CN115721648A - Novel heterocyclic derivatives useful as SHP2 inhibitors - Google Patents
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Abstract
The present invention relates to compounds useful as SHP2 inhibitionNovel heterocyclic derivatives of the agent, in particular to a compound shown in a structural formula I or pharmaceutically acceptable salts thereof, and further relates to application of the compound shown in the structural formula I or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof in preparing medicaments, in particular to application in preparing medicaments for treating, preventing or preventing diseases or discomfort mediated by SHP2 activity.
Description
The application is a divisional application of an invention patent application with the application date of 2018, 5 and 9 months and the application number of 202011087795.6 and the invention name of 'novel heterocyclic derivative capable of being used as SHP2 inhibitor'.
Technical Field
The present invention relates to certain novel pyrazine derivatives (as represented by structural formula I, II, III or IV) that are useful as SHP2 inhibitors, their synthesis, and their use for the treatment of SHP 2-mediated disorders. More particularly, the present invention relates to fused heterocyclic derivatives useful as SHP2 inhibitors, methods of preparing such compounds, and methods of treating SHP2 mediated diseases.
Background
SHP2 (Src homology-2 protein tyrosine phosphatase), a non-receptor protein tyrosine phosphatase encoded by ptpn11 gene, comprises a conserved tyrosine phosphatase domain, two N-terminal Src homology 2 (SH 2) domains, and a C-terminal tail. The two SH2 domains determine the subcellular localization and functional regulation of SHP 2. In the inactive state, the N-terminal SH2 domain blocks PTP domain binding and inactivates it. When the SH2 domain binds to a specific tyrosine residue on the receptor or on a receptor-associated linker protein, the PTP domain is released and the autoamtic inhibition is released. Activation of SHP2, for example, by stimulation with cytokines and growth factors results in exposure of catalytic sites, resulting in enzymatic activation of SHP 2.
SHP2 is widely expressed and is involved in multiple cell signaling processes, such as Ras-Erk, PI3K-Akt, jak-Stat, met, FGFR, EGFR, and insulin receptor and NF-kB pathways, and plays an important role in cell proliferation, differentiation, cell cycle and migration.
Catalytically active hyperactivation of SHP2 caused by germline or somatic mutations has been found in Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, myelodysplastic syndrome, B precursor acute lymphocytic leukemia and acute myelogenous leukemia. In addition, activating mutations of PTPN11 are also found in solid tumors, such as lung cancer, colon cancer, melanoma, neuroblastoma, and liver cancer. Thus, SHP2 or up-regulated SHP2 protein activated in human tumors or other diseases is a new therapeutic target. The compounds of the present invention satisfy the need for small molecule inhibitors of SHP 2.
Disclosure of Invention
The present invention relates to heterocyclic pyrazine compounds which are inhibitors of SHP2 useful in the treatment of diseases mediated by SHP 2. The invention firstly provides a compound with a general formula shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein:
each R 1 Are each independently selected from-H, halogen, -NH 2 CN, -substituted or unsubstituted-C 1-6 Alkoxy, or substituted or unsubstituted-C 1-6 An alkyl group;
R 2 selected from-H, halogen, -NH 2 、-CN、-OH、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 Substituted or unsubstituted-C 1-6 Alkoxy, substituted or unsubstituted-C 1-6 Alkyl or-C 5-10 Heterocyclic ringsA group; or
R 2 To adjacent R 1 Are linked together with the carbon atom to which they are each attached to form a 6-10 membered aromatic ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, and each ring system independently may be optionally unsubstituted or substituted with 1,2 or 3 halogens, -NH 2 、-CN、-C 1-6 Alkyl or-CO-C 1-6 Alkyl substitution;
each Y 1 Independently selected from N or CH;
R 3 is selected from-H or-NH 2 ；
Each R 4a And R 4b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-6 An alkyl group; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached form CO, C = NH, or C = N-OH;
p is 0, 1,2 or 3;
each R 5a And R 5b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-6 An alkyl group; or
R 5a And R 5b Together with the carbon atom to which they are both attached, form a 3-5 membered heterocyclyl or C = NH;
q is 0, 1,2,3 or 4;
w is absent, O, S or NR w (ii) a And R is w is-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-6 alkyl-O-C 1-6 Alkoxy, substituted or unsubstituted-C 1-6 Alkoxy, or substituted or unsubstituted-C 1-6 An alkyl group;
ring A is absent or is a 3-10 membered ring;
when ring A is absent, Y 2 Is CR 2a R 2b 、NR 2a Or O, and Y 3 Is CR 3a R 3b 、NR 3a Or O;
when ring A is a 3-to 10-membered ring:
i) When in use
When represents a single bond, Y 2 Is CR 2a Or N, and Y 3 Is CH or N; or
ii) when
When representing a double bond, Y 2 Is C, and Y 3 Is C;
each R 2a 、R 2b 、R 3a And R 3b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, substituted or unsubstituted-C 1-6 Alkoxy, or substituted or unsubstituted-C 1-6 An alkyl group;
each R 6 Independently selected from-H, halogen, -NR 6a R 6b 、-CN、-OH、-NO 2 Oxo group, = O, carboxy group, -C 1-6 Alkoxy, -C 1-6 Alkyl, -C 1-6 alkenyl-NR 6a R 6b 、-C 1-6 alkenyl-O-C 1-6 Alkyl, -C 1-6 Alkenyl, -CO-OR 6a 、-C 1-6 alkenyl-C 3-10 Heterocyclyl radical, -C 1-6 alkenyl-C 5-10 Heteroaryl, -C 1-6 alkenyl-CO-NR 6a R 6b 、-C 1-6 alkenyl-NR 6a -CO-NR 6a R 6b 、-C 1-6 alkenyl-NR 6a -CO-C 1-6 Alkyl, -CO-NR 6a R 6b 、-CO-CO-NR 6a R 6b 、-C 3-10 Carbocyclyl, -C 3-10 Heterocyclyl, -CO-C 1-6 Alkyl, -CO-C 1-6 alkenyl-NR 6a R 6b 、-CO-NR 6a -C 3-10 heterocyclyl-CO-NR 6a -C 3-10 Heterocyclyl, -CO-C 3-10 Heterocyclyl, -O-C 1-6 alkenyl-CO-OR 6a 、-O-C 1-6 alkenyl-CO-NR 6a R 6b 、-O-C 1-6 alkenyl-NR 6a R 6b 、-O-C 3-10 Carbocyclyl, -O-C 3-10 Heterocyclyl radical, -NR 6a -CO-C 1-6 Alkyl, -NR 6a -CO-NR 6a R 6b 、-NR 6a -CO-C 5-10 Heteroaryl, -NR 6a -C 1-6 olefin-NR 6a R 6b 、-NR 6a -C 1-6 olefin-C 3-10 Heterocyclyl radical, -NR 6a -C 1-6 olefin-C 5-10 Heteroaryl, -NR 6a -SO 2 C 1-6 Alkyl, -S-C 1-6 Alkyl, -SONR 6a R 6b 、-SO 2 NR 6a R 6b 、-SO-C 1-6 Alkyl, -SO 2 C 1-6 Alkyl, -PO (C) 1-6 Alkyl radical) 2 、-PO(C 1-6 Alkoxy group) 2 、-C 3-10 Heterocyclyl or-C 5-10 A heteroaryl group; each R 6 Each independently optionally substituted or unsubstituted with 1,2 or 3 substituents; and n is 0, 1,2,3,4, 5 or 6; or
Two adjacent R 6 Are linked together and form together with the carbon atom to which they are respectively attached a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, C 3-6 Heterocyclyl or C 3-6 Carbocyclyl, and each ring system independently is optionally substituted or unsubstituted with one or more substituents;
each R 6a And R 6b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, substituted or unsubstituted-C 1-6 Alkoxy, or substituted or unsubstituted-C 1-6 An alkyl group.
The invention further provides some preferred technical schemes for the compound shown in the structural formula I.
A compound of the general formula (I) or a pharmaceutically acceptable salt thereof, 2. Each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -C 1-6 An alkyl group; -C 1-6 An alkoxy group; by 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkyl group; or is covered1.2 or 3 halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; a methyl group; an ethyl group; propyl; an isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; by 1,2 or 3-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C 1-3 An alkyl group; or by 1,2 or 3 of-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 C substituted by carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy 1-3 An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 (ii) a -CN; -OH; a methyl group; an ethyl group; propyl; an isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; or methyl substituted with 1,2 or 3 substituents, and each substituent is independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R 2 Is selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 ；-N 3 (ii) a A carboxyl group; -C 1-3 An alkyl group; -C 1-3 An alkoxy group; -NHC 1-3 An alkyl group; -N (C) 1-3 Alkyl radical) 2 ；-CONH 2 ；-CONHC 1-3 An alkyl group; -CON (C) 1-3 Alkyl radical) 2 ；-COC 1-3 An alkyl group; -NHCOC 1-3 An alkyl group; -N (C) 1-3 Alkyl) -CO-C 1-3 An alkyl group; -C 5-10 A heterocyclic group; is substituted by 1,2 or 3 groups selected from-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkyl group; or by 1,2 or 3 groups selected from-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R 2 Is selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 ；-N 3 (ii) a A carboxyl group; a methyl group; an ethyl group; propyl; an isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; -NHCH 3 ；-N(CH 3 ) 2 ；-CONH 2 ；-CONHCH 3 ；-CON(CH 3 ) 2 ；-COCH 3 ；-NH-COCH 3 ；-N(CH 3 )-COCH 3 ；
Or methyl or ethyl by 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 -CN or-OH.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R 2 R adjacent thereto 1 Are linked and taken together with the carbon atom to which they are each linked to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each of said heteroaryl or heterocyclyl groups contains 1 or 2 heteroatoms selected from N or O; and each said ring system is independently optionally substituted by-F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, -CONH 2 Substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl, -C 1-3 alkenyl-O-C 1-3 Alkyl, -C 1-3 alkenyl-COOH, -C 1-3 alkenyl-NHCONH 2 、-CO-N(C 1-3 Alkyl radical) 2 、-C 1-3 alkenyl-NHCO-C 1-3 Alkyl, -CO-CO-N (C) 1-3 Alkyl radical) 2 、-CO-C 1-3 Alkyl, -SONH 2 、-SO 2 NH 2 、-SOCH 3 or-SO 2 CH 3 Substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R 2 R adjacent thereto 1 Are linked and taken together with their respective linking carbon atoms to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each of said heteroaryl or heterocyclyl groups contains 1 heteroatom selected from N or O; and each ring system may be independently optionally substituted by-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, -CONH 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH 2 OCH 3 、-CH 2 COOH、-CH 2 NHCONH 2 、-CON(CH 3 ) 2 、-CH 2 NHCOCH 3 、-CO-CON(CH 3 ) 2 or-COCH 3 Substituted or unsubstituted.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 R adjacent thereto 1 Are linked and form together with the carbon atoms to which they are respectively linked
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 4a And R 4b Are independently selected from-H, -F, -Cl, -Br, -I and-NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-3 An alkyl group; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached form C = O, C = NH or C = N-OH.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 4a And R 4b Are all independently selected from-H, -NH 2 -OH, methyl, ethyl, methoxy or ethoxy; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached, form C = O.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 5a And R 5b Are each independently selected from-H; -F; -Cl; -Br; -I; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -C 1-3 An alkyl group; -C 1-3 An alkoxy group; is substituted by-F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkyl group; or by-F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkoxy group; or
R 5a And R 5b Together with the carbon atom to which they are commonly attached form C = NH, a 3-membered heterocyclyl group, a 4-membered heterocyclyl group, or a 5-membered heterocyclyl group; and each of said heterocyclyl groups independently optionally includes 1 or 2 heteroatoms selected from N or O; and each ring system may be independently optionally substituted by-H, -F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkoxy or-C 1-3 Alkyl is substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 5a Or R 5b Are all independently selected from-H, -NH 2 -OH, methyl, ethyl, methoxy or ethoxy; or
R 5a And R 5b Together with the carbon atom to which they are commonly attached, form C = NH, a 3-membered heterocyclic group, a 4-membered heterocyclic group, or a 5-membered heterocyclic group; and each of said heterocyclyl groups contains 1 heteroatom selected from N or O.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, W is NR w And R is w Selected from-H, -F, -Cl, -Br, -I and-NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 alkyl-O-C 1-3 Alkyl, -C 1-3 Alkoxy or-C 1-3 An alkyl group.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, W is NR w And R is w Selected from-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl-CO-methyl or methyl-CO-methoxy.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, ring a is selected from 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 9-membered carbocyclyl, or 10-membered carbocyclyl; and each heteroaryl or each heterocyclyl independently optionally contains 1,2 or 3 heteroatoms selected from N, O or S.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring a is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl; a 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, or 8-membered carbocyclyl; and each heteroaryl and each heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is selected from
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 2a 、R 2b 、R 3a And R 3b Are all independently selected from-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 2a 、R 2b 、R 3a And R 3b Are all independently selected from-H, -F, -Cl, -Br and-NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R 2a And R 2b Each independently is-H or methyl, and R 3a And R 3b Each independently is-H.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 6 Are independently selected from-H, -F, -Cl, -Br, -NR 6a R 6b -CN, -OH, oxo, = O, carboxy, -C 1-3 Alkoxy, -C 1-4 Alkyl, -C 1-3 alkenyl-NR 6a R 6b 、-C 1-3 alkenyl-O-C 1-3 Alkyl, -C 1-3 alkenyl-CO-OR 6a 、-C 1-3 alkenyl-C 5-6 Heterocyclyl radical, -C 1-3 alkenyl-C 5-6 Heteroaryl, -C 1-3 alkenyl-CO-NR 6a R 6b 、-C 1-3 Alkenyl, -NR 6a -CO-NR 6a R 6b 、-CO-NR 6a R 6b 、-CO-CO-NR 6a R 6b 、-CO-C 1-3 Alkyl, -CO-NR 6a -C 5-6 Heterocyclyl, -CO-C 5-6 Heterocyclyl, -O-C 5-6 Carbocyclic ringRadical, -O-C 5-6 Heterocyclyl radical, -NR 6a -CO-C 1-3 Alkyl, -NR 6a -CO-NR 6a R 6b 、-NR 6a -C 1-3 alkenyl-NR 6a R 6b 、-NR 6a -C 1-6 alkenyl-C 3-6 Heterocyclyl radical, -NR 6a -SO 2 C 1-3 Alkyl, -S-C 1-3 Alkyl, -SO-C 1-3 Alkyl, -SO 2 NR 6a R 6b 、-SO 2 C 1-3 Alkyl, -PO (C) 1-3 Alkyl radical) 2 、-PO(C 1-3 Alkoxy group) 2 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl or 6-membered heteroaryl, and each R 6 Independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-F, -Cl, br, -NH 2 -OH, carboxyl, oxo, = O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; each R is 6a And R 6b Are each independently selected from-H; -F; -Cl; br; i; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -C 1-3 An alkoxy group; -C 1-3 Alkyl or substituted by 1,2 or 3-H, halogen, -NH 2 -CN or-OH substituted-C 1-3 An alkyl group; or
Two adjacent R 6 Taken together and together with the carbon atoms to which they are each attached form a 6-membered aryl, 5-membered carbocyclyl, 5-membered heteroaryl, or 5-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N, O or S; and each said ring system is independently optionally substituted or unsubstituted with 1,2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 - = O, oxo, carboxy, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 6 Are each independently selected from-H; -F; -Cl; -Br; -NR 6a R 6b (ii) a -CN; -OH; oxo radicalA group; = O; a carboxyl group; a methoxy group; an ethoxy group; propoxy group; an isopropoxy group; a methyl group; an ethyl group; propyl; isopropyl group; a tertiary butyl group; -C 1-3 alkenyl-NR 6a R 6b ；-NR 6a -CO-NR 6a R 6b ；-CO-NR 6a R 6b ；-CO-CO-NR 6a R 6b (ii) a -CO-methyl; -CO-ethyl; -CO-NR 6a -C 5-6 A heterocyclic group; -CO-C 5-6 A heterocyclic group; -O-C 5-6 A carbocyclic group; -O-C 5-6 A heterocyclic group; -NR 6a -CO-methyl; -NR 6a -CO-NR 6a R 6b ；-NR 6a -C 1-3 alkenyl-NR 6a R 6b ；-NR 6a -C 1-6 alkenyl-C 3-6 A heterocyclic group; -NR 6a -SO 2 -a methyl group; -NR 6a -SO 2 -an ethyl group; -S-methyl; -S-ethyl; -SO-methyl; -SO-ethyl; -SO 2 NR 6a R 6b ；-SO 2 A methyl group; -SO 2 An ethyl group; -PO (methyl) 2 (ii) a -PO (ethyl) 2 (ii) a -PO (methoxy) 2 (ii) a -PO (ethoxy) 2 (ii) a A 5-membered heterocyclyl containing 1,2 or 3 heteroatoms; a6 membered heterocyclyl containing 1,2 or 3 heteroatoms; a 5-membered heteroaryl group containing 1,2 or 3 heteroatoms; or a6 membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O or S; wherein each R 6 Each independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-F, -Cl, br, -NH 2 -OH, carboxyl, oxo, = O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; each R 6a And R 6b Are each independently selected from-H; -F; -Cl; br; i; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; a methyl group; an ethyl group; a methoxy group; an ethoxy group; by 1,2 or 3 of-H, F, cl, br, -NH 2 -CN or-OH substituted methyl; or by 1,2 or 3 of-H, F, cl, br, -NH 2 Ethyl substituted by-CN or-OH; or
Two adjacent R 6 Taken together and together with the carbon atom to which they are respectively attached form a phenyl group, a 5-membered carbocyclic group, a 5-membered heteroaryl group containing 1 or 2N or O, orA 5-membered heterocyclyl containing 1 or 2N or O; and each said ring system is independently optionally substituted or unsubstituted with 1,2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 - = O, oxo, carboxy, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R 6 Are independently selected from-F, -Cl, -Br, = O, -OH, -CN, -NH 2 、
-SCH 3 、-SOCH 3 、-SO 2 CH 3 、-PO(CH 3 ) 2 、-PO(OC 2 H 5 ) 2 、-NHSO 2 CH 3 、-C(O)NH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, = O, oxo, -OH, -CN, -NH 2 、-Cl、-Br、-CF 3 、-OCF 3 、-SO 2 NH 2 、-SO 2 CH 3 、-CH 2 NH 2 、-SCH 3 、
-NHCOCH 3 、
-NHCONHCH 3 、
Or
Two adjacent R 6 Are linked together and form together with the carbon atoms to which they are respectively attached
In some embodiments, the compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, is a compound shown in structural formula II:
wherein:
R 3 is selected from-H or-NH 2 ；
Each R 4a Or R 4b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or substituted or unsubstituted-C 1-3 An alkyl group; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached form C = O, C = NH, or C = N-OH;
p is 0, 1,2 or 3;
each R 5a Or R 5b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or substituted or unsubstituted-C 1-3 An alkyl group; or
R 5a And R 5b Together with the carbon atom to which they are both attached form a 3-5 membered heterocyclyl; and each of said heterocyclyl groups is independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-H, halogen, -NH 2 -CN or-OH;
q is 0, 1,2,3 or 4;
ring A is a 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
i) When in use
When represents a single bond, Y 2 Is CR 2a Or N, and Y 3 Is CH or N; or
ii) when
When representing a double bond, Y 2 Is C, and Y 3 Is C;
R 2a selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or substituted or unsubstituted-C 1-3 An alkyl group;
each R 6 Independently selected from-H, halogen, -NR 6a R 6b 、-CN、-OH、-NO 2 Oxo, = O, carboxy, -C 1-3 Alkoxy, -C 1-4 Alkyl, -CO-NR 6a R 6b 、-CO-CO-NR 6a R 6b 、-CO-C 1-3 Alkyl, -CO-NR 6a -C 3-10 heterocyclyl-CO-NR 6a -C 3-10 Heterocyclyl, -CO-C 4-6 Heterocyclyl, -O-C 3-6 Carbocyclyl, -O-C 3-6 Heterocyclyl radical, -NR 6a -CO-C 1-3 Alkyl, -NR 6a -CO-NR 6a R 6b 、-NR 6a -CO-C 5-6 Heteroaryl, -NR 6a -SO 2 C 1-3 Alkyl, -S-C 1-3 Alkyl, -SONR 6a R 6b 、-SO 2 NR 6a R 6b 、-SO-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -PO (C) 1-3 Alkyl radical) 2 、-PO(C 1-3 Alkoxy group) 2 、-C 3-6 Heterocyclyl or-C 5-6 Heteroaryl, wherein each R 6 Each independently optionally substituted or unsubstituted with 1,2 or 3 substituents; and n is 0, 1,2 or 3; or
Two adjacent R 6 Connection ofTogether with the carbon atoms to which they are respectively attached form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, C 3-6 Heterocyclyl or C 3-6 Carbocyclyl, each said ring system being independently optionally substituted or unsubstituted with 1,2 or 3 substituents;
each R 6a And R 6b Independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, or substituted or unsubstituted-
An alkyl group.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, each R 5a Or R 5b Independently selected from-H, -Cl, -Br, -NH 2 -OH, carboxyl, methyl, ethyl, methoxy or ethoxy; or
R 5a And R 5b Together with the carbon atom to which they are jointly attached form
And C represents said carbon atom and R 5a And R 5b And (4) connecting.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring a is 6-membered phenyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each heteroaryl group independently comprises 1 or 2 heteroatoms selected from N, O or S; each of said heterocyclyl groups independently contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring A is selected from
In some embodiments, a compound of the general formula shown in structural formula (II) or a pharmaceutically acceptable salt thereof, R 2a Is selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; is-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C 1-3 An alkyl group; or by-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C 1-3 An alkoxy group.
