin-4 (3H) -one; or (b)
(27) (S) -6-amino-2- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- ((2-aminopyrimidin-4-yl) thio) -3-methylpyridin-4 (3H) -one.
15. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1-14 and at least one pharmaceutically acceptable excipient.
16. The pharmaceutical composition according to claim 15, wherein the mass percentage of the compound and pharmaceutically acceptable excipients is 0.0001:1-10.
17. Use of a compound according to any one of claims 1-14 or a pharmaceutical composition according to claim 15 or 16 for the manufacture of a medicament for the treatment of SHP2 mediated diseases.
18. The use according to claim 17, wherein the disease is cancer.
19. The use according to claim 18, wherein the cancer is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, stomach cancer, pancreatic cancer, or a combination thereof.
20. The use according to claim 17, wherein the medicament is for use as an inhibitor of SHP 2.
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US11426422B2 (en) * | 2018-01-30 | 2022-08-30 | Research Development Foundation | SHP2 inhibitors and methods of use thereof |
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2020
- 2020-01-17 CN CN202080008741.8A patent/CN113316574B/en active Active
- 2020-01-17 WO PCT/CN2020/072773 patent/WO2020156242A1/en active Application Filing
- 2020-01-22 TW TW109102505A patent/TW202214589A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107787323A (en) * | 2015-06-19 | 2018-03-09 | 诺华股份有限公司 | For suppressing the compound and composition of SHP2 activity |
WO2018172984A1 (en) * | 2017-03-23 | 2018-09-27 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
WO2019183367A1 (en) * | 2018-03-21 | 2019-09-26 | Relay Therapeutics, Inc. | Shp2 phosphatase inhibitors and methods of use thereof |
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TW202214589A (en) | 2022-04-16 |
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