CN116003321A - Novel heterocyclic derivatives useful as SHP2 inhibitors - Google Patents

Novel heterocyclic derivatives useful as SHP2 inhibitors Download PDF

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CN116003321A
CN116003321A CN202211429905.1A CN202211429905A CN116003321A CN 116003321 A CN116003321 A CN 116003321A CN 202211429905 A CN202211429905 A CN 202211429905A CN 116003321 A CN116003321 A CN 116003321A
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piperidine
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马存波
高攀亮
胡邵京
徐子龙
韩慧峰
吴新平
康迪
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Jacobio Pharmaceuticals Co Ltd
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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Abstract

The invention relates to novel heterocyclic derivatives which can be used as SHP2 inhibitors, in particular to a compound shown in a structural formula I or pharmaceutically acceptable salt thereof, and further relates to application of the compound shown in the structural formula I or pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in preparation of medicines, in particular to application in preparation of medicines for treating, preventing or preventing diseases or discomfort mediated by SHP2 activity.

Description

Novel heterocyclic derivatives useful as SHP2 inhibitors
The present application is a divisional application of the inventive patent application with the application date of 2018, 5, 9, 202011087795.6 and the invention name of "novel heterocyclic derivative useful as SHP2 inhibitor".
Technical Field
The present invention relates to certain novel pyrazine derivatives (as shown in structural formulas I, II, III or IV) useful as SHP2 inhibitors, as well as their synthesis and their use for treating SHP2 mediated disorders. More particularly, the present invention relates to fused heterocyclic derivatives useful as SHP2 inhibitors, methods for preparing such compounds, and methods for treating SHP2 mediated diseases.
Background
SHP2 (Src homology-2 protein tyrosine phosphatase) is a non-receptor protein tyrosine phosphatase encoded by The ptpn11 gene, comprising a conserved tyrosine phosphatase domain, two N-terminal Src homology 2 (SH 2) domains, and a C-terminal tail. Two SH2 domains determine subcellular localization and functional regulation of SHP 2. In the inactive state, the N-terminal SH2 domain will block and inactivate PTP domain binding. When the SH2 domain binds to a specific tyrosine residue on a receptor or receptor-associated linker protein, the PTP domain is released and the autorhibition 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 involved in multiple cell signaling processes such as Ras-Erk, PI3K-Akt, jak-Stat, met, FGFR, EGFR, and insulin receptor and NF-kB pathways, playing an important role in cell proliferation, differentiation, cell cycle and migration.
The catalytically active hyperactivation of SHP2 by germline or somatic mutations has been found in Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, myelodysplastic syndrome, B precursor acute lymphoblastic leukemia and acute myelogenous leukemia. In addition, activating mutations in PTPN11 are also found in solid tumors, such as lung cancer, colon cancer, melanoma, neuroblastoma, and liver cancer. Thus, activated SHP2 or up-regulated SHP2 proteins in human tumors or other diseases become new therapeutic targets. The compounds of the present invention meet the need for small molecule inhibitors of SHP 2.
Disclosure of Invention
The present invention relates to heterocyclic pyrazine compounds useful as SHP2 inhibitors for the treatment of SHP2 mediated diseases. The invention firstly provides a general formula compound shown in a structural formula I and pharmaceutically acceptable salts thereof:
Figure BDA0003942079150000021
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 group 2 Substituted or unsubstituted-C 1-6 Alkoxy, substituted or unsubstituted-C 1-6 Alkyl or-C 5-10 A heterocyclic group; or (b)
R 2 With adjacent R 1 Are linked together with the carbon atoms 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 may be independently optionally unsubstituted or substituted with 1, 2 or 3 halogen, -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 selected from-H or-NH 2 ；
Each R 4a And R is 4b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl or-C 1-6 An alkyl group;
or (b)
R 4a And R is 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 is 5b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl or-C 1-6 An alkyl group;
or (b)
R 5a And R is 5b Together with the carbon atoms to which they are commonly 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 The method comprises the steps of carrying out a first treatment on the surface of the And R is w is-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -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;
Figure BDA0003942079150000022
Represents a single bond or a double bond;
when ring A is absent, Y 2 Is CR (CR) 2a R 2b 、NR 2a Or O, and Y 3 Is CR (CR) 3a R 3b 、NR 3a Or O;
when ring a is a 3-10 membered ring:
i) When (when)
Figure BDA0003942079150000031
When representing a single bond, Y 2 Is CR (CR) 2a Or N, and Y 3 Is CH or N; or (b)
ii) when
Figure BDA0003942079150000032
When representing a double bond, Y 2 Is C and Y 3 Is C;
each R 2a 、R 2b 、R 3a And R is 3b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, 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, =o, carboxyl, -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, -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, -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, -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 group 2 、-PO(C 1-6 Alkoxy group) 2 、-C 3-10 Heterocyclyl or-C 5-10 Heteroaryl; each R 6 Each independently optionally substituted with 1, 2 or 3 substituents or unsubstituted; and n is 0, 1, 2, 3, 4, 5 or 6; or (b)
Two adjacent R 6 Linked together and taken together with the carbon atoms to which they are each 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 with one or more substituents or unsubstituted;
each R 6a And R is 6b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, 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 related to the compounds 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 The method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; -C 1-6 An alkyl group; -C 1-6 An alkoxy group; by 1, 2 or 3 halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkyl group; or by 1, 2 or 3 halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkoxy group.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; a methyl group; ethyl groupThe method comprises the steps of carrying out a first treatment on the surface of the A propyl group; an isopropyl group; methoxy; an ethoxy group; a propoxy group; an isopropoxy group; by 1, 2 or 3-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 alkyl group; or by 1, 2 or 3-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 formula (I) or a pharmaceutically acceptable salt thereof, each R 1 Independently selected from-H; -F; -Cl; -Br; -NH 2 The method comprises the steps of carrying out a first treatment on the surface of the -CN; -OH; a methyl group; an ethyl group; a propyl group; an isopropyl group; methoxy; an ethoxy group; a propoxy group; an isopropoxy group; or methyl substituted with 1, 2 or 3 substituents, each substituent being independently selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 Selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 ；-N 3 The method comprises the steps of carrying out a first treatment on the surface of the 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 group 2 ；-CONH 2 ；-CONHC 1-3 An alkyl group; -CON (C) 1-3 Alkyl group 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 selected from the group consisting of 1, 2 or 3 of-F, -Cl, -Br, -I, -NH 2 -C substituted by a substituent of-CN or-OH 1-3 An alkyl group; or is selected from the group consisting of 1, 2 or 3 of-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 formula (I) or a pharmaceutically acceptable salt thereof, R 2 Selected from-H; -F;-Cl；-Br；-NH 2 ；-CN；-OH；-NO 2 ；-N 3 the method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; a methyl group; an ethyl group; a propyl group; an isopropyl group; methoxy; 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 ；
Figure BDA0003942079150000041
Or methyl or ethyl substituted with 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH 2 -CN or-OH.
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 each attached, a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each of said heteroaryl or heterocyclyl contains 1 or 2 heteroatoms selected from N or O; and each of said ring systems is independently optionally substituted with-F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxyl, 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 group 2 、-C 1-3 alkenyl-NHCO-C 1-3 Alkyl, -CO-CO-N (C) 1-3 Alkyl group 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 formula (I) or a pharmaceutically acceptable salt thereof, R 2 R adjacent thereto 1 Are linked and form, together with the carbon atom to which they are each attached, a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 member selected fromHeteroatoms from N or O; and each of said ring systems may independently optionally be substituted with-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, 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 together with the carbon atoms to which they are respectively attached form
Figure BDA0003942079150000051
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 4a And R is 4b Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxyl or-C 1-3 An alkyl group; or (b)
R 4a And R is 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 formula (I) or a pharmaceutically acceptable salt thereof, each R 4a And R is 4b Are each independently selected from-H, -NH 2 -OH, methyl, ethyl, methoxy or ethoxy; or (b)
R 4a And R is 4b Together with the carbon atoms to which they are commonly attached form c=o.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 5a And R is 5b Are each independently selected from-H; -F; -Cl; -Br; -I; -NH 2 ；-CN；-OH；-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; -C 1-3 An alkyl group; -C 1-3 An alkoxy group; is formed by-F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -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 Carboxyl, -C 1-3 Alkyl or-C 1-3 alkoxy-substituted-C 1-6 An alkoxy group; or (b)
R 5a And R is 5b Together with the carbon atoms to which they are attached form a c=nh, 3 membered heterocyclyl, 4 membered heterocyclyl or 5 membered heterocyclyl; and each of said heterocyclic groups independently optionally comprises 1 or 2 heteroatoms selected from N or O; and each of said ring systems may independently optionally be substituted with-H-F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkoxy or-C 1-3 Alkyl groups are substituted or unsubstituted.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 5a Or R is 5b Are each independently selected from-H, -NH 2 -OH, methyl, ethyl, methoxy or ethoxy; or (b)
R 5a And R is 5b Together with the carbon atoms to which they are attached form a c=nh, 3 membered heterocyclyl, 4 membered heterocyclyl or 5 membered heterocyclyl; and each of said heterocyclic groups comprises 1 heteroatom selected from N or O.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, W is NR w And R is w Selected from the group consisting of-H, -F, -Cl, -Br, -I, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -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 formula (I) or a pharmaceutically acceptable salt thereof, W is NR w And R is w Selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl-CO-methyl or methyl-CO-methoxy.
In some embodiments, a compound of 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 the group consisting of 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; 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
Figure BDA0003942079150000061
Figure BDA0003942079150000062
Figure BDA0003942079150000071
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 2a 、R 2b 、R 3a And R is 3b Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkyl or-C 1-3 An alkoxy group.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 2a 、R 2b 、R 3a And R is 3b Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2a And R is 2b Each independently is-H or methyl, and R 3a And R is 3b Each independently is-H.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 6 Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NR 6a R 6b -CN, -OH, oxo, =o, carboxyl, -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, -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 Carbocyclyl, -O-C 5-6 Heterocyclyl, -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, -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 group 2 、-PO(C 1-3 Alkoxy group) 2 A 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 as described 6a And R is 6b Are each independently selected from-H; -F; -Cl; br; i, a step of I; -NH 2 ；-CN；-OH；-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the 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 (b)
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 group; and each heteroaryl or heterocyclyl group comprises 1 or 2 heteroatoms selected from N, O or S; and each ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 (O), oxo, carboxyl, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 6 Are each independently selected from-H; -F; -Cl; -Br; -NR 6a R 6b The method comprises the steps of carrying out a first treatment on the surface of the -CN; -OH; an oxo group; =o; a carboxyl group; methoxy; an ethoxy group; a propoxy group; an isopropoxy group; a methyl group; an ethyl group; a propyl group; an 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 The method comprises the steps of carrying out a first treatment on the surface of the -CO-methyl; -CO-ethyl; -CO-NR 6a -C 5-6 A heterocyclic group; -CO-C 5-6 A heterocyclic group; -O-C 5-6 Carbocyclyl; -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 -methyl; -NR 6a -SO 2 -ethyl; -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 The method comprises the steps of carrying out a first treatment on the surface of the PO (ethyl) 2 The method comprises the steps of carrying out a first treatment on the surface of the PO (methoxy group) 2 The method comprises the steps of carrying out a first treatment on the surface of the PO (ethoxy) 2 The method comprises the steps of carrying out a first treatment on the surface of the A 5 membered heterocyclyl containing 1, 2 or 3 heteroatoms; a 6 membered heterocyclyl containing 1, 2 or 3 heteroatoms; a 5 membered heteroaryl group containing 1, 2 or 3 heteroatoms; or a 6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein each R is 6 Are each independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from the group consisting of-F, -Cl, br, -NH 2 -OH, carboxyl, oxo, =o, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; each R 6a And R is 6b Are each independently selected from-H; -F; -Cl; br; i, a step of I; -NH 2 ；-CN；-OH；-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; a methyl group; an ethyl group; methoxy; an ethoxy group; is substituted by 1, 2 or 3-H, F, cl, br, -NH 2 -CN or-OH substituted methyl; or 1, 2 or 3-H, F, cl, br, -NH 2 -CN or-OH substituted ethyl; or (b)
Two adjacent R 6 Taken together and taken 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 ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 (O), oxo, carboxyl, -CONH 2 、-PO(CH 3 ) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereofSalts of each R 6 Are each independently selected from-F, -Cl, -Br, =O, -OH, -CN, -NH 2 、
Figure BDA0003942079150000091
-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 、
Figure BDA0003942079150000092
Figure BDA0003942079150000093
Figure BDA0003942079150000094
-NHCOCH 3 、
Figure BDA0003942079150000095
-NHCONHCH 3 、
Figure BDA0003942079150000096
Figure BDA0003942079150000097
Or (b)
Two adjacent R 6 Are linked together and taken together with the carbon atoms to which they are respectively attached to form
Figure BDA0003942079150000098
Figure BDA0003942079150000099
In some embodiments, the compound of formula (I) is a compound of formula II:
Figure BDA00039420791500000910
wherein:
R 3 selected from-H or-NH 2 ；
Each R 4a Or R is 4b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl or substituted or unsubstituted-C 1-3 An alkyl group; or (b)
R 4a And R is 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 is 5b Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl or substituted or unsubstituted-C 1-3 An alkyl group; or (b)
R 5a And R is 5b Together with the carbon atoms to which they are commonly attached form a 3-5 membered heterocyclic group; and each of said heterocyclic groups is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from the group consisting of-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;
Figure BDA0003942079150000101
represents a single bond or a double bond; wherein,,
i) When (when)
Figure BDA0003942079150000102
When representing a single bond, Y 2 Is CR (CR) 2a Or N, and Y 3 Is CH or N; or (b)
ii) when
Figure BDA0003942079150000103
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 Carboxyl 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, carboxyl, -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, -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 group 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 with 1, 2 or 3 substituents or unsubstituted; and n is 0, 1, 2 or 3; or (b)
Two adjacent R 6 Are linked together to form, together with the carbon atoms to which each is attached, a 6 membered aryl, 5 membered heteroaryl, 6 membered heteroaryl, C 3-6 Heterocyclyl or C 3-6 Carbocyclyl, each of said ring systems independently optionally substituted with 1, 2 or 3 substituents or not;
each R 6a And R is 6b Independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, or substituted or unsubstituted
Figure BDA0003942079150000104
An alkyl group.