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, Y 2 Is CH or N, and Y 3 Is CH or N.
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, Y 2 Is C, and Y 3 Is C.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, each R 6 Are all independently selected from-H, -F, -Cl, -Br, -NH 2 、-N(CH 3 ) 2 -CN, -OH, oxo, = O, carboxy, methoxy, ethoxy, methyl, ethyl, isopropyl, tert-butyl, -CH 2 NH 2 、-CH 2 CH 2 OCH 3 、-CH 2 -COOH、-CH 2 NH-CONHCH 3 、-CONH 2 、-CON(CH 3 ) 2 、-CONHOH、-CONHCH 2 CH 2 OH、-CO-CON(CH 3 ) 2 、-COCH 3 、-SO 2 NH 2 、-SO 2 CH 3 、-SCH 3 、-SOCH 3 、-PO(CH 3 ) 2 、-PO(OC 2 H 5 ) 2 、-NHSO 2 CH 3 、-NH-COCH 3 、-NH-CONHCH 3 、
Wherein each R 6 Independently optionally substituted by 1,2 or 3-F, -Cl, -NH 2 -OH, oxo, = O, methyl, ethyl or propyl substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (II), or a pharmaceutically acceptable salt thereof, each R 6a And R 6b Are all independently selected from-H, -Cl, -Br and-NH 2 -OH, carboxyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, methyl substituted with-OH or ethyl substituted with-OH.
In some embodiments, the compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, is a compound shown in structural formula (III):
wherein:
each R 1 And R 2 Are all independently selected from-H, -F, -Cl, -Br and-NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkoxy or-C 1-3 An alkyl group; or
R 1 R adjacent thereto 2 Are linked and together with the carbon atom to which they are each linked form a 5-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N or O, and said 5-membered heterocyclic ring is optionally substituted by 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxoRadical, = O, -CONH 2 or-CO-C 1-3 Alkyl substituted or unsubstituted;
Y 1 is selected from N or CH;
R 3 is selected from-H or-NH 2 ；
Ring B is selected from a benzene ring, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 5-membered heterocycle or a 6-membered heterocycle, and each heteroaryl ring or heterocycle independently optionally contains 1 or 2 heteroatoms selected from N or O;
i) When in use
When represents a single bond, Y 3 Is CH or N; or
ii) when
When representing a double bond, Y 3 Is C;
R 7 selected from halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, -CONH 2 、-NH-COCH 3 Substituted or unsubstituted-C 1-6 Alkoxy, or substituted or unsubstituted-C 1-6 An alkyl group; and m is 0, 1 or 2.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R 1 R adjacent thereto 2 Are linked and form together with the carbon atoms to which they are respectively linked
And said ring system is independently optionally substituted by 1 or 2-F or-COCH 3 Substituted or unsubstituted.
In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, and ring B is selected from
In some embodiments, a compound of the formula (III) or a pharmaceutically acceptable salt thereofPharmaceutically acceptable salts, R 7 Is selected from-NH 2 -CN, oxo, = O, -CONH 2 、-NH-COCH 3 Methyl or methoxy.
In some embodiments, the compound of the general formula (I) or a pharmaceutically acceptable salt thereof, is a compound of the structural formula (IV):
wherein:
each R 1 And R 2 Are each independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -NHC 1-3 An alkyl group; -N (C) 1-3 Alkyl radical) 2 ；-C 1-3 An alkoxy group; -C 1-3 Alkyl or 1,2 or 3 halogen substituted-C 1-3 An alkyl group; or
R 1 R adjacent thereto 2 Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl ring, a 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, or a 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, and each of said ring systems is independently optionally substituted with 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, -CONH 2 、-C 1-3 Alkoxy, -C 1-3 Alkyl or-CO-C 1-3 Alkyl substituted or unsubstituted;
Y 1 is N or CH;
R 3 is-H or-NH 2 ；
Ring D is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, each of which independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
i) When in use
When represents a single bond, Y 2 Is CR 2a Or N, and Y 3 Is CR 3a Or N; or
ii) when
When represents a double bond, Y 2 And Y 3 Are all C;
each R 2a And R 3a Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkoxy or-C 1-3 An alkyl group;
R 8 selected from halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, C 1-4 Alkyl radical, C 1-3 Alkoxy, -SO 2 NR 8a R 8b 、-S-C 1-3 Alkyl, -SO-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -CO-NR 8a R 8b 、-PO(C 1-3 Alkyl radical) 2 、-PO(C 1-3 Alkoxy group) 2 、-NR 8a -CO-C 1-3 Alkyl, -NR 8a -CO-NR 8a R 8b -O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl; and each R 8 Each independently optionally substituted by 1,2 or 3 substituents selected from halogen, methyl, ethyl, methoxy, oxo, -NH 2 A substituent of-CN or-OH; and t is 0, 1,2 or 3; or
Two adjacent R 8 Taken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl or 5-membered heteroaryl, and each said ring system independently is optionally substituted or unsubstituted;
each R 8a And R 8b Are all independently selected from H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkoxy or-C 1-3 An alkyl group.
In some embodiments, a compound of the general formula shown in structural formula (IV), or a pharmaceutically acceptable salt thereof, each R 1 And R 2 Are all independently selected from-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 、-CF 3 Carboxy, -NHCH 3 、-N(CH 3 ) 2 Methoxy, ethoxy, methyl or ethyl; or
R 1 R adjacent thereto 2 Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl group, a 5-membered heterocyclic group containing 1 heteroatom selected from N or O, or a 5-membered heteroaromatic ring including 1 heteroatom selected from N or O; and each said ring system is independently optionally substituted with 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, -CONH 2 Methoxy, ethoxy, methyl, ethyl, -CO-methyl or-CO-ethyl.
In some embodiments, a compound of the general formula shown in structural formula (IV), or a pharmaceutically acceptable salt thereof, each R 1 And R 2 Are all independently selected from-H, -F, -Cl, -Br and-NH 2 、-CN、-OH、-NO 2 、-CF 3 Carboxy, -NHCH 3 、-N(CH 3 ) 2 Methoxy, ethoxy, methyl or ethyl; or
R 1 R adjacent thereto 2 Are bound and form together with the carbon atoms to which they are respectively bound
And each of said ring systems is independently optionally substituted with 1,2 or 3 substituents selected from-F or-COCH 3 Substituted or unsubstituted.
In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and ring D is selected from
In some embodiments, a compound of the general formula shown in structural formula (IV), or a pharmaceutically acceptable salt thereof, each R 2a And R 3a Are each independently selected from-H, methyl or methoxy.
In some embodiments, a compound of the general formula shown in structural formula (IV) or a pharmaceutically acceptable salt thereof, R 8 Selected from-F, -Cl, -Br and-NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, = O, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, -CO-methyl, -SO 2 NR 8a R 8b -S-methyl, -S-ethyl, -SO-methyl, -SO-ethyl, -SO 2 -methyl, -SO 2 -ethyl, -CO-C 3-6 heterocyclyl-CO-NR 8a R 8b -PO (methyl) 2 -PO (ethyl) 2 -PO (methoxy) 2 -PO (ethoxy) 2 、-NR 8a -CO-methyl, -NR 8a -CO-ethyl, -NR 8a -CO-NR 8a R 8b 、-NR 8a -SO 2 Methyl, -O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl, each of said heterocyclyl or heteroaryl containing 1 or 2 heteroatoms selected from O, N or S; each R 8 Independently optionally substituted by 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 -CN, -OH, oxo, = O, methoxy, ethoxy, methyl or ethyl.
In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 8 Selected from-F, -Cl, -Br and-NH 2 CN, -OH, carboxyl, oxo, = O, methyl, ethyl, isopropyl, tert-butyl, CF 3 Methoxy, -SOCH 3 、-SO 2 CH 3 、-SCH 3 、P(O)(CH 3 ) 2 、P(O)(OC 2 H 5 ) 2 、NHS(O) 2 CH 3 、-CONH 2 、-NH-COCH 3 、-NH-CONHCH 3 、-NH-COCH 3 、
In some embodiments, a compound of the general formula shown by structural formulae (I), (II), (III) (IV), or a pharmaceutically acceptable salt thereof, is:
in another aspect, the present invention further provides a pharmaceutical composition, comprising at least one compound represented by formula (I), (II), (III) or (IV) of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Further, in the pharmaceutical composition, the weight ratio of the compound represented by structural formula (I), (II), (III) or (IV) or the pharmaceutically acceptable salt thereof to the auxiliary material is 0.0001-10.
In another aspect, the invention also provides the use of the pharmaceutical composition for the preparation of a medicament.
In some embodiments, the medicament is for treating, preventing, or preventing a disease or disorder mediated by SHP2 activity.
In some embodiments, the disease or disorder mediated by SHP2 activity is cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis, or vision disorders.
In some embodiments, the disease or disorder mediated by SHP2 activity is selected from one or more of the following conditions: 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, and combinations thereof.
The term "halogen" as used herein means, unless otherwise specified, fluorine, chlorine, bromine or iodine. Preferably, halogens include fluorine, chlorine and bromine. The term "halo C 1-6 Alkyl group "," halogeno C 2-6 Alkenyl group "," halogeno C 2-6 Alkynyl "and" halo C 1-6 Alkoxy "means a group in which one or more (especially 1,2 or 3) hydrogen atoms are replaced by a halogen atom, especially a fluorine or chlorine atom. In some embodiments, fluoro C is preferred 1-6 Alkyl, fluoro C 2-6 Alkenyl, fluoro C 2-6 Alkynyl and fluoro C 1-6 Alkoxy, especially fluoro C 1-3 Alkyl radicals, e.g. CF 3 、CHF 2 、CH 2 F、CH 2 CH 2 F、CH 2 CHF 2 、CH 2 CF 3 (ii) a Fluoro C 1-3 Alkoxy radicals, e.g. OCF 3 、OCHF 2 、OCH 2 F、OCH 2 CH 2 F、OCH 2 CHF 2 Or OCH 2 CF 3 (ii) a In particular CF 3 、OCF 3 And OCHF 2 。
Unless otherwise specified, alkyl groups in the present invention include saturated monovalent hydrocarbon groups having straight, branched, or cyclic moieties. For example, alkyl includes 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. Similarly, in the present invention C 1-8 Alkyl is defined as a group having 1,2,3,4, 5,6, 7 or 8 carbon atoms in a linear or branched arrangement.
Alkylene means a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH) 2 -, ethylene (i.e. -CH) 2 -CH 2 -or-CH (CH) 3 ) -) and propylene (i.e., -CH 2 -CH 2 -CH 2 -，-CH(-CH 2 -CH 3 ) -or-CH 2 -CH(CH 3 )-)。
Alkoxy is an oxygen ether formed from a straight, branched or cyclic alkyl group as described above.
The term "aryl" as used herein by itself or as part of another substituent means, unless otherwise stated, a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
As used herein, unless otherwise specified, the term "heterocycle" by itself or as part of another substituent refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic, partially unsaturated or fully saturated ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides. Preferably the ring is three to eight membered and is fully saturated or has one or more unsaturations. Included in this definition are a plurality of degrees of substitution, preferably one, two or three degrees of substitution.
Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, oxadiazole, or oxaza.
As used herein, unless otherwise specified, the term "heteroaryl" by itself or as part of another substituent refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. The polycyclic heteroaryl ring may contain a fused spiro or bridged ring, for example, the cyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring may contain 8 to 12 member atoms. Monocyclic heteroaryl rings may contain 5 to 8 member atoms (carbon number and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzotriazolylacrylyl, quinolinyl, or isoquinolinyl.
As used herein, unless otherwise specified, the term "cycloalkyl" by itself or as part of another substituent means a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsubstituted hydrocarbon group, which optionally includes an alkylene linker through which the cycloalkyl group may be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The terms "carbonyl", "-C = O", "-CO", "-C (O)" and "CO" refer to a group
The term "oxo" refers to the group = O.
The term "oxo" or "= O" means that it forms C = O together with the carbon atom to which it is attached.
Whenever the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent (e.g., aralkyl or dialkylamino), by itself or as part of another substituent, unless otherwise stated, it should be construed as including the limitations given above for "alkyl" and "aryl". The specified number of carbon atoms (e.g., cl-6) shall independently refer to the number of carbon atoms in the alkyl moiety or the number of carbon atoms in the alkyl moiety of the larger substituent in which the alkyl group is the prefix.
Two "R" in the general formula I, II, III or IV 1 The substituents of "may be the same or different. Similar to "R 1 ", and two" Y's of the formulae I, II, III or IV 1 The "may be the same or different.
The compounds described herein, e.g., certain compounds of formula I, II, III or IV, may contain asymmetrically substituted carbon atoms (or chiral centers) in either the R or S configuration. The present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds described herein, when specifically designated by chemical name as the R-or S-isomer, should be understood as having the R-or S-isomer, respectively, as the predominant configuration. For example, in any of the embodiments described herein, such R-or S-designated isomer may be substantially free (e.g., less than 5%, less than 1%, or undetectable by chiral HPLC) of another isomer at each chiral center. The R-or S-isomer can be prepared by the methods exemplified herein, for example, by using a chiral auxiliary such as R-or S-tert-butylsulfinamide during the synthesis. Other methods of preparing the dominant R-or S-isomer herein include, but are not limited to, chiral HPLC purification of a mixture of stereoisomers (e.g., a racemic mixture). General methods for separating stereoisomers (e.g., enantiomers and/or diastereomers) using HPLC are known in the art.
The compounds described herein may exist in isotopically labeled or enriched forms, containing one or more atoms with an atomic mass or mass number different from the atomic mass or mass number most abundant in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36C1, and 125I. Compounds containing other isotopes of these and/or other atoms are within the scope of this invention. In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be replaced with deuterium to provide a corresponding labeled or enriched compound.
As used herein, the term "subject" (alternatively referred to as "patient" in the present invention) refers to an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation or experiment.
As used herein, unless otherwise indicated, the term "ring system" (which may also be referred to as "ring system") includes, but is not limited to, carbocyclic rings, heterocyclic rings, heteroaromatic rings, and the like, and may also include only heterocyclic rings and/or heteroaromatic rings, and specifically includes which rings are determined as the context requires, but in any case "ring system" does not include C-based 1-6 Alkyl or C 1-3 Cycloalkyl radicals of alkyl radicals and not including radicals based on C 1-6 Alkoxy or C 1-3 An alkoxy group.
The compounds of the general formula I, II, III or IV can have different isomeric forms. For example, any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration. The double bonds or especially the substituents on the ring can be present in cis (= Z-) or trans (= E-) form. These compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
When used in the plural (e.g., compound, salt), it includes the singular (e.g., single compound, single salt). "Compound" does not exclude the presence (e.g. in a pharmaceutical preparation) of more than one compound of formula I, II, III or IV (or a salt thereof), "a" merely standing for the indefinite article. Thus "a" may preferably be understood as "one or more", and should not be understood as "a"
"SHP2" refers to "Src homology region-2 containing protein tyrosine phosphatase", also known as SH-PTP2, SH-PTP3, syp, PTP1D, PTP2C, SAP-2 or PTPN11.
Cancers that carry "PTPNll mutations" include, but are not limited to: N58Y; D61Y, V; E69K; a72V, T, D; E76G, Q, K (ALL); G60A; D61Y; E69V; F71K; A72V; T73I; E76G, K; R289G; G503V (AML); G60R; D61Y, V, N; Y62D; E69K; a72T, V; T73I; E76K, V, G, A, Q; el39D; G503A, R; Q506P (JMML); G60V; D61V; E69K; F71L; A72V; E76A (MDS); Y63C (CMML); Y62C; E69K; T507K (neuroblastoma); V46L; N58S; E76V (lung cancer); R138Q (melanoma); E76G (colon cancer).
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Pharmaceutical compositions containing the compounds of the invention as active ingredients and processes for preparing the compounds of the invention are therefore also part of the present invention. In addition, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and as such are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention.
The compounds of the invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salts include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts generally take the form in which a basic nitrogen is protonated by an inorganic or organic acid, representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, isethionic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclamic, salicylic, saccharin or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.
Prodrugs of the compounds of the invention are also included within the scope of the invention. Typically, such prodrugs are functional derivatives of the compounds of the present invention which are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" shall include the use of the compounds of the present invention specifically disclosed, as well as the use of compounds that may not be specifically disclosed, but which may be converted in vivo to the specified compound after administration to a patient for the treatment of various conditions or disorders. Conventional methods for selecting and preparing suitable prodrugs are described, for example, prodrug design, published in 1985 by h.
In the present invention, the definition of any substituent or variable at a particular position is independent of the definition of that substituent or variable at other positions in the molecule. It is to be understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and those methods set forth herein.
The compounds encompassed by the present invention may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. The present invention includes all those possible diastereoisomers and their racemic mixtures, their substantially pure, resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.
The above formulae I, II, III or IV do not indicate stereochemistry determined at a specific position. The present invention includes all stereoisomers of formula I, II, III or IV and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated, defined stereoisomers are also included. The products of these processes may be mixtures of stereoisomers during the synthetic procedures used to prepare these compounds, or during the use of racemization or epimerization procedures known to those skilled in the art.
When tautomers exist for compounds of formula I, II, III or IV, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.
When the compounds of formula I, II, III or IV and pharmaceutically acceptable salts thereof exist in solvate form or in polymorphic form, the present invention includes any possible solvate and polymorphic form. The kind of the solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, or the like can be used.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of formula I, II, III or IV are for pharmaceutical use, they are preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% on a weight basis).
The pharmaceutical composition of the present invention comprises a compound represented by formula I, II, III or IV (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular subject and the nature and severity of the condition to which the active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds represented by formula I, II, III or IV or prodrugs or metabolites thereof or pharmaceutically acceptable salts thereof as active ingredients of the present invention may be combined with a pharmaceutical carrier in intimate admixture according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, for example, as capsules, cachets (cachets) or tablets each containing a predetermined amount of the active ingredient. Furthermore, the composition may be in the form of a powder, granules, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. In addition to the above-described conventional dosage forms, the compounds represented by formula I, II, III or IV, or pharmaceutically acceptable salts thereof, may be administered via a controlled release device and/or a delivery device. The composition may be prepared by any pharmaceutical method. Generally, these methods include the step of bringing into association the active ingredient with the carrier which contains one or more of the necessary ingredients. Typically, the compositions are prepared by uniformly and intimately admixing (unifonm and inteimately admixing) the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired form.
Accordingly, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of formula I, II, III or IV. The compounds of formula I, II, III or IV or pharmaceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations (e.g., suspensions, elixirs (elixirs), and solutions); and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used to form oral solid preparations (e.g., powders, capsules and tablets). Because of their ease of administration, tablets and capsules are the preferred oral dosage units, whereby solid pharmaceutical carriers are employed. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.
Tablets containing the composition of the invention may be prepared by compression or molding, optionally together with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient, and each cachet or capsule preferably contains from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5mg to about 5g of the active agent, in admixture with a suitable and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms generally contain between about 1mg to about 2g of active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants may comprise, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the unwanted growth of microorganisms.
Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injection must be sterile and must be an effective liquid to facilitate injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; it is therefore preferred that the contaminating action of microorganisms such as bacteria and fungi should be prevented. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders (dusting powders) and the like. Further, the composition may be in a form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods using the compounds represented by formula I, II, III or IV of the present invention or pharmaceutically acceptable salts thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5% to about 10% by weight of the compound to produce a cream or ointment having a desired consistency.
The pharmaceutical compositions of the invention may be in a form suitable for rectal administration and the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or molten carrier, followed by cooling and shaping in a mould.
In addition to the above-described carrier ingredients, the above-described pharmaceutical formulations may optionally include one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the target recipient. Compositions containing a compound described by formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or liquid concentrate.
In general, the above conditions may be treated with a daily dosage level of from about 0.01mg/kg body weight to about 150mg/kg body weight per day, or alternatively from about 0.5mg to about 7g per patient. For example, inflammation, cancer, psoriasis, allergy/asthma, diseases and disorders of the immune system, diseases and disorders of the Central Nervous System (CNS) can be effectively treated by administering about 0.01 to 50mg of the compound per kilogram of body weight per day, or about 0.5mg to about 3.5g of the compound per patient per day.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
These and other aspects will become apparent from the following written description of the invention.
Examples
The following intermediates and examples are provided to illustrate the present invention. Unless otherwise expressly indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:
intermediate A1
To a solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (1.50g, 9.25mmol) in DMF (10 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 1.11g, 27.75mmol) portionwise. The mixture was heated to 60 ℃ and stirred at this temperature for 20 minutes. Tert-butyl bis (2-chloroethyl) carbamate (2.46g, 10.17mmol) was added dropwise and the mixture was stirred for 85min. After cooling to RT, the reaction was diluted with EA (200 mL), washed with brine (3X 200 mL) and the organic phase was washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 12,v/v) to give 6-methoxy-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine as a yellow solid]-1' -Carboxylic acid tert-butyl ester (557 mg). MS M/z 332 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 1
Intermediate A2
Step a: diethanolamine (198.15g, 1.88mol), K 2 CO 3 A mixture of (520.95g, 3.77mol), benzyl bromide (386.79g, 2.26mol) and acetonitrile (2000 mL) was stirred at 90 ℃ for 2.5h. After cooling to RT, filtration and rinsing of the filter cake with EA (2X 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM = 1) to give N-benzyldiethanolamine (89.44 g) as a colorless oil. MS: M/z 196 (M + H) + .
Step b: phosphorus tribromide (69.13g, 0.26mol) was added dropwise to a 0 ℃ solution of N-benzyldiethanolamine (30.66g, 0.16mol) in toluene (300 mL). The system was warmed to 105 ℃ and stirred for 16h. After cooling to RT, the volatiles were removed by concentration under reduced pressure. The residue was diluted with water (300 mL) and the pH adjusted to 9 with NaOH. The system was extracted with EA (3X 150 mL), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure to give N-benzyl-2-bromo-N- (2-bromoethyl) ethan-1-amine (41.58 g), which was used in the next step without any further purification. MS M/z 320 (M + H) + .
Step c: in nitrogen atmosphere, the temperature is increased to 6,7-dihydro-5H-cyclopenta [ b ] of 0 DEG C]To a solution of pyridin-5-one (1.70g, 12.77mmol) in DMF (20 mL) was added sodium hydride (60% dispersion in mineral oil, 982mg, 24.55mmol) in three portions, and the mixture was heated to 60 ℃ and stirred at this temperature for 1h. N-benzyl-2-bromo-N- (2-bromoethyl) ethan-1-amine (4.54g, 14.14mmol) was then added and stirred for a further 1h at 60 ℃. After cooling to RT, the reaction was quenched with water (80 mL) and extracted with EA (3X 80 mL). The combined organic phases were washed with water (3X 80 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 1' -benzylspiro [ ring ]Pentadieno [ b ]]Pyridine-6,4' -piperidine]-5 (7H) -one (1.14 g). MS: M/z 293 (M + H) + .
Step d: to 0 ℃ of 1' -benzylspiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]To a solution of-5 (7H) -one (1.05g, 3.59mmol) in DCE (10 mL) was added dropwise chloro-1-chloroethyl chloroformate (903mg, 6.32mmol). The system was stirred at RT for 1.5h. The volatiles were removed by concentration under reduced pressure and the residue was dissolved in MeOH (20 mL) and stirred at 80 ℃ for 4h. The volatiles were removed by concentration under reduced pressure and the residue was dissolved in DCM (20 mL). DIEA (1.33g, 10.32mmol) and (Boc) were added 2 O (1.38g, 6.32mmol). The resulting solution was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 1,v/v) to give 5-oxo-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -carboxylic acid tert-butyl ester (438 mg). MS: M/z 303 (M + H) + .
Intermediate A3
Step a: LDA (2M solution in THF/Hex, 24mL, 48.00mmol) was added dropwise to a-70 ℃ solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (8.14g, 31.64mmol) in THF (80 mL) under nitrogen. After the resulting solution was stirred at this temperature for 70min, 1-bromo-4- (bromomethyl) benzene (7.91g, 31.64mmol) was added in portions. The resulting solution was stirred at-70 ℃ for 3h, then carefully quenched with saturated ammonium chloride solution (50 mL). The separated aqueous phase was extracted with EA (1X 80 mL), the organic phases were combined and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 4- (4-bromobenzyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (14.55 g) as a brown oil, which was used in the next step without any further purification. MS M/z 426 (M + H) + .
Step b: a mixture of 4- (4-bromobenzyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (14.55g, 34.13mmol), naOH (8.12g, 203.00mmol), meOH (80 mL) and water (80 mL) was stirred at 75 ℃ for 16.5h. After cooling to RT, the volatiles were removed by concentration under reduced pressure. The system was extracted with EA (3X 80 mL). The combined organic phases were washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 4- (4-bromobenzyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (16.87 g) which was used in the next step without any further purification. MS M/z 398 (M + H) + .
Step c: a mixture of 4- (4-bromobenzyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (16.87g, 42.36mmol) and PPA (60 mL) was stirred at 120 ℃ for 30min. The reaction solution was poured into an ice-water mixture (300 mL) and the pH was adjusted to 10 with NaOH. Then add (Boc) 2 O (13.86g, 63.53mmol) and stirred at RT for 18h. The reaction was extracted with EA (3X 150 mL). The combined organic phases were freed from Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl-1' -carboxylate (16.87 g), used in the next step without any further purification. MS M/z 380 (M + H) + .
The following compounds were synthesized using the above-described procedure or modified procedure and the corresponding starting materials.
TABLE 2
Intermediate A4
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (2.06g, 5.42mmol), pd (PPh) 3 ) 4 A mixture of (626 mg, 0.54mmol), DBU (252mg, 1.66mmol), t-BuOH (15 mL), water (15 mL) and potassium ferrocyanide trihydrate (1.16g, 2.75mmol) was stirred at 90 ℃ for 22.5h. After cooling to RT, the mixture was diluted with EA (30 mL), filtered, and the filter cake rinsed with EA (15 mL). The filtrate was washed with brine (1X 30 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give 6-cyano-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.86 g). MS: M/z 327 (M)+H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 3
Intermediate A5
4-cyano-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]A mixture of tert-butyl (1' -carboxylate) (0.93g, 2.85mmol), KOH (1.60g, 28.50mmol), meOH (15 mL) and water (15 mL) was stirred at 100 ℃ for 2h. After cooling to RT, the reaction mixture was diluted with water (30 mL) and extracted with EA (60mL, 30mL). The combined organic phases were washed with brine (1X 80 mL) and anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 4-carbamoyl-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl (1.04 g) -1' -carboxylate, used in the next step without any further purification. MS M/z 345 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 4
Intermediate A6
To 6-carbamoyl-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (1.57g, 4.56mmol) of the-1' -carboxylate in DMF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 0.91g, 22.79mmol) followed by CH 3 I (1mL, 16.06mmol). The system was stirred at RT for 17h. Brine (50 m) for reaction solutionL) quenched and extracted with EA (2X 50 mL). The combined organic phases were washed with brine (1X 100 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex = 13,v/v) to give 6- (dimethylcarbamoyl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (0.82 g). MS M/z 373 (M + H) + .
Intermediate A7
Step a-c: step (a-c) using intermediate A3 gave 1'- (tert-butoxycarbonyl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-6-carboxylic acid. MS M/z 346 (M + H) + .
Intermediate A8
To a 50mL stopcock was added 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (998mg, 2.62mmol), DMSO (8 mL), water (4 mL), cuI (217mg, 1.14mmol) and ammonium hydroxide (25%, 4 mL). The system was stirred at 100 ℃ for 5 days. After cooling to RT, the reaction was diluted with brine (20 mL) and EA (30 mL). Separating the organic phase with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 6-amino-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (750 mg). MS M/z 317 (M + H) + .
Intermediate A9
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (531mg, 1.40mmol), methanesulfonamide (371mg, 3.90mmol), K 2 CO 3 (1.10g, 7.95mmol), N, N' -dimethyl-1,2-ethylenediamine (85mg, 0.96mmol), cuI (72mg, 0.38mmol) and 1,4-dioxane (20 mL) was stirred at 110 ℃ for 23h. Further methanesulfonamide (370mg, 3.89mmol), N, N' -dimethyl-1,2-ethylenediamine (85mg, 0.96mmol) and CuI (75mg, 0.39mmol) were added and stirred at the same temperature for 7h. After cooling to RT, the reaction was quenched with water (30 mL) and extracted with EA (3X 50 mL). The combined organic phases were passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex = 23,v/v) to give 6- (methylsulfonylamino) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (562 mg). MS: M/z 395 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 5
Intermediate A10
To 6-amino-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (1' -carboxylate) (0.66g, 2.09mmol) in AcOH (5 mL) and water (10 mL) was added dropwise a solution of sodium cyanate (0.28g, 4.31mmol) in water (2 mL). The system was stirred at 50 ℃ for 4h. After cooling to RT, the reaction was adjusted to pH 12 with aqueous ammonia (25%) and extracted with DCM (60mL, 30mL). The combined organic phases were washed with brine (1X 60 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =2, 1,v/v) to give 1-oxo-6-ureido-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (0.39 g). MS: M/z 360 (M + H) + .
Intermediate A11
To 0 ℃ 6- (methylthio) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (336mg, 0.97mmol) 1' -carboxylate in MeOH (20 mL) and water (20 mL) was added potassium peroxymonosulfate (296mg, 1.76mmol). The system was stirred at 0 ℃ for 1h. Saturated Na for reaction solution 2 S 2 O 3 Quench (10 mL) and concentrate under reduced pressure to remove volatiles. The system was extracted with EA (3X 40 mL) and the combined organic phases were passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =4, 1,v/v) to give 6- (methylsulfinyl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (285 mg). MS M/z 364 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 6
Intermediate A12
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.51g, 3.97mmol), dimethyl-phosphorus oxide (503mg, 6.44mmol), pd (OAc) 2 (92mg，0.41mmol)，Xantphos(457mg，0.79mmol)，K 3 PO 4 A mixture of (1.57g, 7.40mmol) and DMF (30 mL) was stirred at 130 ℃ for 16.5h. After cooling to RT, the reaction was quenched with water (120 mL) and extracted with EA (3X 80 mL). The combined organic phases were washed with brine (1X 120 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM = 1) to give 6- (dimethyl) as a white solidPhosphoryl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (0.81 g). MS M/z 378 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 7
Intermediate A13
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.09g, 2.87mmol), 1H-imidazole (180mg, 2.64mmol), cuBr (34mg, 0.24mmol), cs 2 CO 3 (851mg, 2.61mmol), 1,2,3,4-tetrahydro-8-hydroxyquinoline (74mg, 0.49mmol) and DMSO (10 mL) was stirred at 110 ℃ for 23h. After cooling to RT, the reaction was quenched with water (30 mL) and extracted with EA (1X 40 mL). The organic phase is treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 6- (1H-imidazol-1-yl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine as a yellow solid]-1' -carboxylic acid tert-butyl ester (142 mg). MS M/z 368 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 8
Intermediate A14
1'- (tert-butyloxycarbonyl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-6-Carboxylic acidThe acid (345mg, 1.00mmol), piperidine (129mg, 1.51mmol) and HATU (422mg, 1.11mmol) were stirred in DMF for 1h. The reaction was diluted with water (30 mL) and EA (30 mL). The organic phase was separated, washed with brine (1X 30 mL), and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 1-oxo-6- (piperidine-1-carbonyl) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (380 mg). MS: M/z 413 (M + H) + .
Intermediate A15
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.02g, 2.68mmol), morpholine (0.67g, 7.69mmol), cu (OAc) 2 A mixture of (0.51g, 2.81mmol), DBU (1.03g, 6.77mmol) and DMSO (10 mL) was stirred at 130 ℃ for 23h. After cooling to RT, the reaction was diluted with water (70 mL) and extracted with EA (3X 50 mL). The combined organic phases were passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 1,v/v) to give 6-morpholino-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (467 mg). MS M/z 387 (M + H) + .
Intermediate A16
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (500mg, 1.31mmol), 1-methylpiperazine (270mg, 2.70mmol), cs 2 CO 3 (1306mg，4.01mmol)，Pd 2 (dba) 3 A mixture of (66mg, 0.07mmol), xantPhos (75mg, 0.13mmol) and 1,4-dioxane (18 mL) was stirred at 100 ℃ for 0.5h. After cooling to RT, the reaction was quenched with water and extracted with EA (2X 100 mL). The combined organic phases were washed with brine (1X 100 mL) and anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 6- (4-methylpiperazine)-1-yl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl (0.87 g, crude) 1' -carboxylate, was used in the next step without any further purification. MS M/z 400 (M + H) + .
Intermediate A17
Step a: LDA (2M solution in THF/Hex, 45.00mL, 90.00mmol) was added dropwise to a-60 deg.C solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (15.52g, 60.31mmol) in THF (100 ml) under nitrogen. Naturally heating the system to-20 deg.C, stirring for 50min, cooling to-50 deg.C, and adding CH 3 I (8.56g, 60.31mmol) in THF (20 mL). Then stirred at this temperature for 50min. The reaction solution was carefully quenched with saturated ammonium chloride (80 mL) and extracted with EA (100mL, 50mL). The combined organic phases were washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 4-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (17.70 g) which was used in the next step without any further purification. MS: M/z 216 (M + H-56) + .
Step b: to a 0 deg.C solution of 4-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (17.70g, 65.23mmol) in THF (150 mL) was added LiBH 4 (2M in THF, 98.00mL, 196.00mmol). The system was stirred at 70 ℃ for 18h. After cooling to RT, quench dropwise with water (100 mL). The system was extracted with EA (200mL, 100mL), the combined organic phases were washed with brine (1X 200 mL), anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give tert-butyl 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate (12.90 g), which was used in the next step without any further purification. MS M/z 174 (M + H-56) + .
Step c: to a solution of oxalyl chloride (10.71g, 84.38mmol) in DCM (150 mL) at-78 deg.C was added dropwise a solution of DMSO (10.99g, 140.63mmol) in DCM (30 mL) and stirred at this temperature for 30min. A solution of tert-butyl 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate (12.90g, 56.25mmol) in DCM (30 mL) was added dropwise and stirred at-78 deg.C for 30min. Triethylamine (22.77g, 225.02mmol) was added dropwise and then filtered fromThen the temperature is increased to-20 ℃ and the mixture is stirred for 40min. The reaction was quenched with water (80 mL). The organic phase was collected and the aqueous phase was extracted with DCM (1X 80 mL). The combined organic phases were washed with brine (1X 200 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 20, v/v) to give 4-formyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (11.82 g.) MS: M/z 172 (M + H-56) + .
Step d: LDA (2M solution in THF/Hex, 11.00mL, 22.00mmol) was added dropwise to a-70 deg.C solution of 3-chloropyridine (2.25g, 17.64mmol) in THF (50 mL). The system was warmed to-60 ℃ and stirred for 1.5h. A solution of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (3.95g, 17.37mmol) in THF (10 mL) is added dropwise at-70 ℃. After stirring for 1h, the mixture was quenched with water (50 mL). The organic phase was collected and the aqueous phase was separated and extracted with EA (60mL, 30mL). The combined organic phases were washed with brine (1X 80 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give tert-butyl 4- ((3-chloropyridin-4-yl) (hydroxy) methyl) -4-methylpiperidine-1-carboxylate (8.10 g) which was used in the next step without any purification. MS: M/z 341 (M + H) + .
Step e: to a solution of tert-butyl 4- ((3-chloropyridin-4-yl) (hydroxy) methyl) -4-methylpiperidine-1-carboxylate (8.10g, 23.76mmol) in DCM (50 ml) was added dess-martin oxidizer (20.12g, 47.44mmol). The system was stirred at RT for 16h. The reaction was diluted with DCM (100 mL) and saturated Na 2 S 2 O 3 (25%, 1X 80 mL), saturated NaHCO 3 (1X 80 mL) and brine (1X 100 mL). The organic phase is treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 3,v/v) to give 4- (3-chloroisonicotinyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (4.81 g). MS M/z 339 (M + H) + .
Step f: under a nitrogen atmosphere, 4- (3-chloroisonicotinoyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (6.31g, 18.62mmol), cs 2 CO 3 (6.72g, 21.90mmol), pivalic acid (571mg, 5.60mmol), pd (OAc) 2 (0.22g，0.98mmol)，Cy 3 PH·BF 4 (0.70g, 1.90mmol) and 1,3,a mixture of 5-trimethylbenzene (40 mL) was stirred at 140 ℃ for 72h. After cooling to RT, filtration was followed by EA (3X 40 mL) rinsing. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 1,v/v) to give 5-oxo-5,7-dihydrospiro [ cyclopenta [ c]Pyridine-6,4' -piperidine]-1' -carboxylic acid tert-butyl ester (2.82 g). MS: M/z 303 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 9
Intermediate A18
Step a: to a solution of 3-bromo-6-chloropyridine-2-carboxylic acid (9.98g, 42.21mmol) in MeOH (100 mL) was added H dropwise 2 SO 4 (98%, 10.00 mL). Stirred at 70 ℃ for 3h. After cooling to RT, the pH of the reaction solution was adjusted to 9 by adding ammonia (25%). The volatiles were removed by concentration under reduced pressure. The mixture was diluted with water (60 mL) and extracted with EA (1X 100 mL). The organic phase was washed with brine (1X 60 mL) and anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave methyl 3-bromo-6-chloropyridine-2-carboxylate (10.14 g) as an off-white solid. MS M/z 250 (M + H) + .