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, each R 5a Or R is 5b Independently selected from the group consisting of-H, -Cl, -Br, -NH 2 -OH, carboxyl, methyl, ethyl, methoxy or ethoxy; or (b)
R 5a And R is 5b Together with the carbon atoms to which they are commonly attached form
Figure BDA0003942079150000105
And C represents the carbon atom with R 5a And R is 5b And (5) connection.
In some embodiments, a 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 independently comprises 1 or 2 heteroatoms selected from N, O or S; each of said heterocyclic groups independently comprises 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
Figure BDA0003942079150000111
Figure BDA0003942079150000112
Figure BDA0003942079150000121
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2a Selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; a methyl group; an ethyl group; a propyl group; an isopropyl group; methoxy; an ethoxy group; a propoxy group; an isopropoxy group; is formed by-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 alkyl group; or is formed by-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 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, a compound of formula (II) or a pharmaceutically acceptable salt thereof, each R 6 Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-N(CH 3 ) 2 -CN, -OH, oxo, =o, carboxyl, methoxy, ethoxy, methyl, ethyl, isopropyl, t-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 、
Figure BDA0003942079150000122
Figure BDA0003942079150000131
Figure BDA0003942079150000132
Wherein each R is 6 Independently optionally substituted with 1, 2 or 3-F, -Cl, -NH 2 -OH, oxo, =o, methyl, ethyl or propyl substituted or unsubstituted.
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, each R 6a And R is 6b Are each independently selected from the group consisting of-H, -Cl, -Br, -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 formula (I) is a compound of formula (III):
Figure BDA0003942079150000133
wherein:
each R 1 And R is 2 Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkoxy or-C 1-3 An alkyl group; or (b)
R 1 R adjacent thereto 2 Are linked and form, together with the carbon atoms to which they are respectively attached, 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 halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, oxo, =o, -CONH 2 or-CO-C 1-3 Alkyl substituted or unsubstituted;
Y 1 selected from N or CH;
R 3 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 group or heterocycle independently optionally contains 1 or 2 heteroatoms selected from N or O;
i) When (when)
Figure BDA0003942079150000141
When representing a single bond, Y 3 Is CH or N; or (b)
ii) when
Figure BDA0003942079150000142
When representing a double bond, Y 3 Is C;
R 7 selected from halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, 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 formula (I) or a pharmaceutically acceptable salt thereof, R 1 R adjacent thereto 2 Are linked and together with the carbon atoms to which they are respectively attached form
Figure BDA0003942079150000143
And the ring system is independently optionally substituted with 1 or 2-F or-COCH 3 Substituted or unsubstituted.
In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, ring B is selected from
Figure BDA0003942079150000144
In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt thereof, R 7 Selected from the group consisting of-NH 2 -CN, oxo, =o, -CONH 2 、-NH-COCH 3 Methyl or methoxy.
In some embodiments, the compound of formula (I) is a compound of formula (IV):
Figure BDA0003942079150000145
wherein:
each R 1 And R is 2 Are each independently selected from-H; -F; -Cl; -Br; -NH 2 ；-CN；-OH；-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the A carboxyl group; -NHC 1-3 An alkyl group; -N (C) 1-3 Alkyl group 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 (b)
R 1 R adjacent thereto 2 Connected and forming, together with the carbon atoms to which they are each attached, a 6 membered carbocyclic ring, a 6 membered aryl group, a 5 membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N or O, or a 6 membered heterocyclic ring comprising 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 Carboxyl, 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 said heteroaryl or heterocyclyl independently optionally containing 1 or 2 heteroatoms selected from N, O or S;
Figure BDA0003942079150000151
represents a single bond or a double bond; and is also provided with
i) When (when)
Figure BDA0003942079150000152
When representing a single bond, Y 2 Is CR (CR) 2a Or N, and Y 3 Is CR (CR) 3a Or N; or (b)
ii) when
Figure BDA0003942079150000153
When representing a double bond, Y 2 And Y 3 All are C;
each R 2a And R is 3a Are each independently selected from-H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkoxy or-C 1-3 An alkyl group;
R 8 selected from halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, oxo, = O, C 1-4 Alkyl, 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 group 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 Are each independently optionally substituted with 1, 2 or 3 groups selected from halogen, methyl, ethyl, methoxy, oxo, -NH 2 -CN or-OH; and t is 0, 1, 2 or 3; or (b)
Two adjacent R 8 Together with the carbon atoms to which they are each attached form a 6-membered aryl or 5-membered heteroaryl, and each of said ring systems is independently optionally substituted or unsubstituted;
each R 8a And R is 8b Are each independently selected from H, halogen, -NH 2 、-CN、-OH、-NO 2 Carboxyl, -C 1-3 Alkoxy or-C 1-3 An alkyl group.
In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, each R 1 And R is 2 Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 、-CF 3 Carboxyl, -NHCH 3 、-N(CH 3 ) 2 Methoxy, ethoxy, methyl or ethyl; or (b)
R 1 R adjacent thereto 2 Are linked and form, together with the carbon atoms to which they are respectively attached, a 6 membered carbocyclic ring, a 6 membered aryl group, a 5 membered heterocyclic group containing 1 heteroatom selected from N or OOr a 5 membered heteroaromatic ring comprising 1 heteroatom selected from N or O; and each ring system is independently optionally substituted with 1, 2 or 3 groups selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, oxo, =o, -CONH 2 The substituents of methoxy, ethoxy, methyl, ethyl, -CO-methyl or-CO-ethyl are substituted or unsubstituted.
In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, each R 1 And R is 2 Are each independently selected from the group consisting of-H, -F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 、-CF 3 Carboxyl, -NHCH 3 、-N(CH 3 ) 2 Methoxy, ethoxy, methyl or ethyl; or (b)
R 1 R adjacent thereto 2 Are linked and together with the carbon atoms to which they are respectively attached form
Figure BDA0003942079150000161
And the ring systems are each independently optionally substituted with 1, 2 or 3 groups selected from-F or-COCH 3 Substituted or unsubstituted.
In some embodiments, the ring D is selected from the group consisting of a compound of formula (IV) or a pharmaceutically acceptable salt thereof
Figure BDA0003942079150000162
Figure BDA0003942079150000163
Figure BDA0003942079150000171
In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, each R 2a And R is 3a Are each independently selected from-H, methyl or methoxy.
In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 8 Selected from-F, -Cl, -Br, -NH 2 、-CN、-OH、-NO 2 Carboxyl, 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 with 1, 2 or 3 groups 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, -NH 2 -CN, -OH, carboxyl, oxo, =o, methyl, ethyl, isopropyl, t-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 、
Figure BDA0003942079150000181
Figure BDA0003942079150000182
In some embodiments, the compound of formula (I), (II), (III), (IV) or a pharmaceutically acceptable salt thereof is:
Figure BDA0003942079150000183
Figure BDA0003942079150000191
Figure BDA0003942079150000201
Figure BDA0003942079150000211
Figure BDA0003942079150000221
Figure BDA0003942079150000231
Figure BDA0003942079150000241
Figure BDA0003942079150000251
Figure BDA0003942079150000261
Figure BDA0003942079150000271
Figure BDA0003942079150000281
Figure BDA0003942079150000291
Figure BDA0003942079150000301
Figure BDA0003942079150000311
in another aspect, the present invention also provides a pharmaceutical composition comprising at least one compound of the general formula (I), (II), (III) or (IV) according to the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant.
Further, in the pharmaceutical composition, the weight ratio of the compound shown in the structural formula (I), (II), (III) or (IV) or 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 disorder, fibrosis, or vision disorder.
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, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and combinations thereof.
Unless otherwise indicated herein,the term "halogen" in the present invention refers to fluorine, chlorine, bromine or iodine. Preferably, halogen includes fluorine, chlorine and bromine. The term "halogenated C 1-6 Alkyl "," halo C 2-6 Alkenyl "," halo 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 halogen atoms, especially fluorine or chlorine atoms. 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 The method comprises the steps of carrying out a first treatment on the surface of the Fluoro C 1-3 Alkoxy groups, e.g. OCF 3 、OCHF 2 、OCH 2 F、OCH 2 CH 2 F、OCH 2 CHF 2 Or OCH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the In particular CF 3 、OCF 3 And OCHF 2 。
Unless otherwise indicated, alkyl groups in the present invention include saturated monovalent hydrocarbon groups having straight, branched, or cyclic moieties. For example, alkyl groups include 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 refers to a difunctional 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 oxyether 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 refers to a monocyclic or polycyclic aromatic hydrocarbon unless otherwise indicated. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
The term "heterocycle" as used herein by itself or as part of another substituent, unless otherwise indicated, refers to an unsubstituted and substituted monocyclic or polycyclic, non-aromatic, partially unsaturated, or fully saturated ring system 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 oxazayl.
The term "heteroaryl" as used herein by itself or as part of another substituent, refers to an aromatic ring system containing carbon and at least one heteroatom, unless otherwise specified. Heteroaryl groups may 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, e.g., the cyclic heteroaryl is a polycyclic heteroaryl. The bicyclic heteroaryl ring may contain 8 to 12 member atoms. The monocyclic heteroaryl ring 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, benzofuryl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.
The term "cycloalkyl" as used herein, by itself or as part of another substituent, refers to 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, unless otherwise specified. 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 groups
Figure BDA0003942079150000331
The term "oxo" refers to the group = O.
The term "oxo" or "=o" means that it forms, together with the carbon atom to which it is attached, c=o.
Whenever any one of the terms "alkyl" or "aryl" or its prefix root appears in the name of a substituent (e.g., aralkyl or dialkylamino), it is to be construed as including the limitations of "alkyl" and "aryl" given above, either by itself or as part of another substituent, unless otherwise indicated. The indicated number of carbon atoms (e.g., cl-6) shall refer independently to the number of carbon atoms in the alkyl portion or the number of carbon atoms in the alkyl portion where alkyl is the larger substituent of its prefix root.
Two "R" in the general formulae I, II, III or IV 1 "substituents may be the same or different. Similar to "R 1 ", and two" Y's of the formulae I, II, III or IV 1 "may be the same or different.
The compounds described herein, for example, certain compounds of formula I, II, III or IV, may contain asymmetrically substituted carbon atoms (or chiral centers) of R or S configuration. The invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds described herein, when specifically designated as R-or S-isomer by chemical name, should be understood as having the predominant configuration of R-or S-isomer, respectively. For example, in any of the embodiments described herein, such R-or S-designated isomer may be substantially free (as determined by chiral HPLC, less than 5%, less than 1% or undetectable) of the other isomer of each chiral center. The R-or S-isomer may be prepared by the methods exemplified herein, for example by using chiral auxiliary such as R-or S-t-butylsulfinamide during the synthesis. Other methods of preparing the dominant configuration 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 form containing one or more atoms having 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 these and/or other isotopes of 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 substituted with deuterium to provide the corresponding labeled or enriched compound.
As used herein, the term "subject" (alternatively referred to as a "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.
The term "ring system" (also referred to as "ring system") as used herein includes, but is not limited to, carbocycles, heterocycles, heteroaromatic rings, and the like, may also include only heterocycles and/or heteroaromatic rings, and specifically includes determining which rings are based on context requirements, but in any event, "ring system" does not include C-based 1-6 Alkyl or C 1-3 Cycloalkyl groups of alkyl groups, and excluding C-based groups 1-6 Alkoxy or C 1-3 An alkoxy group.
The compounds of formula I, II, III or IV may 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 bond or in particular the substituents on the ring may be present in cis (=z-) or trans (=e-) form. These compounds can therefore be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
When used in plural (e.g., a compound, a salt), it includes the singular (e.g., a single compound, a single salt). The term "compound" does not exclude the presence (e.g. in a pharmaceutical formulation) of more than one compound of formula I, II, III or IV (or a salt thereof), and "a" merely represents an indefinite article. Thus "a" may be understood preferably as "one or more" and should not be understood as "one",
"SHP2" refers to "Src homology-2 containing protein tyrosine phosphatase", also known as SH-PTP2, SH-PTP3, syp, PTP1D, PTP2C, SAP-2 or PTPN11.