Step b: to a 0 deg.C solution of methyl 3-bromo-6-chloropyridine-2-carboxylate (10.14g, 40.48mmol) in MeOH (150 mL) was added NaBH in portions 4 (4.62g, 122.13mmol). The mixture was warmed to RT and stirred for 16h. The reaction was diluted with brine (110 mL) and concentrated under reduced pressure to remove MeOH. Extracting with EA (100mL, 80mL), and mixing the organic phase with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain (3-bromo-6-chloropyridine)-2-yl) methanol (8.31 g). MS M/z 222 (M + H) + .
Step c: to a solution of (3-bromo-6-chloropyridin-2-yl) methanol (8.31g, 37.35mmol) and triethylamine (7.63g, 75.40mmol) in DCM (100 mL) at-15 deg.C was added MsCl (4.71g, 41.12mmol) dropwise. The mixture was warmed to RT and stirred for 2h. The reaction was quenched with water (50 mL) and the aqueous phase was separated. The organic phase was washed with brine (1X 50 mL) and anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave methanesulfonic acid (3-bromo-6-chloropyridin-2-yl) methyl ester (8.54 g). MS M/z 300 (M + H) + .
Step d: to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (9.66g, 37.54mmol) in THF (30 mL) at-50 deg.C under nitrogen was added LDA (2M solution in THF/Hex, 23.00mL, 46.00mmol) dropwise. Stirring was carried out at this temperature for 1h. A solution of methanesulfonic acid (3-bromo-6-chloropyridin-2-yl) methyl ester (8.54g, 28.41mmol) in THF (15 mL) was added dropwise, warmed to RT naturally and stirred for 1h. The reaction was quenched with brine (60 mL) and extracted with EA (1X 30 mL). The organic phase is treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 4- ((3-bromo-6-chloropyridin-2-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (17.73 g) which was used in the next step without further purification. MS: M/z 461 (M + H) + .
Step e: a mixture of 4- ((3-bromo-6-chloropyridin-2-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (17.73g, 38.39mmol), naOH (8.03g, 200.75mmol), meOH (100 mL), and water (20 mL) was stirred at 65 ℃ for 16h. After cooling to RT, the volatiles were removed by concentration under reduced pressure and the system was diluted with water (150 mL). The pH was adjusted to 6 with a saturated citric acid solution. Extraction with EA (2X 100 mL), combined organic phases were washed with brine (1X 100 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give a mixture of 4- ((3-bromo-6-chloropyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 4- ((3-bromo-6-methoxypyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (18.24 g). MS M/z 433 (M + H) + ,MS:m/z 429(M+H) + .
Step f: in a nitrogen atmosphereNext, to a solution of a mixture of 4- ((3-bromo-6-chloropyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 4- ((3-bromo-6-methoxypyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (3.80g, 8.76mmol) in THF (20 mL) at-15 deg.C was added sodium hydride (60% dispersion in mineral oil, 0.42g, 10.50mmol) in portions. After stirring at this temperature for 1h, the mixture was cooled to-60 ℃. To this mixture was added n-BuLi (2.5M Hex solution, 5mL, 12.50mmol) dropwise, followed by stirring for 1h. The reaction was quenched with water (20 mL) and extracted with EA (1X 40 mL). The organic phase was washed with brine (1X 30 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex =1, 10,v/v) to give 2-chloro-5-oxo-5,7-dihydrospiro [ cyclopenta [ b]Pyridine-6,4' -piperidine]-1' -Carboxylic acid tert-butyl ester and 2-methoxy-5-oxo-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -Carboxylic acid tert-butyl ester mixture (1.48 g). MS M/z 337 (M + H) + .MS:m/z 333(M+H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
Watch 10
Intermediate A19
Step a: LDA (2M solution in THF/Hex, 6.00mL, 12.00mmol) was added dropwise to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (2.83g, 11.00mmol) in THF (50 mL) at-78 deg.C under a nitrogen atmosphere. Stirring was carried out at this temperature for 1h. 2-chloro-5- (chloromethyl) thiazole (dissolved in 3mL THF, 1.69g, 10.06mmol) was added dropwise and stirred for 1h. The reaction was quenched with brine (50 mL) and extracted with EA (2X 30 mL). The combined organic phases were passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1To 4- ((2-chlorothiazol-5-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.15 g). MS M/z 389 (M + H) + .
Step b: LDA (2M solution in THF/Hex, 3.00mL, 6.00mmol) was added dropwise to a-78 deg.C solution of 4- ((2-chlorothiazol-5-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (900mg, 2.31mmol) in THF (50 mL) under a nitrogen atmosphere. After stirring for 30min, quench with brine (30 mL). Extraction with EA (2X 30 mL), combining the organic phases and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-chloro-4-oxo-4,6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester (832 mg). MS: M/z 343 (M + H) + .
Intermediate A20
Step a: LAH (1.51g, 39.90mmol) was added to a 0 deg.C solution of 2-methylnicotinic acid (4.56g, 33.25mmol) in THF (50 mL). The mixture was warmed to RT and stirred for 4h. The reaction was carefully diluted with saturated ammonium chloride (50 mL). Filtering, separating the filtrate, and using anhydrous Na as organic phase 2 SO 4 Dried, filtered again, and the filtrate was concentrated under reduced pressure to give (2-methylpyridin-3-yl) methanol (1.42 g) as a yellow oil. MS: M/z 124 (M + H) + .
Step b: to a solution of (2-methylpyridin-3-yl) methanol (1.41g, 11.45mmol) in DCM (20 mL) at 0 deg.C was added PBr dropwise 3 (1.86g, 6.87mmol). The system was warmed to RT and stirred for 1.5h. NaOH aqueous solution (5M, 10 mL) was added to adjust the pH of the reaction mixture to 8. The aqueous phase was separated and the organic phase was washed with brine (1X 20 mL) and anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure to give 3-bromomethyl-2-methylpyridine (3.52 g) as a yellow oil, which was used in the next step without further purification. MS M/z 186 (M + H) + .
Step c: to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (4.63g, 18.00mmol) in THF (30 mL) at-50 deg.C was added LDA (2M solution in THF/Hex, 12.00mL, 24.00mmol) dropwise and stirred at this temperature for 1h. Adding 3-bromomethyl-2-methylpyridinePyridine (3.25g, 18.00mmol), warmed to RT naturally and stirred for 16h. Saturated NH for reaction solution 4 Cl (50 mL) was diluted carefully. The aqueous phase was separated and the organic phase was washed with brine (1X 50 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 4- ((2-methylpyridin-3-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.87 g) as a red oil which was used in the next step without further purification. MS M/z 363 (M + H) + .
Step d: LDA (2M solution in THF/Hex, 12.00mL, 24.00mmol) was added dropwise to a-20 deg.C solution of 4- ((2-methylpyridin-3-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (4.23g, 11.67mmol) in THF (40 mL), warmed to RT and stirred for 2h. The reaction was carefully diluted with brine (50 mL). Separating the aqueous phase and the organic phase with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, v/v) to give 7' -oxo-7 ',8' -dihydro-5'H-spiro [ piperidine-4,6 ' -quinoline as a yellow oil]-1-carboxylic acid tert-butyl ester (1.23 g). MS M/z 317 (M + H) + .
Intermediate A21
Step a: to a mixture of t-BuOK (5.92g, 52.76mmol) at-60 ℃ and 1,2-dimethoxyethane (50 mL) was added dropwise a solution of 2-tosylacetonitrile (5.08g, 26.02mmol) in 1,2-dimethoxyethane (20 mL). To the system was added dropwise a solution of 2-bromonicotinaldehyde (4.81g, 25.86mmol) in 1,2-dimethoxyethane (20 mL). After stirring at this temperature for 1h, meOH (50 mL) was added, warmed to RT naturally, stirred for 1h and warmed to 85 deg.C, and stirred for an additional 1h. After cooling to RT, the volatiles were removed by concentration under reduced pressure, diluted with brine (200 mL) and extracted with EA (3X 150 mL). The combined organic phases were passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give 2- (2-bromopyridin-3-yl) acetonitrile (2.21 g). MS M/z 197 (M + H) + .
Step b: to 0 ℃ of 2- (2-bromopyridine-3-)Sodium hydride (60% dispersion in mineral oil, 1.12g, 28.03mmol) was added portionwise to a solution of acetonitrile (2.21g, 11.21mmol) in DMF (20 mL). The reaction was warmed to 60 ℃ and stirred for 1.5h. Tert-butyl bis (2-chloroethyl) carbamate (3.26g, 13.46mmol) was added to the mixture and stirred at 60 ℃ for 2h. After cooling to RT, the reaction was quenched with brine (50 mL) and extracted with EA (3X 100 mL). The combined organic phases were washed with brine (3X 80 mL) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 3,v/v) to give 4- (2-bromopyridin-3-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.56 g). MS: m/z 366 (M + H) +.
Step c: under nitrogen atmosphere, 4- (2-bromopyridin-3-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.56g, 4.26mmol), K 2 CO 3 (2.35g, 17.04mmol), trimethylcyclotriboroxane (1.07g, 8.52mmol), pd (PPh) 3 ) 4 (47mg, 0.041mmol), 1,4-dioxane (40 mL) and water (8 mL) were stirred at 110 ℃ for 2h. Supplemented with trimethylcyclotriboroxane (2.15g, 17.13mmol) and Pd (PPh) 3 ) 4 (45mg, 0.039mmol) and stirring for a further 3h. After cooling to RT, the reaction was diluted with brine (100 mL), extracted with EA (3X 100 mL), the organic phases combined and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =2, 1,v/v) to give 4-cyano-4- (2-methylpyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (1.08 g). MS M/z 302 (M + H) + .
Step d: to a solution of tert-butyl 4-cyano-4- (2-methylpyridin-3-yl) piperidine-1-carboxylate (1.08g, 3.58mmol) in MeOH (50 mL) at 0 deg.C was added H dropwise 2 SO 4 (98%, 45 mL). The system was stirred at reflux temperature for 18h. After cooling to room temperature, the reaction was poured into an ice/water mixture (200 mL) and the pH was adjusted to 9 with NaOH. To this mixture was added (Boc) 2 O (11.00g, 50.40mmol) and stirred at room temperature for 2h. Extract with EA (3X 100 mL), combine the organic phases, and remove the aqueous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 4- (2-methyl)Pyridopyridin-3-yl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-methyl ester (467 mg). MS: M/z 335 (M + H) + .
Step e: to a 0 deg.C solution of 4- (2-methylpyridin-3-yl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester-4-methyl ester (467mg, 1.40mmol) in THF (10.50 mL) was added dropwise potassium bis (trimethylsilyl) amide (1M in THF, 7.00mL, 7.00mmol) under a nitrogen atmosphere. It was allowed to warm to RT and stirred for 3.5h, then quenched with saturated ammonium chloride (10 mL) and extracted with EA (3X 40 mL). The combined organic phases are passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 6-oxo-6,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester (170 mg). MS: M/z 303 (M + H) + .
Intermediate A22
Step a: to a 0 deg.C solution of tert-butyl 4-formylpiperidine-1-carboxylate (15.00g, 70.33mmol) in DMF (60 mL) was added lithium tert-butoxide (6.75g, 84.44mmol) in portions. The system was stirred for 30 minutes at 0 ℃. To this mixture was added 3-bromopropene (9.73g, 80.44mmol) dropwise at 0 ℃ and stirred at this temperature for 1h. The reaction was diluted with brine (100 mL) and extracted with EA (3X 200 mL). The organic phases were combined and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 20,v/v) to give 4-allyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester (7.01 g). MS M/z 254 (M + H) + .
Step b: to a solution of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (7.01g, 27.63mmol) in THF (30 mL) at-78 deg.C was added dropwise allyl magnesium bromide (1M solution in THF, 63.55mL, 63.55mmol). Warm to RT and stir for 1.5h. The reaction was quenched with saturated ammonium chloride. Extract with EA (3X 200 mL). The combined organic phases were washed with brine (1X 200 mL) and anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (7).01g)。MS:m/z 282(M+H) + .
Step c: to a solution of tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (7.00g, 24.88mmol) in DCM (50 mL) was added portionwise Daisy-Martin's oxidant (12.66g, 29.85mmol). After stirring at RT for 1.5h, the reaction was diluted with brine (150 mL) and extracted with EA (3X 200 mL). The combined organic phases were passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex =1, 30,v/v) to give 4-acryloyl-4-allylpiperidine-1-carboxylic acid tert-butyl ester (5.63 g). MS M/z 280 (M + H) + .
Step d: a mixture of tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (5.63g, 20.15mmol), grubbs II (428mg, 0.50mmol) and toluene (30 mL) was stirred at 85 ℃ for 3.5h under nitrogen. After cooling to RT, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 5,v/v) to give 1-oxo-8-azaspiro [4.5]Tert-butyl dec-2-ene-8-carboxylate (3.61 g). MS M/z 252 (M + H) + .
Step e: sodium hydride (60% dispersion in mineral oil, 730mg, 18.25mmol) was added in portions to a DMSO (50 mL) solution of trimethyl sulfoxide iodide (3.79g, 17.22mmol), and after stirring for 30min, 1-oxo-8-azaspiro [4.5 ] was added dropwise]Decyl-2-ene-8-carboxylic acid tert-butyl ester (DMSO solution, 3.61g, 14.36mmol). The system was stirred at RT for 1.5h. The reaction was diluted with brine (200 mL) and extracted with EA (3X 200 mL). The combined organic phases were washed with brine (3X 200 mL) and anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-oxo spiro [ bicyclo [3.1.0 ]]Hexane-3,4' -piperidine]-1' -carboxylic acid tert-butyl ester (3.60 g). MS: M/z 266 (M + H) + .
Intermediate A23
Step a: to a solution of tetrahydro-2H-pyran-4-ol (3.54g, 34.66mmol), triethylamine (4.65g, 45.95mmol) in DCM (100 mL) at-10 deg.C was added MsCl (4.61g, 40.24mmol). After the stirring is carried out for 30min,the reaction was diluted with water (100 mL) and extracted with DCM (100mL, 50mL). The combined organic phases were washed with brine (1X 50 mL) and anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave tetrahydro-2H-pyran-4-yl methanesulfonate (6.74 g). MS M/z 181 (M + H) + .
Step b: to 1 '-benzyl-6-methoxyspiro [ indene-2,4' -piperidine]A solution of (1M in DCM, 15.00mL, 15.00mmol) of (1H) -one (4.35g, 13.53mmol) in DCM (200 mL) was added and stirred at 45 ℃ for 13H. Supplement BBr 3 (1M in DCM, 5.00mL, 5.00mmol) and stirred at 45 ℃ for 24h. After cooling to RT, the reaction was diluted with water (150 mL) and NaHCO was added portionwise 3 (20.00 g). The resulting mixture was extracted with DCM (2X 100 mL), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 1 '-benzyl-6-hydroxy spiro [ indene-2,4' -piperidine]-1 (3H) -one (2.80 g), used in the next step without further purification. MS M/z 308 (M + H) + .
Step c: 1 '-benzyl-6-hydroxy spiro [ indene-2,4' -piperidine]-1 (3H) -one (2.80g, 9.11mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (3.40g, 18.87mmol) and K 2 CO 3 A mixture of (8.23g, 59.55mmol) and DMF (60 mL) was stirred at 110 ℃ for 5.5h. Supplemented with tetrahydro-2H-pyran-4-yl methanesulfonate (1.10g, 6.10mmol) and K 2 CO 3 (4.55g, 32.92mmol) and stirred at 110 ℃ for 1.5h. After cooling to RT, the mixture was diluted with water (300 mL) and EA (600 mL). The aqueous phase was separated and extracted with EA (1X 200 mL), the organic phases combined, washed with water (2X 300 mL) and brine (1X 300 mL), over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM =1, 40, v/v) to give 1 '-benzyl-6- ((tetrahydro-2H-pyran-4-yl) oxy) spiro [ indene-2,4' -piperidine]-1 (3H) -one (1.70 g). MS M/z 392 (M + H) + .
Step d: under hydrogen atmosphere, 1 '-benzyl-6- ((tetrahydro-2H-pyran-4-yl) oxy) spiro [ indene-2,4' -piperidine]-1 (3H) -one (1.70g, 4.34mmol) and Pd (OH) 2 A solution of (10%, 1.21 g) MeOH was stirred at RT for 3h. The reaction system was filtered. To the filtrate was added (Boc) 2 O(1.10g，5.04mmol) and stirred at room temperature for 40h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 5,v/v) to give 1-oxo-6- ((tetrahydro-2H-pyran-4-yl) oxy) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.45 g). MS M/z 402 (M + H) + .
Intermediate A24
Under nitrogen atmosphere, 6-bromo-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1017mg, 2.67mmol), diethyl phosphonate (564mg, 4.08mmol), potassium phosphate (1156 mg, 5.45mmol), pd (OAc) 2 A mixture of (63mg, 0.28mmol), xantPhos (307mg, 0.53mmol) and DMF (10 mL) was stirred at 130 ℃ for 21h. After cooling to RT, the reaction was quenched with water (60 mL), filtered, and the filter cake rinsed with EA (2X 30 mL). The filtrates were separated and the aqueous layer was extracted with EA (2X 60 mL). The combined organic phases are passed over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 6- (diethoxyphosphoryl) -1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl (134 mg) 1' -carboxylate, used in the next step without further purification. MS: M/z 438 (M + H) + .
Intermediate A25
Intermediate a25 was synthesized according to the procedure of y.uto et al/bioorg.med.chem.lett.20 (2010) 746-754.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 11
Intermediate A26
Step a: to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (5.23g, 20.32mmol) in THF (30 ml) at-65 deg.C was added LDA (2M solution in THF/Hex, 12.00mL, 24.00mmol) dropwise. The resulting mixture was stirred at this temperature for 1.0h. 2-bromobenzaldehyde (3.44g, 18.59mmol) was added dropwise at-70 ℃. After stirring for 1h, the mixture was quenched with brine (40 mL). Separating the organic phase with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 4- ((2-bromophenyl) (hydroxy) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (9.15 g) which was used in the next step without further purification. MS M/z 442 (M + H) + .
Step b: to a solution of 4- ((2-bromophenyl) (hydroxy) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (9.15g, 20.68mmol) in DCM (70 ml) at-5 deg.C was added dess-martin oxidant (18.02g, 42.49mmol). The system was stirred at RT for 2.5h. With Na 2 S 2 O 3 Aqueous (25%, 1X 80 mL), saturated NaHCO3 (1X 80 mL) and brine (1X 100 mL). The organic phase is passed through anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 5,v/v) to give 4- (2-bromobenzoyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (7.16 g). MS M/z 440 (M + H) + .
Step c: to a solution of 4- (2-bromobenzoyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (2.00g, 4.54mmol) in THF (20 mL) at-80 deg.C was added 1.8mL of n-butyllithium (2.5M in THF/Hex) with nitrogen blanketing. The system naturally returns to the room temperature, and stirring is continued for 1h. The system was quenched by adding 30mL of saturated brine and the organic phase was collected. The aqueous phase was extracted by adding 20mL of EA. The organic phases were combined and anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give 1,3-dioxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (500 mg), MS: M/z 316 (M + H) +.
Intermediate A27
Intermediate A27 was synthesized according to the procedure of J.org.chem.1999,64, 5504-5510.
Intermediate A28
Step a: to a solution of ethyl 2-chlorothiazole-4-carboxylate (24.95g, 130.19mmol) at 0 deg.C in MeOH (250 mL) was added NaBH in portions 4 (17.29g, 456.97mmol). The mixture was warmed to RT and stirred for 2h. The reaction was diluted with water (200 mL) and concentrated under reduced pressure to remove volatiles. The system was extracted with EA (2X 200 mL), the combined organic phases were washed with brine (1X 400 mL), anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give (2-chlorothiazol-4-yl) methanol (18.88 g). MS M/z 150 (M + H) + .
Step b: to a solution of (2-chlorothiazol-4-yl) methanol (18.88g, 130.19mmol) and triethylamine (25.56g, 252.57mmol) in DCM (200 mL) was added MsCl (15.96g, 139.30mmol) dropwise and added dropwise over 15min. The system was stirred for 25min at RT. The reaction was quenched with brine (200 mL) and the aqueous phase was separated. Anhydrous Na for organic phase 2 SO 4 Dried, filtered and concentrated under reduced pressure to give (2-chlorothiazol-4-yl) methyl methanesulfonate, which was used in the next step without further purification. MS M/z 228 (M + H) + .
Step c: LDA (2M THF/Hex solution, 75.00mL, 150.00mmol) was added dropwise to a-60 ℃ solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (35.67g, 138.62mmol) in THF (200 mL) under nitrogen for 30min. Then a solution of methanesulfonic acid (2-chlorothiazol-4-yl) methyl ester in THF (50 mL) was added dropwise, allowed to warm to RT naturally and stirred for 2h. The reaction was quenched with brine (300 mL). Separating the organic phase with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1,4-bisCarboxylic acid 1-tert-butyl 4-ethyl ester (38.12 g). MS M/z 389 (M + H) + .
Step d: LDA (2M solution in THF/Hex, 11.00mL, 22.00mmol) was added dropwise to a-60 deg.C solution of 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (8.51g, 21.88mmol) in THF (80 mL) under a nitrogen atmosphere. After the completion of the dropping, the reaction solution was quenched with brine (50 mL). Separating the organic phase with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give 2-chloro-6-oxo-4,6-dihydrospiro [ cyclopenta [ d]Thiazole-5,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.93 g). MS: M/z 343 (M + H) + .
Intermediate A29
Step (a-c) Synthesis of 1- (tert-butyloxycarbonyl) -4- (thien-2-ylmethyl) piperidine-4-carboxylic acid with reference to step (b-c) of intermediate A28 and step (b) of intermediate A3.
Step d: a mixture of 1- (tert-butoxycarbonyl) -4- (thien-2-ylmethyl) piperidine-4-carboxylic acid (4.92g, 15.12mmol) and PPA (30.12 g) was stirred at 110 ℃ for 5h. The reaction was poured into an ice/water mixture (100 mL) and the pH was adjusted to 10 with NaOH. Then add (Boc) 2 O (5.05g, 23.14mmol) and stirred at room temperature for 18h. Extract with EA (2X 50 mL). The combined organic phases were washed with brine (1X 50 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-tert-butyl-4-oxo-4,6-dihydrospiro [ cyclopenta [ b ]]Thiophene-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.70 g). MS M/z 364 (M + H) + .
Step e: a mixture of 1- (tert-butoxycarbonyl) -4- (thien-2-ylmethyl) piperidine-4-carboxylic acid (4.88g, 15.12mmol), HCl (4M in 1,4-dioxane, 8 mL), and DCM (50 mL) was stirred at RT for 1h. The reaction was concentrated under reduced pressure. PPA (21.15 g) was added and the system was stirred at 110 ℃ for 1.5h. The reaction was poured into an ice/water mixture (100 mL) and the pH adjusted to 10 with NaOH. Then add (Boc) 2 O (5.12g, 23.46mmol) and stirred at room temperature for 18h. Extract with EA (2X 50 mL). The combined organic phases were washed with brine (1X 100 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 10,v/v) to give 4-oxo-4,6-dihydro-4 spiro [ cyclopenta [ b]Thiophene-5,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (2.71 g). MS M/z 308 (M + H) + .
Intermediate A30
A, step a: to a solution of benzyl alcohol (5.15g, 47.62mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 3.01g, 75.25mmol) in portions, and the mixture was stirred for 20min. 4-chloropyridine-2-carboxylic acid (2.68g, 17.01mmol) was added and stirred at 85 ℃ for 3.5h. After cooling to RT, HCl (4M in 1,4-dioxane, 10 mL) was added. The system was used directly in the next step. MS M/z 230 (M + H) + .
Step b: c, reacting the reaction system in the step a with NaHCO 3 (7.51g，89.39mmol)，CH 3 I (1.5 mL) was mixed with DMF (10 mL). After stirring for 0.5h, CH is replenished 3 I (1.5 mL) and stirred for 16h. The reaction was diluted with EA (250 mL), filtered, and the filtrate was washed with brine (2X 150 mL). The organic phase is passed through anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, v/v) to give methyl 4- (benzyloxy) pyridine-2-carboxylate (1.50 g). MS M/z 244 (M + H) + .
Step c: methyl 4- (benzyloxy) pyridine-2-carboxylate (1.50g, 6.17mmol), liBH 4 A mixture of (2M in THF, 9.00mL, 18.00mmol) and THF (40 mL) was stirred at 50 deg.C for 1h. The reaction was diluted with MeOH (15 mL) and water (150 mL) and extracted with EA (200mL, 50mL). The combined organic phases were washed with brine (2X 100 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give (4- (benzyloxy) pyridin-2-yl) methanol (0.50 g). MS M/z 216 (M + H) + .
Step d: a mixture of (4- (benzyloxy) pyridin-2-yl) methanol (0.50g, 2.32mmol), dess-martin oxidant (1.25g, 2.95mmol) and DCM (20 mL) was stirred for 1.5h. The reaction solution is saturated NaHSO 3 Aqueous solution, saturated NaHCO 3 Aqueous and DCM (50 mL). The aqueous phase was separated and extracted with DCM (50 mL). The combined organic phases were washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4- (benzyloxy) pyridine-2-carbaldehyde (0.40 g). MS M/z 214 (M + H) + .
Step e: to a 0 ℃ solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (0.52g, 2.02mmol) in THF (15 mL) was added LDA (2M solution in THF/Hex, 1.30mL, 2.60mmol) dropwise. The system was cooled to-70 ℃ and a solution of 4- (benzyloxy) pyridine-2-carbaldehyde (0.40g, 1.88mmol) in THF (5 mL) was added. It was warmed to-15 ℃ and stirred for 30min, then quenched with saturated ammonium chloride (10 mL), diluted with water (50 mL) and extracted with EA (1X 100 mL). The organic phase was washed with brine (2X 50 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex = 1:1) to give 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.25 g). MS: M/z 471 (M + H) + .
Step f: 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.25g, 0.53mmol), liBH 4 (2M in THF, 1.00mL, 2.00mmol) was stirred at 55 deg.C for 40min in THF (10 mL). The reaction was quenched with MeOH (10 mL) and concentrated under reduced pressure to remove volatiles. The residue was diluted with water (150 mL) and extracted with EA (1X 50 mL). The organic phase was washed with brine (1X 30 mL) and anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave tert-butyl 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (0.22 g). MS: M/z 429 (M + H) + .
Step g: a mixture of tert-butyl 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (0.22g, 0.51mmol), pd/C (10%, 0.12 g) and MeOH (20 mL) was placed in a beakerStirring for 1.5h under hydrogen atmosphere. The reaction mixture was filtered, the filter cake was rinsed with MeOH, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- (hydroxy (4-hydroxypyridin-2-yl) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (154 mg). MS M/z 339 (M + H) + .
Step h: to a solution of tert-butyl 4- (hydroxy (4-hydroxypyridin-2-yl) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (120mg, 0.36mmol) and triphenylphosphine (175mg, 0.67mmol) in THF (10 mL) was added N, N, N ', N' -tetramethylazodicarboxamide (158mg, 0.68mmol). The mixture was stirred at RT for 30min. Purification by silica gel chromatography (eluting with MeOH: DCM = 17,v/v) afforded 1-hydroxy-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (100 mg). MS M/z 321 (M + H) + .
Step i: 1-hydroxy-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]A mixture of tert-butyl (0.35g, 1.09mmol) -1' -carboxylate, dess-martin oxidant (0.72g, 1.70mmol) and DCM (35 mL) was stirred at RT for 2h. Saturated Na for system 2 SO 3 (1X 20 mL) and saturated NaHCO 3 Aqueous (1X 20 mL) wash. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 1,7-dioxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (0.33 g). MS M/z 319 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 12
Intermediate B1
According to the procedure of WO 2017211303A 1, intermediate B1 is synthesized in three steps starting from 4-iodoisatin.
Intermediate B2
According to the procedure of WO 2017211303A 1, 2-amino-3-bromo-6-chloropyrazine is used as a raw material to synthesize an intermediate B2 through 2 steps.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
Watch 13
Intermediate B3
2-fluoro-3-chloro-4-iodopyridine (10.10 g, 39.23mmol) and DMSO (50 mL) were added to a sealed tube, and aqueous ammonia (25%, 50 mL) was added dropwise. The system was stirred at 80 ℃ for 16h. After cooling to RT, the reaction was poured into water (250 mL), filtered to give a precipitate, dissolved in DCM (280 mL), washed with brine (1X 100 mL), and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave 3-chloro-4-iodopyridin-2-amine (7.01 g). MS: M/z 255 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 14
Intermediate B4
Under nitrogen atmosphere, 3-chloro-4-iodopyridin-2-amine (25.53g, 100.33mmol), 3-amino-5-chloropyrazine-2-thiol sodium (20.18g, 109.92mmol), pd 2 (dba) 3 (4.47g，4.88mmol)，XantPhos(5.81g,10.04 mmol) and DIEA (26.12g, 202.10mmol) in 1,4-dioxane (100 mL) were stirred at 70 ℃ for 1.5h. Cooled to room temperature, the reaction was filtered through celite, then washed with 1,4-dioxane (30 mL) and the filtrate was concentrated under reduced pressure. DCM (100 mL) and EA (100 mL) were added to the residue and stirred for 40min. The precipitate was collected and dried in a vacuum oven to give 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (13.86 g). MS: M/z 288 (M + H) + .
The following compounds were synthesized using the above procedure and the corresponding starting materials.
Watch 15
Example 1
(R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidine ] -2-amine
Step a: a mixture of compound 1H-indene (11.62g, 0.10 mol) and LiHMDS (220mL, 1mol/L in THF) in THF (120 mL) was stirred at-50 ℃ for 1H. Tert-butyl bis (2-chloroethyl) carbamate (24.21g, 0.10mol) was added to the reaction solution and stirred at-50 ℃ for 1h. Quench with brine (300 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the compound spiro [ indene-1,4' -piperidine as a yellow solid]-1' -carboxylic acid tert-butyl ester (10.36g, 36%). MS 286 (M + H) + .
Step b: the compound spiro [ indene-1,4' -piperidine]A solution of tert-butyl (117.02g, 0.41mol) 1' -carboxylate and borane dimethylsulfide complex (10 mol/L,220 mL) in THF (800 mL) was stirred at 0 ℃ for 3h. Adding NaOH(2 mol/L, 1.2L) and H 2 O 2 (300 mL) and stirred at 0 ℃ for 1h. Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-hydroxy-2,3-dihydrospiro [ indene-1,4' -piperidine]-1 '-Carboxylic acid tert-butyl ester and 3-hydroxy-2,3-dihydrospiro [ indene-1,4' -piperidine]Tert-butyl-1' -carboxylate, yellow oil (130.33 g, crude). MS:304 (M + H) + .
Step c: 2-hydroxy-2,3-dihydrospiro [ indene-1,4' -piperidine]-1 '-Carboxylic acid tert-butyl ester and 3-hydroxy-2,3-dihydrospiro [ indene-1,4' -piperidine]A mixture of tert-butyl (130.02g, 0.43mol) -1' -carboxylate, dess-Martin oxidant (364.76g, 0.86mol) and DCM (2L) was stirred at 25 ℃ for 12h. The reaction solution was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (1L) and brine (1L), followed by anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the white solid compound 3-oxo-2,3-dihydrospiro [ indene-1,4' -piperidine]Tert-butyl (41.75g, 34%, two-step yield) 1' -carboxylate. MS:302 (M + H) + .
Step d: to the compound 3-oxo-2,3-dihydrospiro [ indene-1,4' -piperidine]To a solution of tert-butyl (41.01g, 0.14mol) of (E) -1' -carboxylate in ethyl titanate (80 mL) was added R- (+) -tert-butylsulfinamide (49.46g, 0.41mol). The system was stirred at 85 ℃ for 2h. EA (0.5L) and water (0.5L) were added to the reaction system. The reaction was filtered and the organic phase was collected. The aqueous phase was extracted with EA (200 mL. Times.2). The combined organic phases were washed with brine (500 mL) and anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain the compound (R, E) -2- ((tert-butylsulfinyl) imino) -2,3-dihydrospiro [ indene-1,4' -piperidine]-1' -carboxylic acid tert-butyl ester (132.05 g, crude). MS:405 (M + H) + The impure sample was used directly in the next step. .
Step e: the compound (R, E) -2- ((tert-butylsulfinyl) imino) -2,3-dihydrospiro [ indene-1,4' -piperidine]A solution of tert-butyl (1' -carboxylate) (132.02g, 0.33mol) in THF (200 mL) was cooled to-50 ℃ and stirred. Adding NaBH 4 (7.71g, 0.51mol), the temperature was naturally raised to RT. Quench with saturated ammonium chloride solution (100 mL). Collecting the organic phase, and adding anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by column chromatographyThe residue is taken to obtain (R) -2- (((R) -tert-butylsulfinyl) amino) -2,3-dihydrospiro [ indene-1,4' -piperidine]Tert-butyl (E) -1' -carboxylate was a white solid (27.25g, 49%, two-step yield). MS:407 (M + H) + .
Step f: (R) -2- (((R) -tert-butylsulfinyl) amino) -2,3-dihydrospiro [ indene-1,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.16g, 3.98mmol), CF 3 A solution of COOH (3.6 mL) in DCM (20 mL) was stirred at 25 ℃ for 1.5h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in NMP (15 mL), and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (1.03g, 3.59mmol) and K were added 2 CO 3 (6.60g, 47.76mmol), stirred at 90 ℃ for 16h. Adding H to the reaction solution 2 O (30 mL) and filtered. The filter cake was dissolved in DCM (40 mL) and washed with brine (40 mL). Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain compound (R) -N- ((R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-3-yl) pyrimidin-4-yl) thio) pyrazin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (1.55g, 70%) as yellow solid.
Step g: to the compound (R) -N- ((R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidine]To a solution of (2-yl) -2-methylpropane-2-sulfinamide (1.52g, 2.72mmol) in DCM (20 mL) was added HCl/1,4-dioxane (2mL, 4 mol/L). The system was stirred at 25 ℃ for 1h and the precipitate was collected by filtration. The filter cake was dispersed in DCM (30 mL) and ammonium hydroxide (5 mL) was added to adjust the pH>10. The mixture was washed with brine (40 mL) and anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give the compound (R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidine]2-amine as a yellow solid (530mg, 42%). MS:454 (M + H) + . 1 H NMR(400MHz,DMSO-d6)δ7.64-7.66(m,2H),7.30(d,1H),7.20(d,1H),7.13-7.15(m,2H),6.78(d,1H),4.05-4.09(m,1H),3.91-3.95(m,1H),3.54-3.60(m,3H),3.12-3.18(m,1H),2.57-2.63(m,1H),1.91-2.09(m,2H),1.66-1.76(m,1H),1.49-1.58(m,1H).
Example 2
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-amine
Step a: sodium hydride (60%) (3.63g, 90.80mmol) was added to a solution of compound 2,3-dihydro-1H-inden-1-one (4.00g, 30.27mmol) in DMF (80 mL). The mixture was stirred at 16 ℃ for 30min. Tert-butyl bis (2-chloroethyl) carbamate (8.06g, 33.29mmol) was added dropwise. The mixture was then stirred at 60 ℃ for 16h. The mixture was quenched with brine (200 mL) and extracted with EA (100 mL. Times.2). The organic phases were combined and washed with brine (100 mL. Times.2) and anhydrous Na 2 SO 4 And (5) drying. After concentration, the residue was purified by column chromatography to give the compound 1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.21g, 13%) dark red oil. MS:302 (M + H) + .
Step b: after heating ethyl titanate (12.00 g) to 90 ℃, the compound 1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl (1.21g, 4.01mmol) of (1' -carboxylic acid and (R) -2-methylpropane-2-sulfinamide (1.22g, 12.04mmol) were added. After stirring at 90 ℃ for 19h. The mixture was poured into EA (200 mL) and brine (200 mL) was added. After stirring for 15 minutes, filtration was carried out. The filtrate was partitioned. The organic phase was washed with brine (200 mL. Times.2) over anhydrous Na 2 SO 4 And (5) drying. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give (R, Z) -1- ((tert-butylsulfinyl) imino) -1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl (1.01g, 62%) 1' -carboxylate as a black solid. MS:405 (M + H) + .
Step c: (R, Z) -1- ((tert-butylsulfinyl) imino) -1,3-dihydrospiro [ indene-2,4' -piperidine]A solution of tert-butyl (1.01g, 2.50mmol) of the (E) -1' -carboxylate in THF (10 mL) was cooled to-50 ℃. Adding NaBH in portions 4 (142mg, 3.74mmol). The mixture was allowed to warm to room temperature, stirred for 15.5h, and then poured into EA (100 mL). The mixture was washed with brine (100 mL. Times.3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatographyThe residue is used to obtain the compound (S) -1- (((R) -tert-butylsulfinyl) amino) -1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl-1-carboxylate (580 mg, 57%) as a yellow oil. MS:407 (M + H) + .
Step d: the compound (S) -1- (((R) -tert-butylsulfinyl) amino) -1,3-dihydrospiro [ indene-2,4' -piperidine]A solution of tert-butyl-1' -carboxylate (580 mg, 1.43mmol) and TFA (1 mL) in DCM (5 mL) was stirred at 20 ℃ for 40min. Concentrating the solution to obtain compound (R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (520mg, 90%) as a yellow oil. MS:307 (M + H) + .
Step e: mixing the compound (R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (260mg, 0.62mmol), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (196mg, 0.68mmol), K 2 CO 3 (427mg, 3.09mmol) and NMP (8 mL) were stirred at 100 ℃ for 16h. The mixture was poured into EA (200 mL) and washed with brine (200 mL × 3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the compound (R) -N- ((S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) inden-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (260mg, 65%) as a yellow solid. MS:558 (M + H) + .
Step f: the compound (R) -N- ((S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (260mg, 0.47mmol) was dissolved in DCM (5 mL) and HCl/1,4-dioxane (4 mol/L,5 mL) was added dropwise. The mixture was stirred at 20 ℃ for 30 minutes. The mixture was concentrated and the residue was dissolved in methanol (2 mL). And EA (5 mL) was added. The solid was collected by filtration to give the compound (S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1-amine (123mg, 54%) as an off-white solid. MS:454 (M + H) + . 1 H NMR(400MHz,DMSO-d6)δ7.81(d，1H)，7.72(s，1H)，7.62(d，1H)，7.27-7.36(m，3H)，6.12(d，1H)，4.21-4.35(m，3H)，2.97-3.24(m，4H)，1.77-1.91(m，2H)，1.49-1.59(m，2H).
Example 3
(R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine ] -2-amine
Step a: a solution of the compound tert-butyl bis (2-chloroethyl) carbamate (11.00g, 45.43mmol) in HCl/1,4-dioxane (4 mol/L,200 mL) was stirred at 20 ℃ for 1h. The solution was concentrated and the residue was dissolved in DCE (200 mL). Triethylamine (22.95g, 227.14mmol) and benzaldehyde (7.23g, 68.14mmol) were added. Then add NaBH (OAc) in portions 3 (24.07g, 113.57mmol). The mixture was stirred at 20 ℃ for 54h, then EA (300 mL) and brine (200 mL) were added. The organic phase was separated and concentrated under reduced pressure. The residue was dissolved in HCl solution (2 mol/L,200 mL) and washed with EA (100 mL). With saturated Na 2 CO 3 The solution adjusted the pH of the aqueous phase to 9. The mixture was extracted with EA (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the compound N-benzyl-2-chloro-N- (2-chloroethyl) ethane-1-amine (8.52g, 81%) as a colorless oil.