Cancers that carry "ptpll 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; g503 and A, 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).
In the present invention, the term "composition" is intended to include products comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. Furthermore, some crystalline forms of the compounds of the present invention may exist as polymorphs and 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 present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, salts of the compounds of the present 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 basic nitrogen is protonated by inorganic or organic acids, 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, hydroxyethanesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexaneaminosulfonic, 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 present invention are also included within the scope of the present 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" will include the use of specifically disclosed compounds of the present invention, as well as the use of compounds that may not be specifically disclosed, but which, upon administration to a patient, can be converted in vivo to the particular compound for the treatment of various conditions or disorders. Conventional methods for selecting and preparing suitable prodrugs are described, for example, in prodrug design, et al, published in 1985 by H.Bundgaard and Elsevier.
In the present invention, the definition of any substituent or variable at a particular position is independent of the definition of the substituent or variable at other positions in the molecule. It will be appreciated that substituents and substitution patterns on the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that 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 diastereoisomers and optical isomers that may be produced. The present invention includes all those possible diastereomers and their racemic mixtures, their substantially pure, resolvable enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The above formulae I, II, III or IV do not show the stereochemistry determined at a specific position. The present invention includes all stereoisomers of formulas I, II, III or IV, and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. During the synthetic methods used to prepare these compounds, or during the use of racemization or epimerization methods known to those skilled in the art, the products of these methods may be mixtures of stereoisomers.
When a tautomer of a compound of formula I, II, III or IV is present, the invention includes any possible tautomer 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 the form of solvates or polymorphs, the present invention includes any possible solvate and polymorphic forms. 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, etc. may be used.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts can 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 can 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 (% by weight).
The pharmaceutical composition of the present invention comprises as an active ingredient a compound represented by formula I, II, III or IV (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. 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 compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. 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 of the present invention represented by formulas I, II, III or IV or a prodrug or metabolite thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, may be combined with the pharmaceutical carrier in intimate admixture (intimate admixture) according to conventional pharmaceutical compounding techniques. The carrier may take a variety of forms depending on the form of formulation desired for administration, such as oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may be provided as separate units suitable for oral administration, such as capsules, cachets (cachets) or tablets each containing a predetermined amount of the active ingredient. Furthermore, the composition may be present in the form of a powder, a granule, 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 usual dosage forms described above, the compounds of formula I, II, III or IV or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery means. The composition may be prepared by any pharmaceutical method. Typically, these methods include the step of bringing the active ingredient into association with the carrier which contains one or more essential ingredients. Typically, the compositions are prepared by uniformly and intimately admixing (uniformly and intimately 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 comprise a pharmaceutically acceptable carrier and a compound of formula I, II, III or IV or a pharmaceutically acceptable salt. 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 (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 the gas carrier include carbon dioxide and nitrogen. In preparing the composition for oral dosage form, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations (e.g., suspensions, elixirs and solutions); and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used to form oral solid preparations (e.g., powders, capsules and tablets). Tablets and capsules are preferred oral dosage units due to their ease of administration, whereby solid pharmaceutical carriers are used. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.
Tablets containing the compositions of the invention may be prepared by compression or moulding, optionally together with one or more auxiliary ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets may be made 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 the human population may contain from about 0.5mg to about 5g of the active agent, admixed with a suitable and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition. The unit dosage form generally contains between about 1mg and about 2g of the 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 compounds 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 detrimental growth of microorganisms.
The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the composition may be in the form of a sterile powder for 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 preferable that the contaminating action of microorganisms such as bacteria and fungi should be prevented. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols), vegetable oils, and suitable mixtures thereof.
The pharmaceutical composition of the present invention may be in a form suitable for topical use, such as aerosol, cream, ointment, lotion, dusting powder, and the like. Furthermore, the composition may be in a form suitable for use in a transdermal device. Using the compounds represented by the formulas I, II, III or IV of the present invention or pharmaceutically acceptable salts thereof, these formulations can be prepared by conventional treatment methods. For example, a cream or ointment is prepared by mixing a hydrophilic material with water and from about 5% to about 10% by weight of the compound to produce a cream or ointment having the desired consistency.
The pharmaceutical composition 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 may be conveniently formed by first mixing the composition with a softened or melted carrier and then cooling and shaping in a mold.
In addition to the carrier ingredients described above, the above 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 the compounds described by formulas I, II, III or IV, or pharmaceutically acceptable salts thereof, may also be prepared in the form of powders or liquid concentrates.
Generally, the above conditions can be treated with a dosage level of about 0.01mg/kg body weight to about 150mg/kg body weight per day, or alternatively, a dosage level of about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergies/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.
However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors including the age, 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 invention. All parts and percentages are by weight and all temperatures are degrees celsius unless explicitly stated otherwise. The following abbreviations are used in the examples:
Figure BDA0003942079150000381
Figure BDA0003942079150000391
intermediate A1
Figure BDA0003942079150000392
Sodium hydride (60% dispersion in mineral oil, 1.11g,27.75 mmol) was added portionwise to a solution of 6-methoxy-2, 3-dihydro-1H-inden-1-one (1.50 g,9.25 mmol) in DMF (10 mL) under nitrogen. The mixture was heated to 60℃and stirred at this temperature for 20 minutes. Tert-butyl bis (2-chloroethyl) carbamate (2.46 g,10.17 mmol) 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 taken up in 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 ]Tert-butyl 1' -carboxylate (557 mg). MS: m/z 332 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 1
Figure BDA0003942079150000401
Intermediate A2
Figure BDA0003942079150000402
Step a: diethanolamine (198.15 g,1.88 mol), K 2 CO 3 A mixture of benzyl bromide (386.79 g,2.26 mol) and acetonitrile (2000 mL) was stirred at 90℃for 2.5h. After cooling to RT, filtration, the filter cake was rinsed with EA (2×100 mL). The filtrate was concentrated under reduced pressure. The residue passes throughPurification by silica gel chromatography (MeOH: DCM=1:10, v/v elution) afforded N-benzyldiethanolamine (89.44 g) as a colourless oil. MS: m/z 196 (M+H) + .
Step b: to a solution of N-benzyldiethanolamine (30.66 g,0.16 mol) in toluene (300 mL) at 0deg.C was added dropwise phosphorus tribromide (69.13 g,0.26 mol). The system was warmed to 105℃and stirred for 16h. After cooling to RT, volatiles were removed by concentration under reduced pressure. The residue was diluted with water (300 mL) and the pH was adjusted to 9 with NaOH. The system was extracted with EA (3X 150 mL), the organic phases combined, dried over anhydrous Na 2 SO 4 Drying and filtering. The filtrate was concentrated under reduced pressure to give N-benzyl-2-bromo-N- (2-bromoethyl) ethane-1-amine (41.58 g), which was used in the next step without any further purification. MS: m/z 320 (M+H) + .
Step c: to 0℃6, 7-dihydro-5H-cyclopenta [ b ] under nitrogen ]Sodium hydride (60% dispersion in mineral oil, 982mg,24.55 mmol) was added in three portions to a solution of pyridin-5-one (1.70 g,12.77 mmol) in DMF (20 mL) and the mixture was then heated to 60℃and stirred at this temperature for 1h. N-benzyl-2-bromo-N- (2-bromoethyl) ethane-1-amine (4.54 g,14.14 mmol) was then added and stirred for an additional 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 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 1' -benzylspiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5 (7H) -one (1.14 g). MS: m/z 293 (M+H) + .
Step d: to 0 ℃ 1' -benzylspiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]To a solution of 5 (7H) -one (1.05 g,3.59 mmol) in DCE (10 mL) was added dropwise 1-chloroethyl chloroformate (803 mg,6.32 mmol). 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 (1.33 g,10.32 mmol) and (Boc) were added 2 O (1.38 g,6.32 mmol). The resulting solution was stirred at RT for 16h. The reaction solution 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' -piperidines]-tert-butyl 1' -carboxylate (438 mg). MS: m/z 303 (M+H) + .
Intermediate A3
Figure BDA0003942079150000411
Step a: LDA (2M in THF/Hex solution, 24mL,48.00 mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (8.14 g,31.64 mmol) in THF (80 mL) at-70℃under nitrogen. After stirring the resulting solution at this temperature for 70min, 1-bromo-4- (bromomethyl) benzene (7.91 g,31.64 mmol) was added in portions. The resulting solution was stirred at-70 ℃ for 3h and 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 the aqueous phase was extracted with 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 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 (14.55 g,34.13 mmol), naOH (8.12 g,203.00 mmol), meOH (80 mL) and water (80 mL) was stirred at 75deg.C for 16.5h. After cooling to RT, volatiles were removed by concentration under reduced pressure. The system was extracted with EA (3X 80 mL). The combined organic phases were treated 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 (16.87 g,42.36 mmol) 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 (13.86 g,63.53 mmol) and stirred at RT for 18h. The reaction was extracted with EA (3X 150 mL). The combined organic phases were taken up with Na-free 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (16.87 g) was used in the next step without any further purification. MS: m/z 380 (M+H) + .
The following compounds were synthesized using the steps described above or modified steps and the corresponding starting materials.
TABLE 2
Figure BDA0003942079150000421
Intermediate A4
Figure BDA0003942079150000422
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (2.06 g,5.42 mmol), pd (PPh) 3 ) 4 (626 mg,0.54 mmol), DBU (252 mg,1.66 mmol), t-BuOH (15 mL), water (15 mL) and potassium ferrocyanide trihydrate (1.16 g,2.75 mmol) were 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 dried over 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 elution) to give 6-cyano-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.86 g). MS: m/z 327 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 3 Table 3
Figure BDA0003942079150000431
Intermediate A5
Figure BDA0003942079150000432
4-cyano-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]A mixture of tert-butyl 1' -carboxylate (0.93 g,2.85 mmol), KOH (1.60 g,28.50 mmol), meOH (15 mL) and water (15 mL) was stirred at 100deg.C for 2h. After cooling to RT, the reaction was diluted with water (30 mL) and extracted with EA (60 mL,30 mL). The combined organic phases were washed with brine (1X 80 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 4-carbamoyl-1-oxo-1, 3-dihydro spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.04 g) was used in the next step without any further purification. MS: m/z 345 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 4 Table 4
Figure BDA0003942079150000433
Intermediate A6
Figure BDA0003942079150000434
To 6-carbamoyl-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of tert-butyl 1' -carboxylate (1.57 g,4.56 mmol) in DMF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 0.91g,22.79 mmol) followed by CH 3 I (1 mL,16.06 mmol). The system was stirred at RT for 17h. The reaction was quenched with brine (50 mL) and extracted with EA (2X 50 mL). The combined organic phases were washed with brine (1X 100 mL), 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 6- (dimethylcarbamoyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Tert-butyl 1' -carboxylate (0.82 g). MS: m/z373 (M+H) + .
Intermediate A7
Figure BDA0003942079150000441
Steps a-c: step (a-c) using intermediate A3 gives 1'- (tert-butoxycarbonyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-6-carboxylic acid. MS: m/z 346 (M+H) + .
Intermediate A8
Figure BDA0003942079150000442
To a 50mL lock tube was added 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (998 mg,2.62 mmol), DMSO (8 mL), water (4 mL), cuI (217 mg,1.14 mmol) 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). The organic phase was separated with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 6-amino-1-oxo-1, 3-dihydro spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (750 mg). MS: m/z 317 (M+H) + .
Intermediate A9
Figure BDA0003942079150000443
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (531 mg,1.40 mmol), methanesulfonamide (375 mg,3.90 mmol), K 2 CO 3 (1.10 g,7.95 mmol), N, N' -dimethyl-1, 2-ethylenediamine (85 mg,0.96 mmol), cuI (72 mg,0.38 mmol) and 1, 4-dioxane (20 mL) were stirred at 110℃for 23h. Methanesulfonamide (370 mg,3.89 mmol), N, N' -dimethyl-1, 2-ethylenediamine (85 mg,0.96 mmol) and CuI (75 mg,0.39 mmol) were added and stirred at the same temperature for 7 hours. After cooling to RT, the reaction was quenched with water (30 mL) and extracted with EA (3X 50 mL). The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: hex=2:3, v/v) to give 6- (methanesulfonylamino) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Tert-butyl 1' -carboxylate (562 mg). MS: m/z 395 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 5
Figure BDA0003942079150000451
Intermediate A10
Figure BDA0003942079150000452
To 6-amino-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl 1' -carboxylate (0.66 g,2.09 mmol) in AcOH (5 mL) and water (10 mL) was added dropwise a solution of sodium cyanate (0.28 g,4.31 mmol) in water (2 mL). The system was stirred at 50℃for 4h. After cooling to RT, the pH of the reaction was adjusted to 12 with aqueous ammonia (25%) and extracted with DCM (60 ml,30 ml). The combined organic phases were washed with brine (1X 60 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=2:1, v/v) to give 1-oxo-6-ureido-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (0.39 g). MS: m/z 360 (M+H) + .