Step b: to a mixed solution of the compounds N-benzyl-2-chloro-N- (2-chloroethyl) ethan-1-amine (8.52g, 36.70mmol) and 3,4-dihydronaphthalen-2 (1H) -one (4.88g, 33.36mmol) in THF (80 mL) and DMSO (50 mL) was added potassium tert-butoxide (9.36g, 83.14mmol). Stirring was carried out at 20 ℃ for 20h. The mixture was concentrated and diluted with EA (200 mL). Then washed with brine (200 mL. Times.3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 1 '-benzyl-3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine as a black oil]2-keto (2.32g, 21%). MS:306 (M + H) + .
Step c: adding the compound 1 '-benzyl-3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine to ethyl titanate]-2-ketone (2.32g, 7.60mmol) and (R) -2-methylpropane-2-sulfinamide (2.76g, 22.79mmol). Stirring was carried out at 100 ℃ for 19h. EA (200 mL) and water (200 mL) were added. Filtering, separating the filtrate, and collecting organic matterAnd (4) phase(s). The organic phase was washed with brine (100 mL × 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (R, E) -N- (1 '-benzyl-3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]-2-ylidene) -2-methylpropane-2-sulfinamide (660mg, 21%) as a yellow oil. MS:409 (M + H) + .
Step d: the compound (R, E) -N- (1 '-benzyl-3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]A solution of-2-ylidene) -2-methylpropane-2-sulfinamide (660mg, 1.62mmol) in THF (10 mL) was cooled to-50 ℃. Then add NaBH in portions 4 (122mg, 3.23mmol). The mixture was stirred for 18h and allowed to warm to RT. Quenched with water (50 mL) and extracted with EA (50 mL. Times.2). The organic phases were combined and washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (R) -N- ((R) -1 '-benzyl-3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (195mg, 29%) as a yellow oil. MS:411 (M + H) + .
Step e: to the compound (R) -N- ((R) -1 '-benzyl-3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]To a solution of (2-yl) -2-methylpropane-2-sulfinamide (195mg, 0.47mmol) in methanol (5 mL) was added palladium hydroxide (20%, 120 mg). Stirred under hydrogen at 40 ℃ for 18h. Filtering and concentrating under reduced pressure to obtain compound (R) -N- ((R) -3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (92mg, 60%). MS:321 (M + H) + .
Step f: the compound (R) -N- ((R) -3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (92mg, 0.29mmol) was dissolved in NMP (3 mL). 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (91mg, 0.32mmol) and K were added 2 CO 3 (198mg, 1.44mmol). Stir at 100 ℃ for 3h, dilute with EA (30 mL), and wash with brine (30 mL × 3). Anhydrous Na for organic phase 2 SO 4 And (5) drying. The residue was purified by Pre-TLC to give (R) -N- ((R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (18mg, 11%) as an off-white solid.
Step g: to the compound (R) -N- ((R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3,4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]To a solution of (2-yl) -2-methylpropane-2-sulfinamide (18mg, 0.03mmol) in 1,4-dioxane (2 mL) was added HCl/1,4-dioxane (4 mol/L,2 mL). After stirring for 30min, concentrate and wash twice with EA. Drying the solid in high vacuum to obtain the compound (R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) 4-dihydro-2H-spiro [ naphthalene-1,4' -piperidine]-2-amine (14mg, 88%) as an off-white solid. MS:468 (M + H) + .
Example 4
(R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4' -piperidine ] -6-amine
Step a: naHMDS (38ml, 2mol/L in THF) was added to a solution of the compound 2-fluoro-3-methylpyridine (5.56g, 50.00mmol) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester 14.15g, 55.00mmol) in toluene (50 mL) at 0 deg.C, warmed to 20 deg.C naturally and stirred for 24h. The reaction was quenched with brine (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 4- (3-methylpyridin-2-yl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester as a yellow oil (6.32g, 36%). MS:349 (M + H) + .
Step b: a solution of compound 4- (3-methylpyridin-2-yl) piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.80g, 13.78mmol) and LDA (2 mol/L,17 mL) in THF (48 mL) was stirred at 0 deg.C for 0.5h. The volatiles were removed by concentration under reduced pressure. The residue was purified by column chromatography to give 6-oxo-5,6-dihydrospiro [ cyclopenta [ b ] as a red oil]Pyridine-7,4' -piperidine]-1' -carboxylic acid tert-butyl ester (0.95g, 23%). MS 303 (M + H) + .
Step c: to 6-oxo-5,6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7,4' -piperidine]-tert-butyl 1' -carboxylate (0.94g, 3.11mol) in Ethyl titanate (5 mL)) To the solution was added (R) -2-methylpropane-2-sulfinamide (1.13g, 9.33mmol). Stirring was carried out at 80 ℃ for 1h. EA (30 mL) and water (20 mL) were added to the reaction. Filtering, and collecting an organic phase in the filtrate. The aqueous phase was extracted with EA (10 mL. Times.2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (R, Z) -6- ((tert-butylsulfinyl) imino) -5,6-dihydrospiro [ cyclopenta [ b ] a]Pyridine-7,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (2.51 g, crude). The reaction was directly put to the next step without further purification. MS:406 (M + H) + .
Step d: the compound (R, Z) -6- ((tert-butylsulfinyl) imino) -5,6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7,4' -piperidine]A solution of tert-butyl (2.12 g, crude) 1' -carboxylate in THF (20 mL) was stirred at-50 ℃. Reacting NaBH 4 (176mg, 4.66mmol) was added to the reaction and the temperature was raised naturally to RT. The reaction was quenched with saturated ammonium chloride solution (30 mL). The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give (R) -6- (((S) -tert-butylsulfinyl) amino) -5,6-dihydrospiro [ cyclopenta [ b ] as a yellow solid]Pyridine-7,4' -piperidine]Tert-butyl (0.21g, 17%, two-step yield) 1' -carboxylate. MS:408 (M + H) + .
Step e: the compound (R) -6- (((S) -tert-butylsulfinyl) amino) -5,6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (204mg, 0.50mmol) and CF 3 A mixture of COOH (1 mL) in DCM (10 mL) was stirred at 25 ℃ for 1.5h. The reaction was concentrated under reduced pressure. The residue was dissolved in NMP (10 mL) and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (144mg, 0.50mmol) and K were added 2 CO 3 (0.82g, 6.00mmol) was stirred at 95 ℃ for 16h. Addition of H 2 O (50 mL), extracted with EA (30 mL. Times.2). The combined organic phases were washed with brine (50 mL) over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain the compound (S) -N- ((R) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5,6-dihydrospiro [ cyclopenta [ b ] b]Pyridine-7,4' -piperidine]-6-yl) -2-methylpropane-2-sulfinamide (302 mg, crude). The reaction was directly put to the next step without further purification. MS:559 (M + H) + .
Step f: to the compound (S) -N- ((R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) pyridine-7,4' -piperidine]To a solution of (6-yl) -2-methylpropane-2-sulfinamide (302mg, 0.54mmol) in DCM (10 mL) was added HCl/1,4-dixoane (4 mol/L,1 mL). The system was stirred at 25 ℃ for 1h and filtered. The filter cake was dissolved in MeOH (2 mL), DCM (15 mL) was added, stirred for 0.5h, and filtered to give the compound (R) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5,6-dihydrospiro [ cyclopenta [ b ] as a yellow solid]Pyridine-7,4' -piperidine]-6-amine (163mg, 71%, two-step yield). MS:455 (M + H) + . 1 H NMR(600MHz,MeOH-d4)δ8.69(d,1H),8.54(d,1H),7.92-7.96(m,1H),7.88(s,1H),7.75(d,1H),6.58(d,1H),4.54-4.67(m,3H),3.89-3.95(m,1H),3.37-3.61(m,3H),2.79-2.86(m,1H),1.93-2.20(m,3H).
Example 5
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-amine
Step a: mixing 6-methoxy-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (557mg, 1.68mmol) and (R) -2-methylpropane-2-sulfinamide (610mg, 5.04mmol) in Ti (OEt) 4 The solution (5 mL) was stirred at 100 ℃ for 16h. After cooling to RT, the reaction was diluted with EA (20 mL) and water (30 mL). Filter through a pad of celite, rinsing with EA. The filtrate was washed with brine (1X 50 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain (R, Z) -1- ((tert-butylsulfinyl) imino) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl (0.98 g) -1' -carboxylate, which was used in the next step without further purification. MS M/z 435 (M + H) + .
Step b: to (R, Z) -1- ((tert-butylsulfinyl) imino) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine](ii) -1' -Carboxylic acid tert-butyl ester (0.98g, 2.25mmol) in THF (10 mL) NaBH was added 4 (0.17g,4.51 mmol). The mixture was warmed to RT and stirred for 24h. The reaction was diluted with EA (50 mL) and water (50 mL), the organic phase separated, washed with brine (1X 50 mL), anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, 5,v/v) to give (S) -1- (((R) -tert-butylsulfinyl) amino) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (380 mg). MS M/z 437 (M + H) + .
Step c: to (S) -1- (((R) -tert-butylsulfinyl) amino) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (1' -carboxylate) (380mg, 0.87mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture was stirred at RT for 1.5h. The system was concentrated under reduced pressure. The residue was dissolved in NMP (10 mL), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (301mg, 1.04mmol) and K were added 2 CO 3 (601mg, 4.35mmol). The system was stirred at 100 ℃ for 16h. After cooling to RT, the reaction was diluted with water (50 mL) and EA (50 mL). The aqueous phase was separated and the organic phase was washed with brine (2X 50 mL) over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM =1, 20, v/v) to give (R) -N- ((S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine `]-3-yl) -2-methylpropane-2-sulfinamide (254 mg). MS: M/z 588 (M + H) + .
Step d: to (R) -N- ((S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of (3-yl) -2-methylpropane-2-sulfinamide (254mg, 0.43mmol) in 1,4-dioxane (3 mL) was added HCl (4M solution in 1,4-dioxane, 3 mL) dropwise and stirred at RT for 30min. Filtering and drying the collected precipitate in a vacuum oven to obtain (S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]-1-amine (221 mg, hydrochloride salt). MS M/z 484 (M + H) + . 1 H NMR(600MHz,MeOH-d4)δ7.90(s,1H),7.76(d,1H),7.28(d,1H),7.12(d,1H),6.95-6.89(m,1H),6.58(d,1H),4.35-4.50(m,3H),3.82(s,3H),3.40-3.49(m,2H),3.08-3.16(m,2H),1.66-2.01(m,4H).
The following examples were synthesized with the corresponding intermediate a and intermediate B, according to the methods described above.
The following examples are in the form of the free base or a pharmaceutically acceptable salt thereof.
Example 82
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -7-amine
Step a: 7-oxo-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]A solution of tert-butyl (936mg, 3.10mmol) of-1' -carboxylate and (R) -2-methylpropane-2-sulfinamide (1045mg, 8.62mmol) in ethyl titanate (8 mL) was stirred at 100 ℃ for 2h. After cooling to RT, the reaction was diluted with EA (50 mL) and water (50 mL). Filter through a pad of celite and rinse the filter cake with EA. Separating organic phase from filtrate, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain (R, Z) -7- ((tert-butylsulfinyl) imino) -5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.41 g). MS M/z 406 (M + H)) + .
Step b: to-40 deg.C of (R, Z) -7- ((tert-butylsulfinyl) imino) -5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]To a solution of tert-butyl (1.41g, 3.48mmol) of (E) -1' -carboxylate in THF (50 mL) was added BH 3 (1M in THF, 10.00mL, 10.00mmol). The mixture was warmed to RT and stirred for 1h. The reaction was quenched with brine (100 mL). The organic phases were collected, the aqueous phase was extracted with EA (1X 60 mL), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL) and stirred at 80 ℃ for 15h. After cooling to RT, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM =1 60, v/v) to give (S) -7- (((R) -tert-butylsulfinyl) amino) -5,7-dihydrospiro [ cyclopenta [ b]Pyridine-6,4' -piperidine]-1' -carboxylic acid tert-butyl ester (309 mg). MS: M/z 408 (M + H) + .
Step c: to (S) -7- (((R) -tert-butylsulfinyl) amino) -5,7-dihydrospiro [ cyclopenta [ b ] b]Pyridine-6,4' -piperidine]To a solution of tert-butyl (309mg, 0.76mmol) 1' -carboxylate in DCM (20 mL) was added HCl (4M in EA, 2mL, 8.00mmol) and stirred at RT for 1.5h. Concentrating under reduced pressure to obtain (S) -5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-7-amine (227 mg). MS: M/z 204 (M + H) + .
Step d: mixing (S) -5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-7-amine (HCl salt, 227mg, 0.73mmol), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (249mg, 0.86mmol), K 2 CO 3 A mixture of (1149mg, 8.31mmol) and acetonitrile (15 mL) was stirred at reflux for 44h. After cooling to RT, the reaction was diluted with brine (100 mL) and extracted with EA (2X 50 mL). The organic phases were combined and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM = 1) to give (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) pyrimidin-5-yl) thio) pyrazin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-7-amine (77 mg). MS M/z 455 (M + H) + . 1 H NMR(400MHz,MeOH-d4)δ8.51(s,1H),7.81(d,1H),7.63(s,1H),7.38(s,1H),5.94(d,1H),4.49-4.30(m,3H),3.37-3.09(m,4H),2.05-1.95(m,1H),1.85-1.70(m,2H),1.60-1.50(m,1H).
The following examples were synthesized with the corresponding intermediate a and intermediate B, according to the methods described above.
In step a of example 82, tert-butylsulfinamide was used instead of (R) -2-methylpropane-2-sulfinamide to give the corresponding racemic product.
The following examples are in the form of the free base or a pharmaceutically acceptable salt thereof.
Example 133
(S) -4- ((5- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -3-chloropyridin-2-ol
Steps a-c (R) -N- ((S) -1'- (5- ((3-chloro-2-methoxypyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine) was obtained by steps (a-c) of example 5]-1-yl) -2-methylpropane-2-sulfinamide MS M/z 558 (M + H) + .
Step d: mixing (R) -N- ((S) -1'- (5- ((3-chloro-2-methoxypyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine]A mixture of-1-yl) -2-methylpropane-2-sulfinamide (112mg, 0.20mmol), DCM (5 mL) and HCl (4M in 1,4-dioxane, 10 mL) was stirred at RT for 17h. The mixture was concentrated under reduced pressure, the residue dissolved in MeOH (10 mL), and stirred at 60 ℃ for an additional 23h. After cooling to RT, the reaction was concentrated under reduced pressure. The residue was dispersed in MeOH (2 mL) and EA (20 mL), the precipitate was collected by filtration and dried under reduced pressure to give (S) -4- ((5- (1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine)]-1' -yl) pyrazin-2-yl) sulfanyl) -3-chloropyridin-2-ol (73 mg). MS M/z 440 (M + H) + . 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.34(s,1H),7.59(d,1H),7.28-7.37(m,3H),7.23(d,1H),5.52(d,1H),4.28-4.40(m,3H),3.21-3.38(m,3H),3.02-2.99(d,1H),1.75-1.82(m,2H),1.52-1.60(m,2H).
The following examples were synthesized by the above-described method using the corresponding starting materials. .
The following examples are in the form of their free bases or pharmaceutically acceptable salts.
Watch 18
Example 137
(S) -1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -6-ol
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of (1-amine) (74mg, 0.14mmol) in DCM (2 mL) was added BBr 3 (1M in DCM, 0.71 mL). The system was stirred at RT for 6h. Concentrating under reduced pressure to remove volatiles, dispersing the residue in water, filtering off the solid, and diluting with saturated NaHCO 3 The aqueous solution adjusted the pH of the filtrate to 7. The resulting precipitate was collected by filtration and dried in a vacuum oven to give (S) -1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine]-6-ol (7 mg). MS M/z 470 (M + H) + .
The following examples were synthesized by the above-described method using the corresponding starting materials.
Watch 19
Example 139
1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methyl-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5-amine
Step a Synthesis of (R, Z) -5- ((tert-butylsulfinyl) imino) -5,7-dihydrospiro [ cyclopenta [ b ] with reference to step a of example 5]Pyridine-6,4' -piperidine]-1' -carboxylic acid tert-butyl ester. MS: M/z 406 (M + H) + .
Step b: to-60 deg.C of (R, Z) -5- ((tert-butylsulfinyl) imino) -5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]Methyllithium (1.3M in diethyl ether, 14mL, 18.20mmol) was added dropwise to a solution of tert-butyl (1.49g, 3.67mmol) 1' -carboxylate in THF (15 mL). The mixture was allowed to warm to RT and stirred for 20h. Dilute with water (10 mL) and EA (20 mL). The aqueous phase was separated and NaOH (1.00g, 25.00mmol) and (Boc) were added 2 O (0.50 mL). The mixture was stirred at RT for 1.5h. Extraction with EA (2X 50 mL), combining the organic phases, washing with brine (1X 30 mL), over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex =1, v/v) to give 5- (((R) -tert-butylsulfinyl) amino) -5-methyl-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -carboxylic acid tert-butyl ester (823 mg). MS M/z 422 (M + H) + .
Step (c-d) Synthesis of 1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methyl-5,7-dihydrospiro [ cyclopenta [ b ] with reference to step (c-d) of example 5]Pyridine-6,4' -piperidine]5-amine (71 mg). MS: M/z 469 (M + H) + . 1 H NMR(400MHz,MeOH-d4)δ8.50-8.44(m,1H),7.93-7.87(m,1H),7.67-7.61(m,2H),7.41-7.35(m,1H),5.97(d,1H),4.54(m,2H),3.35(d,1H),3.23-3.08(m,3H),1.92-1.78(m,2H),1.57-1.48(m,2H),1.44(s,3H).
Example 140
1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3H-spiro [ indolizine-2,4' -piperidine ] -7 (1H) -one
Step a: to-10 ℃ 1-hydroxy-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]To a solution of tert-butyl (100mg, 0.31mmol) of (E) -1' -carboxylate and triethylamine (157mg, 1.55mmol) in THF (10 mL) and DCM (2 mL) was added MsCl (66mg, 0.58mmol). The resulting solution was stirred at RT for 1h. The reaction was diluted with water (50 mL) and extracted with DCM (3X 50 mL). The combined organic phases were passed over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 1- ((methylsulfonyl) oxy) -7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (155 mg). MS: M/z 399 (M + H) + .
Step b: 1- ((methylsulfonyl) oxy) -7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]A mixture of tert-butyl (155mg, 0.39mmol) 1' -carboxylate, sodium azide (136mg, 2.09mmol) and DMF (5 mL) was stirred at 75 deg.C for 1h and at 85 deg.C for 4h. After cooling to RT, the reaction was diluted with EA (30 mL), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM =1, 10,v/v) to give the title 1-azido-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (32 mg). MS M/z 346 (M + H) + .
Step c: 1-azido-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]A solution of tert-butyl (32mg, 0.093mmol) 1' -carboxylate, pd/C (10%, 15 mg) in EtOH (6 mL) was stirred under hydrogen for 3h. Filtering the reaction system, leaching the filter cake with EtOH, and concentrating the filtrate under reduced pressure to obtain 1-amino-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]-1' -carboxylic acid tert-butyl ester (26 mg). MS M/z 320 (M + H) + .