Intermediate A11
Figure BDA0003942079150000453
To 0 ℃ 6- (methylthio) -1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of tert-butyl 1' -carboxylate (336 mg,0.97 mmol) in MeOH (20 mL) and water (20 mL) was added potassium peroxymonosulfate (298 mg,1.76 mmol). The system was stirred at 0deg.C for 1h. Saturated Na was used as the reaction solution 2 S 2 O 3 (10 mL) was quenched and concentrated under reduced pressure to remove volatiles. The system was extracted with EA (3X 40 mL) and the combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gelPurification by the method (eluting with EA: hex=4:1, v/v) gives 6- (methylsulfinyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Tert-butyl 1' -carboxylate (285 mg). MS: m/z 364 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 6
Figure BDA0003942079150000454
Figure BDA0003942079150000461
Intermediate A12
Figure BDA0003942079150000462
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.51 g,3.97 mmol), phosphorus dimethyloxide (503 mg,6.44 mmol), pd (OAc) 2 (92mg，0.41mmol)，Xantphos(457mg，0.79mmol)，K 3 PO 4 A mixture of (1.57 g,7.40 mmol) 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), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH: dcm=1:30, v/v elution) to give 6- (dimethylphosphoryl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine as a white solid]Tert-butyl 1' -carboxylate (0.81 g). MS: m/z 378 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 7
Figure BDA0003942079150000463
Intermediate A13
Figure BDA0003942079150000464
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.09 g,2.87 mmol), 1H-imidazole (180 mg,2.64 mmol), cuBr (34 mg,0.24 mmol), cs 2 CO 3 (851 mg,2.61 mmol), a mixture of 1,2,3, 4-tetrahydro-8-hydroxyquinoline (74 mg,0.49 mmol) 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 was 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 ]-tert-butyl 1' -carboxylate (142 mg). MS: m/z 368 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 8
Figure BDA0003942079150000471
Intermediate A14
Figure BDA0003942079150000472
1'- (Boc) -1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]6-Carboxylic acid (345 mg,1.00 mmol), piperidine (129 mg,1.51 mmol) and HATU (422 mg,1.11 mmol) 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-dihydro spiro [ indene-2, 4' -piperidine]-tert-butyl 1' -carboxylate (380 mg). MS: m/z 413 (M+H) + .
Intermediate A15
Figure BDA0003942079150000473
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.02 g,2.68 mmol), morpholine (0.67 g,7.69 mmol), cu (OAc) 2 (0.51 g,2.81 mmol), DBU (1.03 g,6.77 mmol) and DMSO (10 mL) were 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 taken up in 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 ]Tert-butyl 1' -carboxylate (467 mg). MS: m/z 387 (M+H) + .
Intermediate A16
Figure BDA0003942079150000474
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (500 mg,1.31 mmol), 1-methylpiperazine (270 mg,2.70 mmol), cs 2 CO 3 (1306mg，4.01mmol)，Pd 2 (dba) 3 (66 mg,0.07 mmol), xantPhos (75 mg,0.13 mmol) and 1, 4-dioxane (18 mL) were stirred at 100deg.C 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), dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 6- (4-methylpiperazin-1-yl) -1-oxo-1, 3-dihydro spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (0.87 g, crude) was used in the next step without any further purification. MS: m/z 400 (M+H) + .
Intermediate A17
Figure BDA0003942079150000481
Step a: LDA (2M in THF/Hex solution, 45.00mL,90.00 mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (15.52 g,60.31 mmol) in THF (100 ml) at-60℃under nitrogen. Naturally heating the system to-20deg.C, stirring for 50min, cooling to-50deg.C, and dropwise adding CH 3 A solution of I (8.56 g,60.31 mmol) in THF (20 mL). Then stirred at this temperature for 50min. The reaction was carefully quenched with saturated ammonium chloride (80 mL) and extracted with EA (100 mL,50 mL). The combined organic phases were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 1-tert-butyl 4-ethyl 4-methylpiperidine-1, 4-dicarboxylic acid (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 solution of 1-tert-butyl 4-ethyl 4-methylpiperidine-1, 4-dicarboxylate (17.70 g,65.23 mmol) in THF (150 mL) at 0deg.C was added LiBH 4 (2M in THF, 98.00mL,196.00 mmol). The system was stirred at 70℃for 18h. After cooling to RT, quench by dropwise addition of water (100 mL). The system was extracted with EA (200 mL,100 mL), and the combined organic phases were washed with brine (1X 200 mL) and with 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 (10.71 g,84.38 mmol) in DCM (150 mL) at-78deg.C was added dropwise a solution of DMSO (10.99 g,140.63 mmol) in DCM (30 mL) and stirred at that temperature for 30min. A solution of tert-butyl 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate (12.90 g,56.25 mmol) in DCM (30 mL) was added dropwise and stirred at-78℃for 30min. Triethylamine (22.77 g,225.02 mmol) was added dropwise, then warmed to-20℃naturally, and 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 dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:20, v/v elution) to give 4-formyl-4-methylpiperidine-1-carboxylic acid tert-butyl esterButyl ester (11.82 g.) MS: M/z 172 (M+H-56) + .
Step d: LDA (2M in THF/Hex, 11.00mL,22.00 mmol) was added dropwise to a solution of 3-chloropyridine (2.25 g,17.64 mmol) in THF (50 mL) at-70 ℃. The system was warmed to-60 ℃ and stirred for 1.5h. A solution of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (3.95 g,17.37 mmol) in THF (10 mL) was added dropwise at-70 ℃. After stirring for 1h, the mixture was quenched with water (50 mL). The organic phase was collected, the aqueous phase separated and extracted with EA (60 mL,30 mL). The combined organic phases were washed with brine (1X 80 mL) and dried over 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 (8.10 g,23.76 mmol) in DCM (50 ml) was added dess-martin oxidant (20.12 g,47.44 mmol). 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 was treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:3, v/v elution) to give tert-butyl 4- (3-chloroisonicotinyl) -4-methylpiperidine-1-carboxylate (4.81 g). MS: m/z 339 (M+H) + .
Step f: 4- (3-chloroisonicotinyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (6.31 g,18.62 mmol), cs under nitrogen 2 CO 3 (6.72 g,21.90 mmol), pivalic acid (571 mg,5.60 mmol), pd (OAc) 2 (0.22g，0.98mmol)，Cy 3 PH·BF 4 A mixture of (0.70 g,1.90 mmol) and 1,3, 5-trimethylbenzene (40 mL) was stirred at 140℃for 72h. After cooling to RT, filtration followed by EA (3×40 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' -piperidines]Tert-butyl 1' -carboxylate (2.82 g). MS: m/z 303 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 9
Figure BDA0003942079150000491
Intermediate A18
Figure BDA0003942079150000492
Figure BDA0003942079150000501
Step a: to a solution of 3-bromo-6-chloropyridine-2-carboxylic acid (9.98 g,42.21 mmol) in MeOH (100 mL) was added dropwise H 2 SO 4 (98%, 10.00 mL). Stirred at 70℃for 3h. After cooling to RT, ammonia (25%) was added to adjust the pH of the reaction solution to 9. 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 dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 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 solution of methyl 3-bromo-6-chloropyridine-2-carboxylate (10.14 g,40.48 mmol) in MeOH (150 mL) at 0deg.C was added NaBH in portions 4 (4.62 g,122.13 mmol). Naturally heating to RT and stirring for 16h. The reaction was diluted with brine (110 mL) and concentrated under reduced pressure to remove MeOH. Extracted with EA (100 mL,80 mL) and the organic phase was extracted with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give (3-bromo-6-chloropyridin-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 (8.31 g,37.35 mmol) and triethylamine (7.63 g,75.40 mmol) in DCM (100 mL) at-15℃was added MsCl (4.71 g,41.12 mmol) dropwise. Naturally heating to RT and stirring for 2h. The reaction solution was quenched with water (50 mL) and the aqueous phase was separated. The organic phase was washed with brine (1X 50 mL) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give methyl (3-bromo-6-chloropyridin-2-yl) methanesulfonate (8.54 g). MS: M/z 300 (M+H) + .
Step d: LDA (2M in THF/Hex solution, 23.00mL,46.00 mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (9.66 g,37.54 mmol) in THF (30 mL) at-50℃under nitrogen. Stirring is carried out at this temperature for 1h. A solution of methanesulfonic acid (3-bromo-6-chloropyridin-2-yl) methyl ester (8.54 g,28.41 mmol) 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 was 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 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 (17.73 g,38.39 mmol), naOH (8.03 g,200.75 mmol), meOH (100 mL) and water (20 mL) was stirred at 65℃for 16h. After cooling to RT, volatiles were removed by concentration under reduced pressure and the system was diluted with water (150 mL). The pH was adjusted to 6 with saturated citric acid solution. Extracted with EA (2X 100 mL) and the combined organic phases were washed with brine (1X 100 mL) and dried over 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 elution) 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: sodium hydride (60% dispersion in mineral oil, 0.42g,10.50 mmol) was added portionwise 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 (3.80 g,8.76 mmol) in THF (20 mL) at-15 ℃ under nitrogen. Stirring at this temperature for 1h The mixture was cooled to-60 ℃. To the mixture was added dropwise n-BuLi (2.5M Hex solution, 5mL,12.50 mmol) 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), 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' -piperidines]-1' -carboxylic acid tert-butyl ester and 2-methoxy-5-oxo-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]Mixtures of tert-butyl 1' -carboxylate (1.48 g). MS: m/z 337 (M+H) + .MS：m/z 333(M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
Table 10
Figure BDA0003942079150000511
Intermediate A19
Figure BDA0003942079150000512
Step a: LDA (2M solution in THF/Hex, 6.00mL,12.00 mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (2.83 g,11.00 mmol) in THF (50 mL) at-78deg.C under nitrogen. Stirring is carried out at this temperature for 1h. 2-chloro-5- (chloromethyl) thiazole (dissolved in 3ml of THF, 1.69g,10.06 mmol) 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 taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:20, v/v elution) to give 4- ((2-chlorothiazol-5-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (1.15 g). MS: m/z 389 (M+H) + .
Step b: to 4- ((2-chlorothiazol-5-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (900 mg,2.31 mmol) in THF (5) at-78deg.C under nitrogenTo 0 mL) solution was added LDA (2M in THF/Hex, 3.00mL,6.00 mmol) dropwise. After stirring for 30min, quench with brine (30 mL). Extracted with EA (2X 30 mL), the organic phases were combined, dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-chloro-4-oxo-4, 6-dihydro spiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]Tert-butyl 1' -carboxylate (832 mg). MS: m/z 343 (M+H) + .
Intermediate A20
Figure BDA0003942079150000521
Step a: to a solution of 2-methylnicotinic acid (4.56 g,33.25 mmol) in THF (50 mL) at 0deg.C was added LAH (1.51 g,39.90 mmol). Naturally heating to RT and stirring for 4h. The reaction solution was carefully diluted with saturated ammonium chloride (50 mL). Filtering, separating filtrate, and collecting organic phase with anhydrous Na 2 SO 4 Dried, filtered again, and the filtrate 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 (1.41 g,11.45 mmol) in DCM (20 mL) at 0deg.C was added dropwise PBr 3 (1.86 g,6.87 mmol). The system was warmed to RT and stirred for 1.5h. Aqueous NaOH (5M, 10 mL) was added to adjust the pH of the reaction solution to 8. The aqueous phase was separated and the organic phase was washed with brine (1X 20 mL) and dried over 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 (4.63 g,18.00 mmol) in THF (30 mL) at-50deg.C was added LDA (2M in THF/Hex, 12.00mL,24.00 mmol) dropwise and stirred at this temperature for 1h. 3-bromomethyl-2-methylpyridine (3.25 g,18.00 mmol) was added, warmed to RT naturally and stirred for 16h. Saturated NH for reaction solution 4 Cl (50 mL) was carefully diluted. The aqueous phase was separated and the organic phase was washed with brine (1X 50 mL), anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to give 4- ((2-methylpyridine) as a red oil1-tert-butyl 4-ethyl (4.87 g) piperidin-3-yl-methyl-piperidine-1, 4-dicarboxylic acid was used in the next step without further purification. MS: m/z 363 (M+H) + .
Step d: to a solution of 4- ((2-methylpyridin-3-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (4.23 g,11.67 mmol) in THF (40 mL) at-20deg.C was added LDA (2M in THF/Hex solution, 12.00mL,24.00 mmol) dropwise, warmed to RT and stirred for 2h. The reaction was carefully diluted with brine (50 mL). The aqueous phase was separated and the organic phase was taken up in 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 7' -oxo-7 ',8' -dihydro-5 ' h-spiro [ piperidine-4, 6' -quinoline as a yellow oil]Tert-butyl 1-carboxylate (1.23 g). MS: m/z 317 (M+H) + .
Intermediate A21
Figure BDA0003942079150000531
Step a: to a mixture of t-BuOK (5.92 g,52.76 mmol) at-60℃in 1, 2-dimethoxyethane (50 mL) was added dropwise a solution of 2-toluenesulfonylacetonitrile (5.08 g,26.02 mmol) in 1, 2-dimethoxyethane (20 mL). A solution of 2-bromonicotinaldehyde (4.81 g,25.86 mmol) in 1, 2-dimethoxyethane (20 mL) was added dropwise to the system. After stirring at this temperature for 1h, meOH (50 mL) was added, the temperature was naturally raised to RT, stirred for 1h and to 85℃and stirred for a further 1h. After cooling to RT, volatiles were removed by concentration under reduced pressure, diluted with brine (200 mL) and extracted with EA (3×150 mL). The combined organic phases were taken up in 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 elution) to give 2- (2-bromopyridin-3-yl) acetonitrile (2.21 g). MS: m/z197 (M+H) + .
Step b: to a solution of 2- (2-bromopyridin-3-yl) acetonitrile (2.21 g,11.21 mmol) in DMF (20 mL) at 0deg.C was added sodium hydride (60% dispersion in mineral oil, 1.12g,28.03 mmol) in portions. The reaction system was warmed to 60 ℃ and stirred for 1.5h. Tert-butyl bis (2-chloroethyl) carbamate (3.26 g,13.46 mmol) was added to the mixture The mixture was stirred at 60℃for 2h. After cooling to RT, the reaction was quenched with brine (50 mL) and extracted with EA (3×100 mL). The combined organic phases were washed with brine (3X 80 mL), 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 tert-butyl 4- (2-bromopyridin-3-yl) -4-cyanopiperidine-1-carboxylate (1.56 g). MS: m/z 366 (M+H) +.
Step c: 4- (2-bromopyridin-3-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.56 g,4.26 mmol), K under nitrogen 2 CO 3 (2.35 g,17.04 mmol), trimethylboroxine (1.07 g,8.52 mmol), pd (PPh 3 ) 4 (47 mg,0.041 mmol) and water (8 mL) were stirred at 110℃for 2h. Trimethylcyclotriboroxine (2.15 g,17.13 mmol) and Pd (PPh) were supplemented 3 ) 4 (45 mg,0.039 mmol) and stirred 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, 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=2:1, v/v) to give tert-butyl 4-cyano-4- (2-methylpyridin-3-yl) piperidine-1-carboxylate (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 (1.08 g,3.58 mmol) in MeOH (50 mL) at 0deg.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 the mixture was added (Boc) 2 O (11.00 g,50.40 mmol) and stirred at room temperature for 2h. Extracted with EA (3X 100 mL), the organic phases were combined, 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) to give 4- (2-methylpyridin-3-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-methyl ester (467 mg). MS: m/z 335 (M+H) + .
Step e: to 4- (2-methylpyridin-3-yl) piperidine-1, 4-dicarboxylic acid at 0℃under nitrogenTo a solution of 1-tert-butyl-4-methyl ester (467 mg,1.40 mmol) in THF (10.50 mL) was added dropwise potassium bis (trimethylsilyl) amide (1M in THF, 7.00mL,7.00 mmol). Naturally warmed to RT and stirred for 3.5h, then quenched with saturated ammonium chloride (10 mL) and extracted with EA (3×40 mL). The combined organic phases were taken up in 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' -piperidines]-tert-butyl 1' -carboxylate (170 mg). MS: m/z 303 (M+H) + .
Intermediate A22
Figure BDA0003942079150000541
Step a: to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (15.00 g,70.33 mmol) in DMF (60 mL) at 0deg.C was added lithium tert-butoxide (6.75 g,84.44 mmol) in portions. The system was stirred at 0℃for 30 minutes. 3-bromopropene (9.73 g,80.44 mmol) was added dropwise to the mixture at 0deg.C and stirred at that temperature for 1h. The reaction was diluted with brine (100 mL) and extracted with EA (3X 200 mL). The organic phases were combined with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:20, v/v elution) to give tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (7.01 g). MS: m/z 254 (M+H) + .
Step b: to a solution of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (7.01 g,27.63 mmol) in THF (30 mL) at-78deg.C was added allylmagnesium bromide (1M in THF, 63.55mL,63.55 mmol) dropwise. Heat to RT and stir for 1.5h. The reaction system was quenched with saturated ammonium chloride. Extracted with EA (3X 200 mL). The combined organic phases were washed with brine (1X 200 mL) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (7.01 g). MS: m/z 282 (M+H) + .
Step c: to a solution of tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (7.00 g,24.88 mmol) in DCM (50 mL) was added portionwiseston-Martin oxidant (12.66 g,29.85 mmol). After stirring for 1.5h at RT, the reaction was diluted with brine (150 mL) and extracted with EA (3X 200 mL). The combined organic phases were taken up in 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 tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (5.63 g). MS: m/z 280 (M+H) + .
Step d: a mixture of tert-butyl 4-propenoyl-4-allylpiperidine-1-carboxylate (5.63 g,20.15 mmol), grubbs II (428 mg,0.50 mmol) and toluene (30 mL) was stirred at 85deg.C for 3.5h under nitrogen. After cooling to RT, the mixture was concentrated under reduced pressure. Purification of the residue by silica gel chromatography (EA: hex=1:5, v/v elution) gives 1-oxo-8-azaspiro [4.5 ]]Dec-2-ene-8-carboxylic acid tert-butyl ester (3.61 g). MS: m/z 252 (M+H) + .
Step e: to a solution of trimethylsulfoxide iodide (3.79 g,17.22 mmol) in DMSO (50 mL) was added sodium hydride (60% dispersion in mineral oil, 730mg,18.25 mmol) in portions, and after stirring for 30min, 1-oxo-8-azaspiro [4.5 ] was added dropwise ]Tert-butyl dec-2-ene-8-carboxylate (DMSO solution, 3.61g,14.36 mmol). 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 dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-oxo-spiro [ bicyclo [3.1.0 ]]Hexane-3, 4' -piperidines]Tert-butyl 1' -carboxylate (3.60 g). MS: m/z 266 (M+H) + .
Intermediate A23
Figure BDA0003942079150000551
Step a: to a solution of tetrahydro-2H-pyran-4-ol (3.54 g,34.66 mmol) and triethylamine (4.65 g,45.95 mmol) in DCM (100 mL) at-10deg.C was added MsCl (4.61 g,40.24 mmol). After stirring for 30min, the reaction was diluted with water (100 mL) and extracted with DCM (100 mL,50 mL). The combined organic phases were washed with brine (1X 50 mL), dried over anhydrous Na 2 SO 4 Drying, filtering and decompressingConcentration 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]To a solution of 1 (3H) -one (4.35 g,13.53 mmol) in DCM (200 mL) was added (1M in DCM, 15.00mL,15.00 mmol) and stirred at 45℃for 13H. Supplement BBr 3 (1M in DCM, 5.00mL,5.00 mmol) and stirred at 45℃for 24h. After cooling to RT, the reaction was diluted with water (150 mL) and NaHCO was added in portions 3 (20.00 g). The resulting mixture was extracted with DCM (2X 100 mL), the organic phases were combined, and the mixture was taken up in 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) was 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 (2.80 g,9.11 mmol), tetrahydro-2H-pyran-4-ylmethane sulfonate (3.40 g,18.87 mmol) and K 2 CO 3 A mixture of (8.23 g,59.55 mmol) and DMF (60 mL) was stirred at 110℃for 5.5h. Additional tetrahydro-2H-pyran-4-ylmethane sulfonate (1.10 g,6.10 mmol) and K 2 CO 3 (4.55 g,32.92 mmol) 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 were combined, washed with water (2X 300 mL) and brine (1X 300 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (MeOH: dcm=1:40, v/v elution) afforded 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 environment, 1 '-benzyl-6- ((tetrahydro-2H-pyran-4-yl) oxy) spiro [ indene-2, 4' -piperidine ]-1 (3H) -one (1.70 g,4.34 mmol) 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 (Boc) 2 O (1.10 g,5.04 mmol) and stirred at room temperature for 40h. The reaction system was concentrated under reduced pressure. Purification of the residue by silica gel chromatography (EA: hex=1:5, v/v elution) givesTo 1-oxo-6- ((tetrahydro-2H-pyran-4-yl) oxy) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.45 g). MS: m/z402 (M+H) + Intermediate A24
Figure BDA0003942079150000561
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1017 mg,2.67 mmol), diethyl phosphonate (564 mg,4.08 mmol), potassium phosphate (1156 mg,5.45 mmol), pd (OAc) 2 (63 mg,0.28 mmol), xantPhos (307 mg,0.53 mmol) and DMF (10 mL) were 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 (2 x 30 mL). The filtrate was separated and the aqueous layer was extracted with EA (2X 60 mL). The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (eluting with EA) gives 6- (diethoxyphosphoryl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine ]Tert-butyl 1' -carboxylate (134 mg) was used in the next step without further purification. MS: m/z 438 (M+H) + .
Intermediate A25
Figure BDA0003942079150000562
Intermediate a25 was synthesized according to the procedure of y.uto et al/biorg.med.chem.lett.20 (2010) 746-754.
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 11
Figure BDA0003942079150000571
Intermediate A26
Figure BDA0003942079150000572
Step a: to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (5.23 g,20.32 mmol) in THF (30 ml) at-65℃was added LDA (2M in THF/Hex, 12.00mL,24.00 mmol) dropwise. The resulting mixture was stirred at this temperature for 1.0h. 2-bromobenzaldehyde (3.44 g,18.59 mmol) was added dropwise at-70 ℃. After stirring for 1h, the mixture was quenched with brine (40 mL). The organic phase was separated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 1-tert-butyl 4-ethyl 4- ((2-bromophenyl) (hydroxy) methyl) piperidine-1, 4-dicarboxylic acid (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 4-ethyl ester (9.15 g,20.68 mmol) in DCM (70 ml) at-5℃was added dess-martin oxidant (18.02 g,42.49 mmol). 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 was treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:5, v/v elution) to give 1-tert-butyl 4-ethyl 4- (2-bromobenzoyl) piperidine-1, 4-dicarboxylate (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 (2.00 g,4.54 mmol) in THF (20 mL) at-80℃was added 1.8mL of n-butyllithium (2.5M in THF/Hex) under nitrogen. The system naturally returns to room temperature, and stirring is continued for 1h. The system was quenched with 30mL saturated brine and the organic phase was collected. The aqueous phase was extracted with 20mL of EA. The organic phases were combined, anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. Purification of the residue by silica gel chromatography (EA: hex=1:10, v/v elution) gives 1, 3-dioxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-tert-butyl 1' -carboxylate (500 mg), MS: m/z 316 (m+h) +.
Intermediate A27
Figure BDA0003942079150000581
Intermediate a27 was synthesized according to the procedure of j.org.chem.1999, 64, 5504-5510.
Intermediate A28
Figure BDA0003942079150000582
Step a: to a solution of ethyl 2-chlorothiazole-4-carboxylate (24.95 g,130.19 mmol) in MeOH (250 mL) at 0deg.C was added NaBH in portions 4 (17.29 g,456.97 mmol). Naturally heating to RT and stirring 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), and dried over 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 (18.88 g,130.19 mmol) and triethylamine (25.56 g,252.57 mmol) in DCM (200 mL) was added MsCl (15.96 g,139.30 mmol) dropwise for 15min. The system was stirred at RT for 25min. The reaction was quenched with brine (200 mL) and the aqueous phase was separated. Anhydrous Na for organic phase 2 SO 4 Drying, filtration and concentration under reduced pressure gave methanesulfonic acid (2-chlorothiazol-4-yl) methyl ester, which was used in the next step without further purification. MS: m/z 228 (M+H) + .
Step c: LDA (2M in THF/Hex, 75.00mL,150.00 mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (35.67 g,138.62 mmol) in THF (200 mL) at-60℃under nitrogen for 30min. Then, a solution of methanesulfonic acid (2-chlorothiazol-4-yl) methyl ester in THF (50 mL) was added dropwise, and the temperature was naturally raised to RT and stirred for 2h. The reaction was quenched with brine (300 mL). The organic phase was separated with 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 elution) to give 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (38.12 g). MS: m/z 389 (M+H) + .
Step d: LDA (2M in THF/Hex solution, 11.00mL,22.00 mmol) was added dropwise to a solution of-60deg.C 1-tert-butyl 4-ethyl 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (8.51 g,21.88 mmol) in THF (80 mL) under nitrogen. After completion of the dropwise addition, the reaction mixture was quenched with brine (50 mL). The organic phase was separated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (with EA: hex=1:10, v/v elution) gives 2-chloro-6-oxo-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]Tert-butyl 1' -carboxylate (1.93 g). MS: m/z 343 (M+H) + .
Intermediate A29
Figure BDA0003942079150000591
Steps (a-c): 1- (tert-Butoxycarbonyl) -4- (thiophen-2-ylmethyl) piperidine-4-carboxylic acid was synthesized with reference to step (b-c) of intermediate A28 and step (b) of intermediate A3.
Step d: a mixture of 1- (tert-butoxycarbonyl) -4- (thiophen-2-ylmethyl) piperidine-4-carboxylic acid (4.92 g,15.12 mmol) 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 (5.05 g,23.14 mmol) and stirred at room temperature for 18h. Extracted with EA (2X 50 mL). The combined organic phases were washed with brine (1X 50 mL), dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-tert-butyl-4-oxo-4, 6-dihydro spiro [ cyclopenta [ b ]]Thiophene-5, 4' -piperidines]Tert-butyl 1' -carboxylate (1.70 g). MS: m/z 364 (M+H) + .