Step d: to 1-amino-7-oxo-1,7-dihydro-3H-spiro [ indolizine-2,4' -piperidine]To a solution of tert-butyl (26mg, 0.081mmol) of (E) -1' -carboxylate in DCM (2 mL) was added TFA (2 mL) and stirred at room temperature for 30min. The system was concentrated under reduced pressure. The residue was dissolved in NMP (2.5 mL) and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (46mg, 0.16mmol) and K were added 2 CO 3 (395mg, 2.86mmol), and stirred at 95 ℃ for 16h. After cooling to RT, it was diluted with DCM (30 mL), filtered and concentrated under reduced pressure.The residue was purified by Pre-TLC (eluting with MeOH: DCM = 13,v/v) to give 1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3H-spiro [ indolizine-2,4' -piperidine]-7 (1H) -one (2 mg). MS: M/z 471 (M + H) + .
The following examples were synthesized by the above-described method using the corresponding starting materials.
Watch 20
Example 142
3- ((2-amino-3-chloropyridin-4-yl) thio) -6- (1-imino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrazin-2-amine
Step a Synthesis of (R, Z) -1- ((tert-butylsulfinyl) imino) -1,3-dihydrospiro [ indene-2,4' -piperidine by step a of example 5]1' -Carboxylic acid tert-butyl ester MS M/z 405 (M + H) + .
Step b: to (R, Z) -1- ((tert-butylsulfinyl) imino) -1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (405mg, 1.00mmol) 1' -carboxylate in DCM (10 mL) was added TFA (1 mL) and stirred at RT for 1.5h. The system was concentrated under reduced pressure. The residue was dissolved in NMP (10 mL), and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (288mg, 1.00mmol) and K were added 2 CO 3 (1.38g, 10.00mmol). The system was stirred at 100 ℃ for 18h. After cooling to RT, it was diluted with water (50 mL) and extracted with EA (3X 30 mL). The combined organic phases were washed with brine (1X 100 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM = 1) 5,v/v to give 3- ((2-amino-3-chloropyridin-4-yl) thio) -6- (1-imino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) pyrazin-2-amine (50 mg). MS M/z 452 (M + H) + . 1 H NMR(400MHz,MeOH-d4)δ7.83(d,1H),7.37-7.74(m,5H),5.96(d,1H),4.43-4.58(m,2H),3.12-3.28(m,4H),2.01-2.06(m,2H),1.56-1.60(m,2H).
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 21
Example 148
1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -7-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-amine
A, step a: to 7-methoxy-1-oxo-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (552mg, 1.07mmol) of (E) -1' -carboxylate in MeOH (10 mL) were added hydroxylamine hydrochloride (348mg, 5.01mmol) and AcONa (822mg, 10.02mmol). The system was stirred at RT for 4h. The reaction was concentrated under reduced pressure. The residue was dissolved in EA (15 mL) and water (15 mL), the organic phase was separated, washed with brine (1X 15 mL), and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to give (Z) -1- (hydroxyimino) -7-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine as a yellow solid]-1' -carboxylic acid tert-butyl ester (520 mg). MS: m/z 347 (M + H) + .
Step b: mixing (Z) -1- (hydroxyimino) -7-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (510mg, 1.47mmol), ptO 2 A mixture of (30 mg) and AcOH (10 mL) was stirred under hydrogen at 60 ℃ for 17h. After cooling to RT, the reaction was diluted with EA (45 mL) and water (45 mL), the aqueous phase was separated and washed with K 2 CO 3 The solid adjusted the pH to 10. The system was extracted with DCM (2X 30 mL), and the combined organic phases were washed with brine (1X 50 mL) and anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 1-amino-7-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine as colorless oil]-1' -carboxylic acid tert-butyl ester (202 mg). And (2) MS: m/z 333 (M + H) + .
Step c: to 1-amino-7-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl-1' -carboxylate (199mg, 0.60mmol) in DCM (10 mL) was added TFA (1 mL) and stirred at RT for 1.5h. The system was concentrated under reduced pressure. The residue was dissolved in NMP (5 mL) and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (144mg, 0.50mmol) and K were added 2 CO 3 (691mg, 5.90mmol). The system was stirred at 95 ℃ for 3h. After cooling to RT, the reaction was diluted with water (50 mL) and extracted with EA (1X 50 mL). The organic phase was washed with brine (1X 50 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with MeOH: DCM =1:5,v/v) to give 1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -7-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine]-1-amine (20 mg). MS: m/z 484 (M + H) + . 1 H NMR(400MHz，DMSO-d6)δ7.66(s，1H)，7.64(d，1H)，7.36-7.28(m，1H)，6.90(d，1H)，6.88(d，1H)，5.75(d，1H)，4.29(s，1H)，4.20(d，1H)，4.09(d，1H)，3.83(s，3H)，3.30-3.15(m，2H)，3.10(d，1H)，2.96(d，1H)，1.87-1.76(m,1H),1.70-1.54(m,2H),1.41(d,1H).
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 22
Example 150
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methoxy-4,6-dihydrospiro [ cyclopenta [ d ] thiazole-5,4' -piperidine ] -4-amine
Step (a-b) Synthesis of (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4,6-dihydrospiro [ cyclopenta [ d ] with reference to step (a-b) of example 5]Thiazoles-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester. MS M/z 448 (M + H) + .
Step c: (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4,6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5,4' -piperidine]A mixture of tert-butyl (403mg, 0.90mmol) 1' -carboxylate, naOH (358mg, 8.95mmol) and MeOH (15 mL) was stirred at 65 ℃ for 5h. After cooling to RT, the volatiles were removed by concentration under reduced pressure. The residue was dissolved in water and the pH adjusted to 7 by addition of saturated aqueous citric acid. The system was extracted with EA (3X 30 mL) and the combined organic phases were dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to give (S) -4- (((R) -tert-butylsulfinyl) amino) -2-methoxy-4,6-dihydrospiro [ cyclopenta [ d ] as a brown oil]Thiazole-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester (360 mg). MS: M/z 444 (M + H) + .
Step (d-e) Synthesis of (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methoxy-4,6-dihydrospiro [ cyclopenta [ d ] d) referring to step (c-d) of example 5]Thiazole-5,4' -piperidine]-4-amine. MS M/z 491 (M + H) + .
Example 151
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4,6-dihydrospiro [ cyclopenta [ d ] thiazole-5-, 4' -piperidine ] -4-amine
Step (a-b) Synthesis of (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4,6-dihydrospiro [ cyclopenta [ d ] with reference to step (a-b) of example 5]Thiazole-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester. MS: M/z 448 (M + H) + .
Step c (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4,6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5,4' -piperidine]A mixture of tert-butyl-1' -carboxylate (2.50g, 5.58mmol), TEA (2 mL), pd/C (10%, 690 mg) and MeOH (50 mL) was stirred under hydrogen at 40 ℃ for 24h. Filtration was carried out and Pd/C (10%, 1.32 g) was added to the filtrate. Stirring is carried out for a further 16h at 50 ℃ under a hydrogen atmosphere. Filtering, and concentrating the filtrate under reduced pressure. By silica gel colorThe residue was purified by chromatography (eluting with EA: hex =1, v/v) to give (S) -4- (((R) -tert-butylsulfinyl) amino) -4,6-dihydrospiro [ cyclopenta [ d]Thiazole-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.28 g). MS M/z 414 (M + H) + .
Step (d-e) Synthesis of (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4,6-dihydrospiro [ cyclopenta [ d ] referring to step (c-d) of example 5]Thiazole-5,4' -piperidine]-4-amine. MS: M/z 461 (M + H) + . 1 H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.63-7.66(m,2H),5.76(d,1H),3.99-4.07(m,2H),3.87(s,1H),3.28-3.38(m,2H),2.78-2.93(m,2H),1.47-1.87(m,4H).
In step a of example 5, tert-butylsulfinamide was used instead of (R) -2-methylpropane-2-sulfinamide to give the corresponding racemic product.
The following examples were synthesized with the corresponding starting materials with reference to the above-described methods.
TABLE 23
EXAMPLE 155
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4,6-dihydrospiro [ cyclopenta [ d ] thiazole-5,4' -piperidine ] -6-amine
Step a Synthesis of (R, Z) -6- ((tert-butylsulfinyl) imino) -2-chloro-4,6-dihydrospiro [ cyclopenta [ d ] referring to step a of example 5]Thiazole-5,4' -piperidine]-1' -carboxylic acid tert-butyl ester. MS M/z 446 (M + H) + .
Step b: to (R, Z) -6- ((tert-butylsulfinyl) imino) -2-chloro-4,6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5,4' -piperidine](ii) A solution of tert-butyl (4.25g, 9.53mmol) of (1) -carboxylate in THF (30 mL) was added BH 3 (1M in THF, 30.00mL, 30.00mmol). The mixture was warmed to RT and stirred for 18h. Salt is used in the reaction systemWater (50 mL) was quenched. The organic phase was separated off and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with (EA: hex =1, 2,v/v), to give (S) -6- (((R) -tert-butylsulfinyl) amino) -4,6-dihydrospiro [ cyclopenta [ d]Thiazole-5,4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.12 g). MS M/z 414 (M + H) + .
Step (c-d) Synthesis of (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4,6-dihydrospiro [ cyclopenta [ d ] referring to step (c-d) of example 5]Thiazole-5,4' -piperidine]-6-amine. 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.63-7.66(m,2H)5.76(d,1H),4.19-4.23(m,2H),4.09(s,1H),3.15-3.32(m,2H),2.80-2.93(m,2H),1.60-1.87(m,4H).MS:m/z 461(M+H) + .
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 24
Example 157
(S) -1'- (6-amino-5- ((3-fluoro-1H-indol-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-amine
(S) -1- (4- ((3-amino-5- (1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine)]-1' -yl) pyrazin-2-yl) thio) -3,3-difluoroindolin-1-yl) ethan-1-one (86mg, 0.16mmol) was dissolved in MeOH (8 mL) and NaOH (17mg, 0.43mmol) was added. The system was stirred for a further 21h at 65 ℃. After cooling to RT, the reaction was concentrated under reduced pressure. The residue was diluted with water (10 mL) and EA (20 mL). The separated organic phase was washed with brine (10 mL) and anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Adding EA (5 mL) and Hex (3 mL) for pulping, filtering to collect precipitate, and drying under reduced pressure to obtain (S) -1' - (6-amino-5- ((3-fluoro-1H-indol-4-yl) thio) pyrazin-2-yl) -1,3-dihydrocarbonSpiro [ indene-2,4' -piperidine]-1-amine (14 mg). 1 H NMR(400MHz,DMSO-d6)δ7.59(s,1H),7.37-7.21(m,5H),7.13(d,1H),7.00-6.93(m,1H),6.40(d,1H),4.18(d,2H),3.97(s,1H),3.09(m,3H),2.72(m,1H),1.77-1.62(m,2H),1.50-1.47(m,1H),1.20-1.16(m,1H)MS:461(M+H) + .
Example 158
(S) -1- (1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -6-yl) ethan-1-one
Synthesis of (S) -1- (((R) -tert-butylsulfinyl) amino) -6-cyano-1,3-dihydrospiro [ indene-2,4' -piperidine ] with reference to step (a-b) of example 5]-1' -carboxylic acid tert-butyl ester. MS M/z 432 (M + H) + .
Step c: to-50 deg.C (S) -1- (((R) -tert-butylsulfinyl) amino) -6-cyano-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of tert-butyl (430mg, 1.00mmol) of the-1' -carboxylate in THF (10 mL) was added dropwise methylmagnesium bromide (3M solution in THF/Hex, 0.50mL, 1.50mmol). Naturally warming to room temperature and stirring for 24h. The reaction was quenched with brine (10 mL). Separating the organic phase with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain (S) -6-acetyl-1- (((R) -tert-butylsulfinyl) amino) -1,3-dihydrospiro [ indene-2,4' -piperidine]Tert-butyl-1' -carboxylate (0.72 g), which was used in the next step without further purification. MS M/z 449 (M + H) + .
Synthesis of (S) -1- (1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine) with reference to step (c-d) of example 5]-6-yl) ethan-1-one. MS:496 (M + H) + .
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 25
The following examples can be synthesized using the methods described above and suitable starting materials:
watch 26
Pharmacological testing
Example a phosphatase activity assay (single dose):
single dose inhibition assay PTP was activated by co-incubation of a solution of the SHP2 enzyme (diluted to 0.5nM in the reaction solution) with dPEG8 peptide in a reaction solution (60mM 3, 3-dimethyl glutarate (pH 7.2), 75mM NaCl,75mM KCl,1mM EDTA,0.05% Tween 20,2mM Dithiothreitol (DTT)) for 30 minutes using 6,8-difluoro-4-methylumbelliferone phosphate (DiFMUP) as the reaction substrate. DMSO (0.5% (V/V) or compound (100 nM) was added to the mixture and incubation was continued at room temperature for 30min. DiFMUP (12. Mu.M, total volume of reaction solution 100. Mu.L) was added to start the reaction, after incubation for 30min the fluorescence intensity of the reaction solution (excitation light 340nM, emission light 450 nM) was measured using 2104-0020EnVision Xcite Multilabel Reader (Perkinelmer). Three wells were set for each dose. The fluorescence value of the control well (DMSO) was set to 100%, and the inhibitory activity of the compound-treated wells was expressed as a percentage of the control wells.
TABLE A
Phosphatase activity assay (IC 50 assay):
IC 50 value detection, using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as substrate, SHP2 enzyme solution (diluted to 0.5nM in reaction solution) andthe dPEG8 peptide was incubated in the reaction solution (60mM dimethyl 3, 3-glutarate (pH 7.2), 75mM NaCl,75mM KCl,1mM EDTA,0.05% Tween 20,2mM Dithiothreitol (DTT)) for 30 minutes to activate PTP. DMSO (0.5% (V/V) or a compound (concentration: 0.3 nM-1. Mu.M) was added to the mixture, incubation was continued at room temperature for 30min, diFMUP (12. Mu.M, total volume of reaction solution: 100. Mu.L) was added to start the reaction, and after incubation for 30min, the fluorescence intensity (excitation light 340nM, emission light 450 nM) of the reaction solution was measured with 2104-0020EnVision Xcite Multilabel Reader (Perkinelmer). The IC of the present invention, in which the compound inhibits the enzymatic activity of SHP2, was used 50 See table B.
TABLE B
Example C cell proliferation assay:
MV-4-11 cells (4000 cells/well) were plated in 96-well plates in a medium of 100. Mu.L/well (IMDM containing 3% Fetal Bovine Serum (FBS), from Gibco). After 24 hours of incubation, compounds of the invention formulated to different concentrations were added. On day 8, 30. Mu.L of MTS/PMS reagent (purchased from Promega, sigma, respectively) was added to each well, and absorbance was measured according to the protocol (Promega). IC of the Compounds of the invention 50 The values are shown in Table C.
Watch C
Example D p-ERK cell level assay
The level of activation of ERK1/2 was detected by immunoblotting using an anti-p-ERK 1/2 antibody. Briefly, MV-4-11 human leukemia cells were incubated with a range of compounds (concentrations from 0.3nM to 100 nM) for 2 hours. Cells were lysed using RIPA buffer (Thermo Fisher Scientific, rockford, IL, USA) containing a cocktail of Halt protease inhibitors and total cellular protein was recovered. mu.L of total protein was separated by SDS-PAGE under reducing conditions and transferred to PVDF membrane (Bio-Rad). After blocking with Tris buffered saline solution containing 5% bsa, the membrane was incubated with primary antibody overnight at 4 ℃ followed by 1 hour incubation with horseradish peroxidase (HRP) labeled secondary antibody. The bound secondary antibody is detected using chemiluminescence.
Example E MV-4-11 xenograft tumor model
MV-4-11 cell culture was expanded, collected and injected subcutaneously into 5-8 week old female NOD/SCID mice (5X 10) 6 Individual cells per mouse, n = 6-10 per group). When the average tumor volume is about 100-200mm 3 At that time, oral gavage (0.1-10 mpk/dose) is initiated. During the treatment period (once or twice a day for 2-4 weeks), tumor volumes were measured using a vernier caliper. Differences in tumor volume between groups were counted using a one-way ANOVA analysis. Solvent is a negative control.
The compounds provided herein are preferably formulated into pharmaceutical compositions for administration by various routes. Most preferably, the pharmaceutical composition is for oral administration, such pharmaceutical compositions and methods for their preparation are well known in the art, see, e.g., remington: pharmaceutical science and practice (edited by A.Jannaro et al, 19 th edition, mic publishing company, 1995) [ REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A.Gennaro, et al, eds.,19 th ed.,Mack Publishing Co.,1995)]The compounds of formula I, II, III or IV are generally effective over a wide dosage range.
In summary, most of the compounds listed in this invention are very potent and selective with an IC50 of less than 10nM. They also show good antitumor effects in vivo models. For example, daily dosages typically fall within the range of about 0.2mg to 100mg dosages, preferably 0.2mg to 50mg dosages, more preferably 0.2mg to 20mg dosages. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage ranges do not limit the scope of the invention in any way. It will be understood that the actual amount of the compound administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's condition.
Claims (42)
1. The use of a compound or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by the activity of SHP2,
wherein the compound is a compound represented by structural formula I:
the method is characterized in that:
each R 1 Are each independently selected from-H; halogen; -NH 2 ；-CN；-C 1-6 An alkoxy group; -C 1-6 An alkyl group; by 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkyl group; or by 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkoxy group;
R 2 is selected from-H; a halogen; -NH 2 ；-CN；-OH；-NHC 1-6 An alkyl group; -N (C) 1-6 Alkyl radical) 2 ；-C 1-6 An alkoxy group; -C 1-6 An alkyl group; is substituted by 1,2 or 3 substituents selected from-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkyl group; or is substituted by 1,2 or 3 groups selected from-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkoxy group; or
R 2 To adjacent R 1 Are linked together with the carbon atom to which they are each attached to form a 6-10 membered aromatic ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, and each ring system independently may be optionally unsubstituted or substituted with 1,2 or 3 halogens, -NH 2 、-CN、-C 1-6 Alkyl or-CO-C 1-6 Alkyl substitution;
each Y 1 Independently selected from N or CH;
R 3 is selected from-H or-NH 2 ；
Each R 4a And each R 4b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-6 An alkyl group; or
R 4a And R 4b Together with the carbon atom to which they are commonly attached form CO, C = NH, or C = N-OH;
p is 0, 1 or 2;
each R 5a And R 5b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-6 An alkyl group; or
R 5a And R 5b Together with the carbon atom to which they are both attached form a 3-5 membered heterocyclyl or C = NH;
q is 0, 1,2 or 3;
w is absent, O or NR w (ii) a And R is w is-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-6 Alkoxy or-C 1-6 An alkyl group;
ring A is a 3-10 membered ring and ring A is selected from 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl;
wherein,
represents a double bond, Y 2 Is C, and Y 3 Is C;
each R 6 Independently selected from-H, halogen, -NR 6a R 6b 、-CN、-OH、-NO 2 Oxo, carboxy, -C 1-6 Alkoxy, -C 1-6 Alkyl, -C 1-6 Alkenyl, -CO-OR 6a 、-NR 6a -CO-NR 6a R 6b 、-CO-NR 6a R 6b 、-C 3-10 Heterocyclyl, -CO-C 1-6 Alkyl, -CO-C 3-10 Heterocyclyl, -O-C 3-10 Carbocyclyl, -O-C 3-10 Heterocyclyl radical, -NR 6a -CO-C 1-6 Alkyl, -NR 6a -SO 2 C 1-6 Alkyl, -S-C 1-6 Alkyl and substituted benzeneSONR 6a R 6b 、-SO 2 NR 6a R 6b 、-SO-C 1-6 Alkyl, -SO 2 C 1-6 Alkyl, -PO (C) 1-6 Alkyl radical) 2 、-PO(C 1-6 Alkoxy group) 2 、-C 3-10 Heterocyclyl or-C 5-10 A heteroaryl group; each R 6 Each independently optionally substituted with 1,2 or 3 substituents selected from-F, -Cl, br, -NH 2 -OH, carboxyl, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and n is 0, 1,2,3,4, 5 or 6; or
Two adjacent R 6 Taken together and together with the carbon atoms to which they are respectively attached form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C 3-6 Heterocyclyl or-C 3-6 Carbocyclyl, and each ring system is independently optionally substituted or unsubstituted with 1,2 or 3 substituents, each independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Oxo, carboxy, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;
each R 6a And each R 6b Are each independently selected from-H; halogen; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -C 1-6 An alkoxy group; -C 1-6 An alkyl group; or by 1,2 or 3 of-H, halogen, -NH 2 -CN or-OH substituted-C 1-3 An alkyl group.