Step e: a mixture of 1- (tert-butoxycarbonyl) -4- (thiophen-2-ylmethyl) piperidine-4-carboxylic acid (4.88 g,15.12 mmol), HCl (4M in 1, 4-dioxane, 8 mL) and DCM (50 mL) was stirred at RT for 1h. The reaction system was concentrated under reduced pressure. PPA (21.15 g) was added and the system stirred at 110℃for 1.5h. The reaction solution was poured into an ice/water mixture (100 mL) and the pH was adjusted to 10 with NaOH. Then add (Boc) 2 O (5.12 g,23.46 mmol) and at room temperatureStirring for 18h. Extracted with EA (2X 50 mL). The combined organic phases were washed with brine (1X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (with EA: hex=1:10, v/v elution) gives 4-oxo-4, 6-dihydro-4 spiro [ cyclopenta [ b ]]Thiophene-5, 4' -piperidines]Tert-butyl 1' -carboxylate (2.71 g). MS: m/z 308 (M+H) + .
Intermediate A30
Figure BDA0003942079150000601
Step a: to a solution of benzyl alcohol (5.15 g,47.62 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 3.01g,75.25 mmol) in portions and stirred for 20min. 4-chloropyridine-2-carboxylic acid (2.68 g,17.01 mmol) was added and stirred at 85℃for 3.5h. After cooling to RT, HCl (4M in 1, 4-dioxane, 10 mL) is added. The system was used directly in the next step. MS: m/z 230 (M+H) + .
Step b: combining the reaction system of step a with NaHCO 3 (7.51g，89.39mmol)，CH 3 I (1.5 mL) and DMF (10 mL) were mixed. After stirring for 0.5h, CH is added 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 was treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:1, v/v elution) 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 (1.50 g,6.17 mmol), liBH 4 A mixture of (2M in THF, 9.00mL,18.00 mmol) and THF (40 mL) was stirred at 50deg.C for 1h. The reaction was diluted with MeOH (15 mL) and water (150 mL) and extracted with EA (200 mL,50 mL). The combined organic phases were washed with brine (2X 100 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) 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 (0.50 g,2.32 mmol), dess-martin oxidant (1.25 g,2.95 mmol) and DCM (20 mL) was stirred for 1.5h. The reaction mixture was treated with saturated NaHSO 3 Aqueous solution, saturated NaHCO 3 The aqueous solution and DCM (50 mL) were diluted. The aqueous phase was separated and extracted with DCM (50 mL). The combined organic phases were treated 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 solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (0.52 g,2.02 mmol) in THF (15 mL) at 0deg.C was added LDA (2M in THF/Hex, 1.30mL,2.60 mmol) dropwise. The system was cooled to-70℃and a solution of 4- (benzyloxy) pyridine-2-carbaldehyde (0.40 g,1.88 mmol) in THF (5 mL) was added. Naturally warmed to-15 ℃ and stirred for 30min, then quenched with saturated ammonium chloride (10 mL), diluted with water (50 mL) and extracted with EA (1 x 100 mL). The organic phase was washed with brine (2X 50 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=1:1) to give 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 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 4-ethyl ester (0.25 g,0.53 mmol), liBH 4 (2M in THF, 1.00mL,2.00 mmol) in THF (10 mL) was stirred at 55deg.C for 40min. The reaction was quenched with MeOH (10 mL) and the volatiles were removed by concentration under reduced pressure. 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 dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give 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 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (0.22 g,0.51 mmol), pd/C (10%, 0.12 g) and MeOH (20 mL) was stirred under hydrogen atmosphere1.5h. The reaction solution 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 (120 mg,0.36 mmol) and triphenylphosphine (175 mg,0.67 mmol) in THF (10 mL) was added N, N, N ', N' -tetramethylazodicarbonamide (158 mg,0.68 mmol). The mixture was stirred at RT for 30min. Purification by silica gel chromatography (with MeOH: dcm=1:7, v/v elution) afforded 1-hydroxy-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-tert-butyl 1' -carboxylate (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 1' -carboxylate (0.35 g,1.09 mmol), dess-martin oxidant (0.72 g,1.70 mmol) 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) was washed. 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 ]]Tert-butyl 1' -carboxylate (0.33 g). MS: M/z 319 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
Table 12
Figure BDA0003942079150000621
Intermediate B1
Figure BDA0003942079150000622
According to the procedure of WO 2017211303A 1, intermediate B1 was synthesized in three steps starting from 4-iodoisatin.
Intermediate B2
Figure BDA0003942079150000623
According to the procedure of WO2017211303 A1, intermediate B2 was synthesized in 2 steps starting from 2-amino-3-bromo-6-chloropyrazine.
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 13
Figure BDA0003942079150000624
Intermediate B3
Figure BDA0003942079150000625
2-fluoro-3-chloro-4-iodopyridine (10.10 g,39.23 mmol) and DMSO (50 mL) were added to a lock 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 dried over 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 procedure described above and the corresponding starting materials.
TABLE 14
Figure BDA0003942079150000626
Intermediate B4
Figure BDA0003942079150000631
3-chloro-4-iodopyridin-2-amine (25.53 g,100.33 mmol), sodium 3-amino-5-chloropyrazine-2-thiolate (20.18 g,109.92 mmol), pd under nitrogen 2 (dba) 3 (4.47g，4.88mmol)，XantPhos(5.81g，10.04mA mixture of mol) and DIEA (26.12 g,202.10 mmol) in 1, 4-dioxane (100 mL) was 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 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/z288 (M+H) + .
The following compounds were synthesized using the procedure described above and the corresponding starting materials.
TABLE 15
Figure BDA0003942079150000632
Figure BDA0003942079150000641
Example 1
(R) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-amine
Figure BDA0003942079150000642
Step a: a mixture of compound 1H-indene (11.62 g,0.10 mol) and LiHMDS (220 mL,1mol/L in THF) in THF (120 mL) was stirred at-50℃for 1H. Tert-butyl bis (2-chloroethyl) carbamate (24.21 g,0.10 mol) was added to the reaction solution and stirred at-50℃for 1h. Quenched by addition of 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 ]Tert-butyl 1' -carboxylate (10.36 g, 36%). MS 286 (M+H) + .
Step b: the compound spiro [ indene-1, 4' -piperidine]A solution of tert-butyl 1' -carboxylate (117.02 g,0.41 mol) and borane dimethyl sulfide complex (10 mol/L,220 mL) in THF (800 mL) was stirred at 0deg.C for 3h. Adding NaOH (2 mol/L, 1.2L) and H 2 O 2 (300 mL) and stirred at 0deg.C for 1h. The organic phase was collected with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain 2-hydroxy-2, 3-dihydro-spiro [ 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-dihydro-spiro [ 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 1' -carboxylate (130.02 g,0.43 mol), dess-martin oxidant (364.76 g,0.86 mol) and DCM (2L) was stirred at 25℃for 12h. The reaction mixture was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (1L) and brine (1L) and with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gives the compound 3-oxo-2, 3-dihydrospiro [ indene-1, 4' -piperidine as a white solid]Tert-butyl 1' -carboxylate (41.75 g,34% yield in two steps). MS:302 (M+H) + .
Step d: to the compound 3-oxo-2, 3-dihydro-spiro [ indene-1, 4' -piperidine]To a solution of tert-butyl 1' -carboxylate (41.01 g,0.14 mol) in ethyl titanate (80 mL) was added R- (+) -tert-butylsulfonamide (49.46 g,0.41 mol). The system was stirred at 85℃for 2h. EA (0.5L) and water (0.5L) were added to the reaction system. The reaction system 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), dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain the compound (R, E) -2- ((tert-butylsulfinyl) imino) -2, 3-dihydro spiro [ indene-1, 4' -piperidine]Tert-butyl 1' -carboxylate (132.05 g, crude). MS:405 (M+H) + Directly used in the next step without purification. .
Step e: the compound (R, E) -2- ((tert-butylsulfinyl) imino) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]A solution of tert-butyl 1' -carboxylate (132.02 g,0.33 mol) in THF (200 mL) was cooled to-50℃and stirred. Adding NaBH 4 (7.71 g,0.51 mol) was warmed to RT naturally. Quenched with saturated ammonium chloride solution (100 mL). The organic phase was collected with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by column chromatographyThe remainder, obtain (R) -2- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydro spiro [ indene-1, 4' -piperidine) ]Tert-butyl 1' -carboxylate was a white solid (27.25 g,49% yield over two steps). MS:407 (M+H) + .
Step f: (R) -2- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]Tert-butyl 1' -carboxylate (1.16 g,3.98 mmol), 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 (1.03 g,3.59 mmol) and K were then added 2 CO 3 (6.60 g,47.76 mmol) was stirred at 90℃for 16h. H was added 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, filtration and concentration under reduced pressure gives the 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-methylpropan-2-sulfinamide (1.55 g, 70%) as a 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-methylpropan-2-sulfinamide (1.52 g,2.72 mmol) in DCM (20 mL) was added HCl/1, 4-dioxane (2 mL,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), dried over anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure. Purification of the residue by column chromatography gives 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 (530 mg, 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 [ inden-2, 4' -piperidin ] -1-amine
Figure BDA0003942079150000661
Step a: sodium hydride (60%) (3.63 g,90.80 mmol) was added to a solution of compound 2, 3-dihydro-1H-inden-1-one (4.00 g,30.27 mmol) in DMF (80 mL). The mixture was stirred at 16℃for 30min. Tert-butyl bis (2-chloroethyl) carbamate (8.06 g,33.29 mmol) 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), dried over 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]Tert-butyl 1' -carboxylate (1.21 g, 13%), dark red oil. MS:302 (M+H) + .
Step b: after ethyl titanate (12.00 g) was heated to 90 ℃, the compound 1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine ]Tert-butyl 1' -carboxylate (1.21 g,4.01 mmol) and (R) -2-methylpropane-2-sulfinamide (1.22 g,12.04 mmol) were added. After stirring for 19h at 90 ℃. The mixture was poured into EA (200 mL) and brine (200 mL) was added. After stirring for 15 minutes, filtration was performed. The filtrate was separated. The organic phase was washed with brine (200 mL. Times.2), dried over anhydrous Na 2 SO 4 And (5) drying. The solid was filtered off and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography gives (R, Z) -1- ((tert-butylsulfinyl) imino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (1.01 g, 62%) 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' -carboxylate (1.01 g,2.50 mmol) in THF (10 mL) was cooled to-50 ℃. Adding NaBH in portions 4 (142 mg,3.74 mmol). Naturally warmed to room temperature, stirred for 15.5h, and then poured into EA (100 mL). With brine (100 mL. Times.3)) The mixture was washed. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gives 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' -formate (580 mg,1.43 mmol) and TFA (1 mL) in DCM (5 mL) was stirred at 20deg.C for 40min. Concentrating the solution to obtain the compound (R) -N- ((S) -1, 3-dihydro spiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (520 mg, 90%) as a yellow oil. MS 307 (M+H) + .
Step e: the compound (R) -N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (260 mg,0.62 mmol), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (196 mg,0.68 mmol), K 2 CO 3 (427 mg,3.09 mmol) and NMP (8 mL) were stirred at 100deg.C 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-methylpropan-2-sulfinamide (260 mg, 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-methylpropan-2-sulfinamide (260 mg,0.47 mmol) 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 (123 mg, 54%) as an off-white solid. MS 454 (M+H) + .1H 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 [ naphthalen-1, 4' -piperidin ] -2-amine
Figure BDA0003942079150000681
Step a: a solution of the compound tert-butyl bis (2-chloroethyl) carbamate (11.00 g,45.43 mmol) 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 (22.95 g,227.14 mmol) and benzaldehyde (7.23 g,68.14 mmol) were added. Then NaBH (OAc) is added in portions 3 (24.07 g,113.57 mmol). 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 adjusts 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 N-benzyl-2-chloro-N- (2-chloroethyl) ethane-1-amine (8.52 g, 81%) as a colourless oil.
Step b: to a mixed solution of the compound N-benzyl-2-chloro-N- (2-chloroethyl) ethane-1-amine (8.52 g,36.70 mmol) and 3, 4-dihydronaphthalen-2 (1H) -one (4.88 g,33.36 mmol) in THF (80 mL) and DMSO (50 mL) was added potassium tert-butoxide (9.36 g,83.14 mmol). Stirring is 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-one (2.32 g, 21%). MS:306 (M+H) + .
Step c: addition of the compound 1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine to Ethyl titanate]-2-one (2.32 g,7.60 mmol) and (R) -2-methylpropane-2-sulfinamide (2.76 g,22.79 mmol). At 100Stirring at a temperature of about 1deg.C for 19h. EA (200 mL) and water (200 mL) were added. After filtration, the filtrate was separated into layers and the organic phase was collected. The organic phase was washed with brine (100 ml×5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gives the compound (R, E) -N- (1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine) ]-2-subunit) -2-methylpropane-2-sulfinamide (660 mg, 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-subunit) -2-methylpropane-2-sulfinamide (660 mg,1.62 mmol) in THF (10 mL) was cooled to-50deg.C. Then add NaBH in portions 4 (122 mg,3.23 mmol). The mixture was stirred for 18h and warmed to RT naturally. Quench with water (50 mL) and extract 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. Purification of the residue by column chromatography gives the compound (R) -N- ((R) -1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]-2-yl) -2-methylpropan-2-sulfinamide (195 mg, 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-methylpropan-2-sulfinamide (195 mg,0.47 mmol) in methanol (5 mL) was added palladium hydroxide (20%, 120 mg). Stirring is carried out for 18h at 40℃under hydrogen. Filtering and concentrating under reduced pressure to obtain compound (R) -N- ((R) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine) ]-2-yl) -2-methylpropan-2-sulfinamide (92 mg, 60%). MS:321 (M+H) + .
Step f: the compound (R) -N- ((R) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]-2-yl) -2-methylpropan-2-sulfinamide (92 mg,0.29 mmol) was dissolved in NMP (3 mL). 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (91 mg,0.32 mmol) and K 2 CO 3 (198mg, 1.44 mmol). Stirred at 100deg.C for 3h, diluted with EA (30 mL), and washed with brine (30 mL. Times.3). Anhydrous Na for organic phase 2 SO 4 And (5) drying. Purification of the residue by Pre-TLC gave (R) -N- ((R) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyri-dineOxazin-2-yl) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidines]-2-yl) -2-methylpropan-2-sulfinamide (18 mg, 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-methylpropan-2-sulfinamide (18 mg,0.03 mmol) in 1, 4-dioxane (2 mL) was added HCl/1, 4-dioxane (4 mol/L,2 mL). After stirring for 30min, it was concentrated and washed twice with EA. The solid was dried under high vacuum to give 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 (14 mg, 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 ] pyridin-7, 4' -piperidin ] -6-amine
Figure BDA0003942079150000701
Step a: naHMDS (38 mL,2mol/L in THF) was added to a solution of the compound 2-fluoro-3-methylpyridine (5.56 g,50.00 mmol) and piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester 14.15g,55.00 mmol) in toluene (50 mL) at 0deg.C, warmed naturally to 20deg.C 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 the compound 4- (3-methylpyridin-2-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (6.32 g, 36%) as a yellow oil. MS:349 (M+H) + .
Step b: a solution of the compound 4- (3-methylpyridin-2-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (4.80 g,13.78 mmol) and LDA (2 mol/L,17 mL) in THF (48 mL) was stirred at 0deg.C for 0.5h. The volatiles were removed by concentration under reduced pressure. Purification of the residue by column chromatography to give 6-oxo-5, 6-dihydrospiro [ cyclopenta [ b ] as a red oil]Pyridine-7, 4' -piperidines]Tert-butyl 1' -carboxylate (0.95 g, 23%). MS 303 (M+H) + .
Step c: to 6-oxo-5, 6-dihydro-spiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]To a solution of tert-butyl 1' -carboxylate (0.94 g,3.11 mol) in ethyl titanate (5 mL) was added (R) -2-methylpropane-2-sulfinamide (1.13 g,9.33 mmol). Stirred at 80℃for 1h. EA (30 mL) and water (20 mL) were added to the reaction solution. The organic phase in the filtrate was collected by filtration. 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 ]]Pyridine-7, 4' -piperidines]Tert-butyl 1' -carboxylate (2.51 g, crude). The next step was directly carried forward 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' -piperidines]A solution of tert-butyl 1' -carboxylate (2.12 g, crude) in THF (20 mL) was stirred at-50 ℃. NaBH is carried out 4 (176 mg,4.66 mmol) was added to the reaction and warmed 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' -piperidines]Tert-butyl 1' -carboxylate (0.21 g,17%, two-step yield). MS:408 (M+H) + .
Step e: the compound (R) -6- (((S) -tert-butylsulfinyl) amino) -5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]Tert-butyl 1' -carboxylate (204 mg,0.50 mmol) and CF 3 A mixture of COOH (1 mL) and DCM (10 mL) was stirred at 25℃for 1.5h. The reaction 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 (144 mg,0.50 mmol) and K were added 2 CO 3 (0.82 g,6.00 mmol) was stirred at 95℃for 16h. Adding H 2 O (50 mL) was extracted with EA (30 mL. Times.2). The combined organic phases were washed with brine (50 mL), dried 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-chloropyridine)4-yl) thio) pyrazin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]-6-yl) -2-methylpropan-2-sulfinamide (302 mg, crude). The next step was directly carried forward 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) pyridin-7, 4' -piperidine]To a solution of-6-yl) -2-methylpropan-2-sulfinamide (302 mg,0.54 mmol) 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) and DCM (15 mL) was then added and 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' -piperidines]-6-amine (163 mg,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 [ inden-2, 4' -piperidin ] -1-amine
Figure BDA0003942079150000711
Step a: 6-methoxy-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-tert-butyl 1' -carboxylate (557 mg,1.68 mmol) and (R) -2-methylpropane-2-sulfinamide (610 mg,5.04 mmol) Ti (OEt) 4 (5 mL) the solution was stirred at 100deg.C for 16h. After cooling to RT, the reaction was diluted with EA (20 mL) and water (30 mL). Filtered through a pad of celite and rinsed with EA. The filtrate was washed with brine (1X 50 mL), dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to give (R, Z) -1- ((tert-butylsulfinyl) imino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Tert-butyl 1' -carboxylate (0.98 g), without further treatmentPurification was used in the next step. MS: M/z 435 (M+H) + .
Step b: to (R, Z) -1- ((tert-butylsulfinyl) imino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl-1' -carboxylate (0.98 g,2.25 mmol) in THF (10 mL) was added NaBH 4 (0.17 g,4.51 mmol). Naturally heating to RT and stirring for 24h. The reaction was diluted with EA (50 mL) and water (50 mL), the organic phase was separated, washed with brine (1X 50 mL), and dried over 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)]-tert-butyl 1' -carboxylate (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 (380 mg,0.87 mmol) in DCM (10 mL) was added TFA (2 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 (301 mg,1.04 mmol) and K were added 2 CO 3 (601 mg,4.35 mmol). 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) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (eluting with MeOH: dcm=1:20, v/v) afforded (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-methylpropan-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-methylpropan-2-sulfinamide (254 mg,0.43 mmol) in 1, 4-dioxane (3 mL) was added HCl (4M in 1, 4-dioxane, 3 mL) dropwise and stirred at RT for 30min. Filtration and drying of the collected precipitate in a vacuum oven gives (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-amine (221 mg, hydrochloride). 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 intermediates a and B by reference to the above procedure.
The following examples are in the form of the free base or a pharmaceutically acceptable salt thereof.
Figure BDA0003942079150000731
Figure BDA0003942079150000741
Figure BDA0003942079150000751
Figure BDA0003942079150000761
Figure BDA0003942079150000771
Figure BDA0003942079150000781
Figure BDA0003942079150000791
Figure BDA0003942079150000801
Figure BDA0003942079150000811
Figure BDA0003942079150000821
Figure BDA0003942079150000831
Figure BDA0003942079150000841
Figure BDA0003942079150000851
Figure BDA0003942079150000861
Figure BDA0003942079150000871
Example 82
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -7-amine
Figure BDA0003942079150000881
Step a: 7-oxo-5, 7-dihydro-spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]A solution of tert-butyl 1' -carboxylate (936 mg,3.10 mmol) and ethyl (R) -2-methylpropane-2-sulfinamide (1045 mg,8.62 mmol) in ethyl titanate (8 mL) was stirred at 100deg.C for 2h. After cooling to RT, the reaction was diluted with EA (50 mL) and water (50 mL). Filtration through a pad of celite The filter cake was rinsed with EA. Separating the organic phase from the filtrate with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to give (R, Z) -7- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]Tert-butyl 1' -carboxylate (1.41 g). MS: m/z 406 (M+H) + .
Step b: (R, Z) -7- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ] at-40 DEG C]Pyridine-6, 4' -piperidines]To a solution of tert-butyl-1' -carboxylate (1.41 g,3.48 mmol) in THF (50 mL) was added BH 3 (1M in THF, 10.00mL,10.00 mmol). Naturally heating to RT and stirring for 1h. The reaction was quenched with brine (100 mL). The organic phases were collected, the aqueous phase extracted with EA (1X 60 mL), the organic phases combined 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. Purification of the residue by silica gel chromatography (eluting with MeOH: dcm=1:60, v/v) gives (S) -7- (((R) -tert-butylsulfinyl) amino) -5, 7-dihydrospiro [ cyclopenta [ b)]Pyridine-6, 4' -piperidines]-tert-butyl 1' -carboxylate (309 mg). MS: m/z 408 (M+H) + .
Step c: to (S) -7- (((R) -tert-butylsulfinyl) amino) -5, 7-dihydrospiro [ cyclopenta [ b ] ]Pyridine-6, 4' -piperidines]To a solution of tert-butyl 1' -carboxylate (309 mg,0.76 mmol) in DCM (20 mL) was added HCl (4M in EA, 2mL,8.00 mmol) and stirred at RT for 1.5h. Concentrating under reduced pressure to obtain (S) -5, 7-dihydro spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-7-amine (227 mg). MS: m/z 204 (M+H) + .
Step d: (S) -5, 7-dihydro-spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-7-amine (HCl salt, 227mg,0.73 mmol), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (247 mg,0.86 mmol), K 2 CO 3 A mixture of (1149 mg,8.31 mmol) 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 (2×50 mL). The organic phases were combined with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Chromatography on silica gel (MeOH in dcm=1:6, vV elution) the residue was purified 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' -piperidines]-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 intermediates a and B by reference to the above procedure.
In step a of example 82, (R) -2-methylpropane-2-sulfinamide was replaced with tert-butylsulfinamide to give the corresponding racemic product.
The following examples are in the form of the free base or a pharmaceutically acceptable salt thereof.
Figure BDA0003942079150000901
Figure BDA0003942079150000911
Figure BDA0003942079150000921
Figure BDA0003942079150000931
Figure BDA0003942079150000941
Figure BDA0003942079150000951
Figure BDA0003942079150000961
Figure BDA0003942079150000971
Figure BDA0003942079150000981
Figure BDA0003942079150000991
Figure BDA0003942079150001001
Example 133
(S) -4- ((5- (1-amino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -3-chloropyridin-2-ol
Figure BDA0003942079150001011
Steps a-c: by step (a-c) of example 5, (R) -N- ((S) -1'- (5- ((3-chloro-2-methoxypyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide MS: m/z 558 (M+H) + .
Step d: (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-methylpropan-2-sulfinamide (112 mg,0.20 mmol), 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 was 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) thioPhenyl) -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 procedure using the corresponding starting materials. .
The following examples are in the form of their free bases or pharmaceutically acceptable salts.
TABLE 18
Figure BDA0003942079150001012
Figure BDA0003942079150001021
Example 137
(S) -1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -6-ol
Figure BDA0003942079150001022
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1, 3-dihydro-spiro [ indene-2, 4' -piperidine)]A solution of 1-amine (74 mg,0.14 mmol) 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 volatile substances, dispersing the residue in water, filtering to obtain solid, and concentrating with saturated NaHCO 3 The aqueous solution adjusts 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 procedure using the corresponding starting materials.
TABLE 19
Figure BDA0003942079150001031
Example 139
1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methyl-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine
Figure BDA0003942079150001032
Step a: (R, Z) -5- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ] is synthesized according to step a of example 5 ]Pyridine-6, 4' -piperidines]-tert-butyl 1' -carboxylate. MS: m/z 406 (M+H) + .
Step b: (R, Z) -5- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ] at-60 DEG C]Pyridine-6, 4' -piperidines]To a solution of tert-butyl 1' -carboxylate (1.49 g,3.67 mmol) in THF (15 mL) was added dropwise methyllithium (1.3M in diethyl ether, 14mL,18.20 mmol). Naturally heating to RT and stirring for 20h. Diluted with water (10 mL) and EA (20 mL). The aqueous phase was separated and NaOH (1.00 g,25.00 mmol) and (Boc) were added 2 O (0.50 mL). The mixture was stirred at RT for 1.5h. Extracted with EA (2X 50 mL), the organic phases were combined, washed with brine (1X 30 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (eluting with EA: hex=1:1, v/v) gives 5- (((R) -tert-butylsulfinyl) amino) -5-methyl-5, 7-dihydrospiro [ cyclopenta [ b)]Pyridine-6, 4' -piperidines]Tert-butyl 1' -carboxylate (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' -piperidines]-5-amine (71 mg): 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 [ indolizin-2, 4' -piperidin ] -7 (1H) -one
Figure BDA0003942079150001041
Step a: to-10deg.C 1-hydroxy-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]To a solution of tert-butyl 1' -carboxylate (100 mg,0.31 mmol), triethylamine (157 mg,1.55 mmol) in THF (10 mL) and DCM (2 mL) was added MsCl (66 mg,0.58 mmol). 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 taken up in anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to give 1- ((methylsulfonyl) oxy) -7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine)]Tert-butyl 1' -carboxylate (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 1' -carboxylate (155 mg,0.39 mmol), sodium azide (136 mg,2.09 mmol) and DMF (5 mL) was stirred at 75℃for 1h and 85℃for 4h. After cooling to RT, the reaction was diluted with EA (30 mL), filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH: dcm=1:10, v/v elution) to give 1-azido-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine ]-tert-butyl 1' -carboxylate (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 1' -carboxylate (32 mg,0.093 mmol), pd/C (10%, 15 mg) in EtOH (6 mL) is 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-room temperature1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-tert-butyl 1' -carboxylate (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 1' -carboxylate (26 mg,0.081 mmol) 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 (46 mg,0.16 mmol) and K were added 2 CO 3 (399mg, 2.86 mmol) was stirred at 95℃for 16h. After cooling to RT, it was diluted with DCM (30 mL), filtered and concentrated under reduced pressure. Purification of the residue by Pre-TLC (eluting with MeOH: DCM=1:3, v/v) gave 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 procedure using the corresponding starting materials.