2. Use according to claim 1, characterized in that: each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-C 1-6 An alkyl group; -C 1-6 An alkoxy group; by 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkyl group; or by 1,2 or 3 halogens, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkoxy group.
3. The use according to claim 1, wherein each R is 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 (ii) a -CN; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; propoxy group; an isopropoxy group; by 1,2 or 3-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C 1-3 An alkyl group; or by 1,2 or 3 of-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 C substituted by carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy 1-3 An alkoxy group.
4. The use according to claim 1, wherein each R is 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 (ii) a -CN; a methyl group; an ethyl group; propyl; an isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; or methyl substituted with 1,2 or 3 substituents, and each substituent is independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
5. The use according to claim 1, wherein R 2 Is selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-C 1-3 An alkyl group; -C 1-3 An alkoxy group; -NHC 1-3 An alkyl group; -N (C) 1-3 Alkyl radical) 2 (ii) a Is substituted by 1,2 or 3 substituents selected from-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkyl group; or is substituted by 1,2 or 3 groups selected from-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkoxy group.
6. The use according to claim 1, wherein R 2 Is selected from-H; -F; -Cl;-Br；-NH 2 (ii) a -CN; -OH; a methyl group; an ethyl group; propyl; an isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; -NHCH 3 ；-N(CH 3 ) 2 (ii) a Or methyl or ethyl substituted by 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 -CN or-OH.
7. The use according to claim 1, wherein R 2 R adjacent thereto 1 Are linked and taken together with the carbon atom to which they are each linked to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each said heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N or O; and each said ring system is independently optionally substituted by-F, -Cl, -Br, -I, -NH 2 CN or CO-C 1-3 Alkyl is substituted or unsubstituted.
8. The use according to claim 1, wherein R 2 R adjacent thereto 1 Are linked and taken together with their respective linking carbon atoms to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 heteroatom selected from N or O; and each ring system may be independently optionally substituted by-F, -Cl, -Br, -NH 2 -CN, methyl, ethyl, propyl, isopropyl or-COCH 3 Substituted or unsubstituted.
9. Use according to claim 1, R 2 R adjacent thereto 1 Are linked and form together with the carbon atoms to which they are respectively linked
10. Use according to claim 1, characterized in that: each R 4a And R 4b Are independently selected from-H, -F, -Cl, -Br, -I and-NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-3 An alkyl group; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached form C = O, C = NH or C = N-OH.
11. The use according to claim 1, wherein each R is 4a And each R 4b Independently selected from-H, -NH 2 -OH, methyl or ethyl; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached, form C = O.
12. The use according to claim 1, wherein each R is 5a And each R 5b Independently selected from-H; -F; -Cl; -Br; -I; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -C 1-3 An alkyl group; or
R 5a And R 5b Together with the carbon atom to which they are both attached, form C = NH, a 3-membered heterocyclyl, a 4-membered heterocyclyl, or a 5-membered heterocyclyl; and each of said heterocyclyl groups independently optionally includes 1 or 2 heteroatoms selected from N or O.
13. The use of claim 1, wherein each R 5a And each R 5b Independently selected from-H, -NH 2 -OH, methyl or ethyl; or
R 5a And R 5b Together with the carbon atom to which they are commonly attached, form C = NH, a 3-membered heterocyclic group, a 4-membered heterocyclic group, or a 5-membered heterocyclic group; and each of said heterocyclyl groups contains 1 heteroatom selected from N or O.
14. The use according to claim 1, wherein W is NR w And R is w Selected from-H, -F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkoxy or-C 1-3 An alkyl group.
15. The use of claim 1, wherein W is NRw and R is w Selected from-H, -F, -Cl, -Br and-NH 2 、-CN、-OH、-NO 2 Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
16. The use of any one of claims 1-15, wherein ring a is selected from 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl; and each heteroaryl group independently optionally contains 1,2 or 3 heteroatoms selected from N, O or S.
17. The use of claim 16, wherein ring a is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl; and each heteroaryl group independently optionally contains 1 or 2 heteroatoms selected from N, O or S.
18. The use according to claim 16, wherein ring a is selected from
19. The use of claim 1, wherein each R 6 Are all independently selected from-H, -F, -Cl, -Br, -NR 6a R 6b -CN, -OH, oxo, carboxyl, -C 1-3 Alkoxy, -C 1-4 Alkyl, -C 1-3 Alkenyl, -NR 6a -CO-NR 6a R 6b 、-CO-NR 6a R 6b 、-CO-C 1-3 Alkyl, -CO-C 5-6 Heterocyclyl, -O-C 5-6 Carbocyclyl, -O-C 5-6 Heterocyclyl radical, -NR 6a -CO-C 1-3 Alkyl, -NR 6a -SO 2 C 1-3 Alkyl, -S-C 1-3 Alkyl, -SO-C 1-3 Alkyl, -SO 2 NR 6a R 6b 、-SO 2 C 1-3 Alkyl, -PO (C) 1-3 Alkyl radical) 2 、-PO(C 1-3 Alkoxy group) 2 5-membered heterocyclic group6-membered heterocyclyl, 5-membered heteroaryl or 6-membered heteroaryl, and each R 6 Independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-F, -Cl, br, -NH 2 -OH, carboxyl, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; each R is 6a And R 6b Are each independently selected from-H; -F; -Cl; -Br; -I; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; -C 1-3 An alkoxy group; -C 1-3 Alkyl or substituted by 1,2 or 3-H, halogen, -NH 2 -CN or-OH substituted-C 1-3 An alkyl group; or
Two adjacent R 6 Taken together and together with the carbon atoms to which they are each attached form a 6-membered aryl, 5-membered carbocyclyl, 5-membered heteroaryl, or 5-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N, O or S; and each said ring system is independently optionally substituted or unsubstituted with 1,2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Oxo, carboxy, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
20. The use according to claim 1, wherein each R is 6 Are each independently selected from-H; -F; -Cl; -Br; -NR 6a R 6b (ii) a -CN; -OH; an oxo group; a carboxyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; a methyl group; an ethyl group; propyl; isopropyl group; a tertiary butyl group; -NR 6a -CO-NR 6a R 6b ；-CO-NR 6a R 6b (ii) a -CO-methyl; -CO-ethyl; -CO-C 5-6 A heterocyclic group; -O-C 5-6 A carbocyclic group; -O-C 5-6 A heterocyclic group; -NR 6a -CO-methyl; -NR 6a -SO 2 -a methyl group; -NR 6a -SO 2 -an ethyl group; -S-methyl; -S-ethyl; -SO-methyl; -SO-ethyl; -SO 2 NR 6a R 6b ；-SO 2 A methyl group; -SO 2 An ethyl group;-PO (methyl) 2 (ii) a -PO (ethyl) 2 (ii) a -PO (methoxy) 2 (ii) a -PO (ethoxy) 2 (ii) a A 5-membered heterocyclyl containing 1,2 or 3 heteroatoms; a6 membered heterocyclyl containing 1,2 or 3 heteroatoms; a 5-membered heteroaryl group containing 1,2 or 3 heteroatoms; or a6 membered heteroaryl group containing 1,2 or 3 heteroatoms, wherein the heteroatoms are selected from N, O or S; wherein each R 6 Independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-F, -Cl, br, -NH 2 -OH, carboxyl, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; each R 6a And R 6b Are each independently selected from-H; -F; -Cl; -Br; -I; -NH 2 ；-CN；-OH；-NO 2 (ii) a A carboxyl group; a methyl group; an ethyl group; a methoxy group; an ethoxy group; by 1,2 or 3 of-H, -F, -Cl, -Br, -NH 2 -CN or-OH substituted methyl; or by 1,2 or 3 of-H, -F, -Cl, -Br, -NH 2 -CN or-OH substituted ethyl; or
Two adjacent R 6 Taken together and together with the carbon atoms to which they are each attached form a phenyl group, a 5-membered carbocyclyl group, a 5-membered heteroaryl group containing 1 or 2N or O, or a 5-membered heterocyclyl group containing 1 or 2N or O; and each said ring system is independently optionally substituted or unsubstituted with 1,2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Oxo, carboxy, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
21. The use of claim 1, wherein each R 6 Are independently selected from-F, -Cl, -Br, = O, -OH, -CN, -NH 2 、
-SCH 3 、-SOCH 3 、-SO 2 CH 3 、-PO(CH 3 ) 2 、-PO(OC 2 H 5 ) 2 、-NHSO 2 CH 3 、-C(O)NH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, -CF 3 、-OCF 3 、-SO 2 NH 2 、-CH 2 NH 2 、
-NHCONHCH 3 、
Or
Two adjacent R 6 Are linked together and form together with the carbon atoms to which they are respectively attached
22. The use of claim 1, wherein the compound is a compound of structural formula II:
the method is characterized in that:
R 3 is selected from-H or-NH 2 ；
Each R 4a Or R 4b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-3 An alkyl group; or
R 4a And R 4b Together with the carbon atoms to which they are commonly attached form C = O, C = NH, or C = N-OH;
p is 0, 1 or 2;
each R 5a Or R 5b Are all independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy or-C 1-3 An alkyl group; or
R 5a And R 5b Together with the carbon atom to which they are both attached form a 3-5 membered heterocyclyl; and each of said heterocyclyl groups is independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-H, halogen, -NH 2 -CN or-OH;
q is 0, 1,2 or 3;
ring a is benzene, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring or a 9-membered heteroaromatic group;
each R 6 Independently selected from-H, halogen, -NR 6a R 6b 、-CN、-OH、-NO 2 "= O, carboxy, -C 1-3 Alkoxy, -C 1-4 Alkyl, -CO-NR 6a R 6b 、-CO-C 1-3 Alkyl, -CO-C 4-6 Heterocyclyl, -O-C 3-6 Carbocyclyl, -O-C 3-6 Heterocyclyl radical, -NR 6a -CO-C 1-3 Alkyl, -NR 6a -CO-NR 6a R 6b 、-NR 6a -SO 2 C 1-3 Alkyl, -S-C 1-3 Alkyl, -SONR 6a R 6b 、-SO 2 NR 6a R 6b 、-SO-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -PO (C) 1-3 Alkyl radical) 2 、-PO(C 1-3 Alkoxy group) 2 、-C 3-6 Heterocyclyl or-C 5-6 Heteroaryl, wherein each R 6 Each independently optionally substituted or unsubstituted with 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 -OH, carboxyl, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and n is 0, 1,2 or 3; or
Two adjacent R 6 Is connected toTaken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, C 3-6 Heterocyclyl or C 3-6 Carbocyclyl, and each said ring system is independently optionally substituted or unsubstituted with 1,2 or 3 substituents, and each substituent is independently selected from-F, -Cl, -Br, -NH 2 ，-CN，-OH，-NO 2 Oxo, carboxy, -CONH 2 ,-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
each R 6a And each R 6b Independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkyl, or substituted by 1,2 or 3-H, halogen, -NH 2 -CN or-OH substituted-C 1-3 An alkyl group.
23. The use of claim 22, wherein each R 5a Or R 5b Are all independently selected from-H, -Cl, -Br and-NH 2 -OH, carboxyl, methyl or ethyl; or
R 5a And R 5b Together with the carbon atom to which they are commonly attached to form
And C represents said carbon atom and R 5a And R 5b And (4) connecting.
24. The use of claim 22 or 23, wherein ring a is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, or 9-membered heteroaryl; and each heteroaryl group independently comprises 1 or 2 heteroatoms selected from N, O or S.
25. The use of claim 24, wherein ring a is selected from:
26. the use of claim 22, wherein each R 6 Independently selected from-H, -F, -Cl, -Br, -NH 2 、-N(CH 3 ) 2 CN, -OH, oxo, carboxyl, methoxy, ethoxy, methyl, ethyl, isopropyl, tert-butyl, -CH 2 NH 2 、-CH 2 CH 2 OCH 3 、-CH 2 -COOH、-CONH 2 、-CON(CH 3 ) 2 、-CONHOH、-CONHCH 2 CH 2 OH、-COCH 3 、-SO 2 NH 2 、-SO 2 CH 3 、-SCH 3 、-SOCH 3 、-PO(CH 3 ) 2 、-PO(OC 2 H 5 ) 2 、-NHSO 2 CH 3 、-NH-COCH 3 、-NH-CONHCH 3 、
Wherein each R 6 Independently optionally substituted by 1,2 or 3-F, -Cl, -NH 2 -OH, oxo, methyl, ethyl or propyl substituted or unsubstituted.
27. The use of claim 22, wherein each R 6a And R 6b Are all independently selected from-H, -Cl, -Br and-NH 2 -OH, carboxyl, methyl, ethyl, methyl substituted by-OH or ethyl substituted by-OH.
28. The use of claim 1, wherein the compound is a compound of structural formula III:
the method is characterized in that:
each R 1 And each R 2 Are all independently selected from-H, -F, -Cl, -Br and-NH 2 、-CN、-C 1-3 Alkoxy or-C 1-3 An alkyl group; or
R 1 R adjacent thereto 2 Are linked and together with the carbon atom to which they are each attached form a 5-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N or O, and said 5-membered heterocyclic ring is optionally substituted with 1,2 or 3 halogens, -NH 2 CN or CO-C 1-3 Alkyl substituted or unsubstituted;
Y 1 is selected from N or CH;
R 3 is selected from-H or-NH 2 ；
Ring B is selected from a phenyl ring, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring, and each heteroaromatic ring independently optionally contains 1 or 2 heteroatoms selected from N or O;
when representing a double bond, Y 3 Is C;
R 7 selected from halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, -CONH 2 、-NH-COCH 3 、-C 1-6 Alkoxy or-C 1-6 An alkyl group; and m is 0, 1 or 2.
29. The use of claim 28, wherein R 1 R adjacent thereto 2 Are bound and form together with the carbon atoms to which they are respectively bound
And said ring system is independently optionally substituted by 1 or 2-F or-COCH 3 Substituted or unsubstituted.
30. The use according to claim 28 or 29, wherein ring B is selected from
Or
31. The use of claim 28, wherein R 7 Is selected from-NH 2 -CN, oxo, -CONH 2 、-NH-COCH 3 Methyl or methoxy.
32. Use according to claim 1, characterized in that: the compound is a compound represented by structural formula IV:
the method is characterized in that:
each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-C 1-3 An alkoxy group; -C 1-3 Alkyl or 1,2 or 3 halogen substituted-C 1-3 An alkyl group;
each R 2 Independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NHC 1-3 An alkyl group; -N (C) 1-3 Alkyl radical) 2 ；-C 1-3 An alkoxy group; -C 1-3 Alkyl or 1,2 or 3-F, -Cl, -Br or-I substituted-C 1-3 An alkyl group;
or
R 1 R adjacent thereto 2 Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl ring, a 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, or a 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, and each of said ring systems is independently optionally substituted with 1,2 or 3 halogens, -NH 2 、-CN、-C 1-3 Alkyl or-CO-C 1-3 Alkyl substituted or unsubstituted;
Y 1 is N or CH;
R 3 is-H or-NH 2 ；
Ring D is selected from 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl, and each of said heteroaryl or heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
R 8 selected from halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, C 1-4 Alkyl radical, C 1-3 Alkoxy, -SO 2 NR 8a R 8b 、-S-C 1-3 Alkyl, -SO-C 1-3 Alkyl, -SO 2 -C 1-3 Alkyl, -CO-NR 8a R 8b 、-PO(C 1-3 Alkyl radical) 2 、-PO(C 1-3 Alkoxy group) 2 、-NR 8a -CO-C 1-3 Alkyl, -NR 8a -CO-NR 8a R 8b -O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl; and each R 8 Each independently optionally substituted by 1,2 or 3 substituents selected from halogen, methyl, ethyl, methoxy, oxo, -NH 2 or-OH is substituted or unsubstituted; and t is 0, 1,2 or 3; or
Two adjacent R 8 Taken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl or 5-membered heteroaryl, and each said ring system independently is optionally substituted or unsubstituted;
each R 8a And R 8b Are all independently selected from H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxy, -C 1-3 Alkoxy or-C 1-3 An alkyl group.
33. Use according to claim 32, characterized in that: each R 1 And R 2 Are all independently selected from-H, -F, -Cl, -Br, -NH 2 -CN, methoxy, ethoxy, methyl or ethyl; or
R 1 R adjacent thereto 2 Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl group, a 5-membered heterocyclic group containing 1 heteroatom selected from N or O, or a 5-membered heteroaromatic ring including 1 heteroatom selected from N or O; and each said ring system is independently optionally substituted with 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 and-CN, -methyl, -ethyl, -CO-methyl or-CO-ethyl.
34. The use of claim 32, wherein each R 1 And R 2 Are all independently selected from-H, -F, -Cl, -Br, -NH 2 -CN, methoxy, ethoxy, methyl or ethyl; or
R 1 R adjacent thereto 2 Are linked and form together with the carbon atoms to which they are respectively linked
And said ring systems are each independently optionally substituted by 1,2 or 3 substituents selected from-F or-COCH 3 Substituted or unsubstituted.
35. Use according to any one of claims 32 to 34, wherein ring D is selected from
36. The use of claim 32, wherein R 8 Selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxy, oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, -CO-methyl, -SO 2 NR 8a R 8b -S-methyl, -S-ethyl, -SO-methyl, -SO-ethyl, -SO 2 -methyl, -SO 2 -ethyl, -CO-C 3-6 heterocyclyl-CO-NR 8a R 8b -PO (methyl) 2 、-PO (Ethyl) 2 -PO (methoxy) 2 -PO (ethoxy) 2 、-NR 8a -CO-methyl, -NR 8a -CO-ethyl, -NR 8a -CO-NR 8a R 8b 、-NR 8a -SO 2 Methyl, -O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl, each of said heterocyclyl or heteroaryl containing 1 or 2 heteroatoms selected from O, N or S; each R 8 Independently optionally substituted by 1,2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 -OH, oxo, methoxy, ethoxy, methyl or ethyl.
37. The use of claim 32, wherein R 8 Selected from-F, -Cl, -Br, -NH 2 CN, -OH, carboxyl, oxo, methyl, ethyl, isopropyl, tert-butyl, CF 3 Methoxy, -SOCH 3 、-SO 2 CH 3 、-SCH 3 、P(O)(CH 3 ) 2 、P(O)(OC 2 H 5 ) 2 、NHS(O) 2 CH 3 、-CONH 2 、-NH-COCH 3 、-NH-CONHCH 3 、
Or
2R 8 Composition of
Or a benzene ring.
38. The use according to claim 1, wherein the compound is selected from the group consisting of:
39. the use according to claim 1, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
40. The use according to claim 39, wherein in the pharmaceutical composition the weight ratio of compound or pharmaceutically acceptable salt thereof to adjuvant is from 0.0001-10.
41. The use of claim 1, wherein the disease or disorder mediated by SHP2 activity is cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis or vision disorders.
42. The use of claim 41, wherein the disease or disorder mediated by SHP2 activity is selected from one or more of the following conditions: 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, and combinations thereof.
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| CN112409334B (en) | 2022-12-02 |
| CN112174935A (en) | 2021-01-05 |
| CN116003321A (en) | 2023-04-25 |
| CN112409334A (en) | 2021-02-26 |
| CN112174935B (en) | 2022-12-06 |
| CN110143949A (en) | 2019-08-20 |
| CN115969853A (en) | 2023-04-18 |
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