Table 20
Figure BDA0003942079150001051
Example 142
3- ((2-amino-3-chloropyridin-4-yl) thio) -6- (1-imino-1, 3-dihydrospiro [ inden-2, 4 '-piperidin ] -1' -yl) pyrazin-2-amine
Figure BDA0003942079150001052
Step a: (R, Z) -1- ((tert-butylsulfinyl) imino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was synthesized by step a of example 5]-t-butyl 1' -carboxylate 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 1' -carboxylate (405 mg,1.00 mmol) 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 added3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (288 mg,1.00 mmol) and K 2 CO 3 (1.38 g,10.00 mmol). 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), dried 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=1:5, 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 with reference to the above procedure.
Table 21
Figure BDA0003942079150001071
Example 148
1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -7-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine
Figure BDA0003942079150001081
Step a: to 7-methoxy-1-oxo-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of tert-butyl 1' -carboxylate (552 mg,1.07 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (348 mg,5.01 mmol) and AcONa (82 mg,10.02 mmol). The system was stirred at RT for 4h. The reaction system 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 obtain (Z) -1- (hydroxyimino) -7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine as yellow solid]-tert-butyl 1' -carboxylate (520 mg). MS: m/z 347 (M+H) + .
Step b: (Z) -1- (hydroxyimino) -7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl 1' -carboxylate (510 mg,1.47 mmol), 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 the reaction mixture was quenched with K 2 CO 3 The solids were brought to a pH of 10. The system was extracted with DCM (2X 30 mL) and the combined organic phases were washed with brine (1X 50 mL) and with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain colorless oily 1-amino-7-methoxy-1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-tert-butyl 1' -carboxylate (202 mg). 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, 0.60 mmol) 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 (144 mg,0.50 mmol) and K were added 2 CO 3 (691 mg,5.90 mmol). The system was stirred at 95℃for 3h. After cooling to RT, the reaction was diluted with water (50 mL) and extracted with EA (1×50 mL). The organic phase was washed with brine (1X 50 mL) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the residue by Pre-TLC (eluting with MeOH: DCM=1:5, v/v) gave 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 with reference to the above procedure.
Table 22
Figure BDA0003942079150001091
Example 150
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methoxy-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4' -piperidin ] -4-amine
Figure BDA0003942079150001092
Steps (a-b): (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' -piperidines]-tert-butyl 1' -carboxylate. MS: m/z 448 (M+H) + .
Step c: (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]A mixture of tert-butyl 1' -carboxylate (403 mg,0.90 mmol), naOH (356 mg,8.95 mmol) and MeOH (15 mL) was stirred at 65℃for 5h. After cooling to RT, volatiles were removed by concentration under reduced pressure. The residue was dissolved in water and the pH was adjusted to 7 by the addition of saturated aqueous citric acid. The system was extracted with EA (3X 30 mL) and the combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated 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' -piperidines]Tert-butyl 1' -carboxylate (360 mg). MS: m/z 444 (M+H) + .
Step (d-e): (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methoxy-4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step (c-d) of example 5 ]Thiazole-5, 4' -piperidines]-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 ] thiazol-5-, 4' -piperidin ] -4-amine
Figure BDA0003942079150001101
Steps (a-b): (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' -piperidines]-tert-butyl 1' -carboxylate. MS: m/z 448 (M+H) + .
Step c: (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]A mixture of tert-butyl 1-carboxylate (2.50 g,5.58 mmol), TEA (2 mL), pd/C (10%, 690 mg) and MeOH (50 mL) was stirred under hydrogen at 40℃for 24h. The filtrate was filtered, and Pd/C (10%, 1.32 g) was added thereto. Stirring is carried out under hydrogen at 50℃for a further 16h. Filtering, and concentrating the filtrate under reduced pressure. Purification of the residue by silica gel chromatography (eluting with EA: hex=1:1, v/v) gives (S) -4- (((R) -tert-butylsulfinyl) amino) -4, 6-dihydrospiro [ cyclopenta [ d)]Thiazole-5, 4' -piperidines]Tert-butyl 1' -carboxylate (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 ] with reference to step (c-d) of example 5 ]Thiazole-5, 4' -piperidines]-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, (R) -2-methylpropane-2-sulfinamide was replaced with tert-butylsulfinamide to give the corresponding racemic product.
The following examples were synthesized with the corresponding starting materials with reference to the above procedure.
Table 23
Figure BDA0003942079150001111
EXAMPLE 155
(S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4' -piperidin ] -6-amine
Figure BDA0003942079150001112
Step a: (R, Z) -6- ((tert-butylsulfinyl) imino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] as per step a of example 5]Thiazole-5, 4' -piperidines]-tert-butyl 1' -carboxylate. 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' -piperidines]To a solution of tert-butyl-1' -carboxylate (4.25 g,9.53 mmol) in THF (30 mL) was added BH 3 (1M in THF, 30.00mL,30.00 mmol). Naturally heating to RT and stirring for 18h. The reaction was quenched with brine (50 mL). The organic phase was separated off using 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' -piperidines]Tert-butyl 1' -carboxylate (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 ] with reference to step (c-d) of example 5]Thiazole-5, 4' -piperidines]-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 with reference to the above procedure.
Table 24
Figure BDA0003942079150001121
Example 157
(S) -1'- (6-amino-5- ((3-fluoro-1H-indol-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine
Figure BDA0003942079150001122
(S) -1- (4- ((3-amino-5- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazin-2-yl) thio) -3, 3-difluoroindol-1-yl) ethan-1-one (86 mg,0.16 mmol) is dissolved in MeOH (8 mL) and NaOH (17 mg,0.43 mmol) is 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), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Adding EA (5 mL) and Hex (3 mL) for beating, filtering, collecting 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-dihydro spiro [ 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 [ inden-2, 4' -piperidin ] -6-yl) ethan-1-one
Figure BDA0003942079150001131
Steps a-b: (S) -1- (((R) -tert-butylsulfinyl) amino) -6-cyano-1, 3-dihydrospiro [ indene-2, 4' -piperidine) was synthesized according to the procedure (a-b) of example 5]-tert-butyl 1' -carboxylate. MS: m/z 432 (M+H) + .
Step c: to-50 ℃ (S) -1- (((R) -tert-butylsulfinyl) amino) -6-cyano-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl-1' -carboxylate (430 mg,1.00 mmol) in THF (10 mL) was added dropwise methyl acetateMagnesium bromide (3M in THF/Hex, 0.50mL,1.50 mmol). Naturally heating to room temperature and stirring for 24h. The reaction was quenched with brine (10 mL). The organic phase was separated 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-dihydro spiro [ indene-2, 4' -piperidine)]Tert-butyl 1' -carboxylate (0.72 g) was used in the next step without further purification. MS: m/z 449 (M+H) + .
Steps d-e: (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) was synthesized according 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 with reference to the above procedure.
Table 25
Figure BDA0003942079150001141
The following examples can be synthesized using the methods described above and suitable starting materials:
table 26
Figure BDA0003942079150001142
Figure BDA0003942079150001151
Figure BDA0003942079150001161
Figure BDA0003942079150001171
Figure BDA0003942079150001181
Figure BDA0003942079150001191
Figure BDA0003942079150001201
Figure BDA0003942079150001211
Figure BDA0003942079150001221
Figure BDA0003942079150001231
Figure BDA0003942079150001241
Pharmacological test
Example a phosphatase activity assay (single dose):
single dose inhibition activity assay, PTP was activated by co-incubating a solution of SHP2 enzyme (diluted to 0.5nM in the reaction) with dPEG8 peptide in the reaction (60 mM dimethyl 3, 3-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, the reaction was started, and after 30min incubation the fluorescence intensity (excitation light 340nM, emission light 450 nM) of the reaction solution was measured with 2104-0020 EnVision Xcite Multilabel Reader (Perkinelmer).
Table A
Figure BDA0003942079150001242
Figure BDA0003942079150001251
Figure BDA0003942079150001261
Phosphatase activity assay (IC 50 assay):
IC 50 the value was measured using 6, 8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as the reaction substrate, and SHP2 enzyme solution (diluted to 0.5nM in the reaction solution) and dPEG8 peptide were incubated together in the reaction solution (60 mM 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 and incubation was continued at room temperature for 30min, diFMUP (12. Mu.M, total volume of reaction solution: 100. Mu.L) was added, the reaction was started, and after incubation for 30min, the fluorescence intensity (excitation light: 340nM, emission light: 450 nM) of the reaction solution was measured by using 2104-0020 EnVision Xcite Multilabel Reader (Perkinelmer). Compounds of the present invention were used as ICs for inhibiting SHP2 enzyme activity 50 See table B.
Table B
Figure BDA0003942079150001271
Example C cell proliferation assay:
MV-4-11 cells (4000 cells/well) were inoculated into 96-well plates at 100. Mu.L/well (IMDM with 3% Fetal Bovine Serum (FBS), from Gibco). After culturing for 24 hoursThe compounds of the present invention are added in varying concentrations. On day 8, 30. Mu.L MTS/PMS reagent (available from Promega, sigma, respectively) was added to each well and absorbance was measured according to the reagent instructions (Promega). IC of the Compounds of the invention 50 The values are shown in Table C.
Table C
Figure BDA0003942079150001272
Example D p-ERK cell level detection
An antibody against p-ERK1/2 was used to detect the level of ERK1/2 activation by immunoblotting. Briefly, MV-4-11 human leukemia cells were added to a series of compounds (ranging in concentration from 0.3nM to 100 nM) and incubated for 2 hours. Cells were lysed with RIPA buffer (Thermo Fisher Scientific, rockford, IL, USA) containing a mixture of hall protease inhibitors and total cellular proteins were harvested. 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 with horseradish peroxidase (HRP) -labeled secondary antibody. Bound secondary antibodies were detected using chemiluminescence.
Example E MV-4-11 xenograft tumor model
MV-4-11 cell culture was expanded, collected and subcutaneously injected into 5-8 week old female NOD/SCID mice (5X 10) 6 Individual cells/mouse, n=6-10/group). When the average tumor volume is about 100-200mm 3 At this time, oral gavage administration (0.1-10 mpk/dose) was initiated. During the treatment period (once or twice a day for 2-4 weeks), tumor volumes were measured using vernier calipers. Differences in tumor volume between groups were counted using one-way ANOVA analysis. The solvent was the 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. ramington: pharmaceutical science and practice (A. Janus)Row et al, 19 th edition, mich publishing Co., 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 IC50 below 10nM. They also show good antitumor effect in vivo models. For example, the daily dose generally falls within the range of about 0.2mg to 100mg, preferably 0.2mg to 50mg, more preferably 0.2mg to 20 mg. In some cases, dosage levels below the lower limit of the above range may be sufficient, while in other cases, larger dosages may be employed. The above dosage ranges do not limit the scope of the invention in any way. It will be appreciated that the actual amount of compound administered will be determined by the physician, based on 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 (10)

1. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
Figure FDA0003942079140000011
Figure FDA0003942079140000021
Figure FDA0003942079140000031
Figure FDA0003942079140000041
2. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
Figure FDA0003942079140000042
Figure FDA0003942079140000051
3. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
Figure FDA0003942079140000052
4. A compound selected from
Figure FDA0003942079140000053
5. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
Figure FDA0003942079140000061
6. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
Figure FDA0003942079140000062
Figure FDA0003942079140000071
7. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
Figure FDA0003942079140000072
Figure FDA0003942079140000081
Figure FDA0003942079140000091
8. A compound selected from
Figure FDA0003942079140000092
Figure FDA0003942079140000093
Wherein R is a protecting group selected from +.>
Figure FDA0003942079140000094
9. The compound according to claim 8, which is
Figure FDA0003942079140000095
10. Preparation method
Figure FDA0003942079140000096
Wherein said method comprises the compound 1->
Figure FDA0003942079140000101
And Compound 2->
Figure FDA0003942079140000102
Is a step of alkylation reaction. />
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JP2018509448A (en) * 2015-03-25 2018-04-05 ノバルティス アーゲー Combination medicine
JP6718889B2 (en) * 2015-06-19 2020-07-08 ノバルティス アーゲー Compounds and compositions for inhibiting the activity of SHP2
KR20230109185A (en) * 2016-06-07 2023-07-19 자코바이오 파마슈티칼스 컴퍼니 리미티드 Novel heterocyclic derivatives useful as shp2 inhibitors
CN115969853A (en) * 2018-05-09 2023-04-18 北京加科思新药研发有限公司 Novel heterocyclic derivatives useful as SHP2 inhibitors

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CN112174935B (en) 2022-12-06
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CN115721648A (en) 2023-03-03
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