CN111848591B - HDAC inhibitors and methods of making and using the same - Google Patents

HDAC inhibitors and methods of making and using the same Download PDF

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CN111848591B
CN111848591B CN201910321788.9A CN201910321788A CN111848591B CN 111848591 B CN111848591 B CN 111848591B CN 201910321788 A CN201910321788 A CN 201910321788A CN 111848591 B CN111848591 B CN 111848591B
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CN111848591A (en
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李进
张登友
楚洪柱
吕开智
刘立川
胡静
侯燕燕
陈伟
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Hitgen Inc
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Hitgen Inc
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Abstract

The invention discloses a compound shown as a formula I, a stereoisomer thereof and a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition containing the compound shown in the formula I and application of the compound in preparing HDAC inhibitor medicines. The compounds of the present invention or pharmaceutical compositions thereof may be used to treat cell proliferative disorders, autoimmune disorders, inflammation, neurodegenerative disorders or viral disorders.

Description

HDAC inhibitors and methods of making and using the same
Technical Field
The present invention relates to HDAC inhibitors, methods of making and uses thereof.
Background
Tumor refers to a new organism formed by clonal abnormal hyperplasia caused by the loss of normal regulation and control of local tissue cells on the gene level under the action of various tumorigenic factors. Epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modifications of other components in chromatin higher order structures, which alter chromatin conformation, resulting in changes in gene transcription regulation, and dysregulation of gene transcription causing cell proliferation disorders, resulting in tumor production.
Histone acetylation plays a central role in transcriptional regulation in eukaryotic cells. Its action is regulated by a pair of functionally antagonistic proteases Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). In normal cells, the pair of enzymes is in a state of dynamic equilibrium. In general, increased histone acetylation levels are associated with increased gene transcription activity, while too low acetylation levels are associated with suppressed gene expression. Studies have found that HDACs are overexpressed and recruited by transcription factors, leading to abnormal suppression of specific genes, leading to tumors and other diseases; inhibition of HDAC activity will lead to growth inhibition and apoptosis in many cancer cells. Therefore, HDACs have become the newest and most popular target in the current field of antineoplastic drug development.
HDAC inhibitors have the function of interfering with histone deacetylase. There are generally two broad categories: NAD + -dependent enzymes and Zn2+ -dependent enzymes. Zn2+ -dependent proteases include HDACs I (including HDACs 1,2, 3 and 8), II (including HDACs 4,5, 6, 7, 9 and 10), IV (including HDAC 11) subfamily; NAD + -dependent enzymes are mainly of the HDACs subgroup III. The mechanism of action of HDAC inhibitors is to modulate gene expression in the treatment of cancer by inhibiting HDAC, blocking the repression of gene expression due to dysfunction of HDAC recruitment, and altering chromatin structure by altering the degree of acetylation of histones. It has obvious curative effect on treating blood system tumor and solid tumor by inducing growth arrest, differentiation or apoptosis of tumor cell. HDAC inhibitors are tumor specific and cytotoxic to proliferating and quiescent variant cells, whereas normal cells are more than 10-fold tolerant to them and do not cause growth arrest and apoptosis in normal cells.
Five HDAC inhibitors are currently on the market. SAHA marketed in 2006, with a Pan-HDAC as an active target; FK-288 marketed in 2011 has the action targets of HDAC1 and HDAC 2; PXD101 marketed in 2014 has the action targets of HDAC1 and HDAC 2; the effect targets of the cidam amine marketed in 2015 are HDAC1, HDAC2, HDAC3 and HDAC 10; LBH589 marketed in 2015, the target of action is HDAC (MOLT-4 cells). The five HDAC inhibitors have certain problems in the aspects of anticancer activity, toxic and side effects, subtype selectivity and the like.
Therefore, there is an urgent need for a novel compound having histone deacetylase inhibitory activity.
Disclosure of Invention
The invention provides a compound shown as a formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof:
Figure BDA0002039788050000021
wherein,
x is selected from O, S;
X1selected from N, CR2；
R、R1、R2And each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, 3-to 10-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group, a 3-to 10-membered cycloalkyl group;
R4is selected from-NRhRi、-ORc、-SRc、-(CH2)rRc4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
r is 0, 1,2 or 3;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
Rh、Riare each independently selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted with m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
Rcselected from 3-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein cycloalkyl and heteroThe ring, spiro ring, heterospiro ring, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
wherein when X is1Is CH, ring A is
Figure BDA0002039788050000031
R4Is composed of
Figure BDA0002039788050000032
When n and m are not 0 at the same time.
In some embodiments of the invention, R in formula I is preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R is hydrogen, fluoro, chloro, bromo, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula I1Preferably hydrogen, halogen, cyano, C1～C6Alkyl, aryl, heteroaryl, and heteroaryl,3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R1Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula I2Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R2Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, each R in formula I3Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, each R3Is hydrogen, fluorine,Chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, the A ring in formula I is preferably selected from a benzene ring.
In some embodiments of the invention, the A ring in formula I is preferably selected from a 5-membered aromatic heterocycle. More preferably, the heteroatoms in the 5-membered aromatic heterocycle are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000041
Figure BDA0002039788050000042
In some embodiments of the invention, the A ring in formula I is preferably selected from a 6-membered heteroaromatic ring. More preferably, the heteroatoms in the 6-membered heteroaromatic ring are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000043
Figure BDA0002039788050000044
In some embodiments of the invention, R in formula I4Preferably 4-to 10-membered cycloalkyl, wherein the cycloalkyl may be substituted by m RdAnd (4) substitution. More preferably, R4Selected from 4-6 membered cycloalkyl.
In some embodiments of the invention, R in formula I4Preferably 4-to 10-membered heterocycle, wherein the heterocycle may be substituted by m RdAnd (4) substitution. More preferably, the heteroatom in the 4-10 membered heterocycle is nitrogen, oxygen, sulfur. Further preferably, R4Is selected from
Figure BDA0002039788050000045
Figure BDA0002039788050000046
In some embodiments of the invention, R in formula I4Preferably selected from 6-12 membered spirocyclic ring and 6-12 membered heterospirocyclic ring, wherein the spirocyclic ring and the heterospirocyclic ring can be substituted by m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-12 membered heterospirocycles are nitrogen, oxygen, sulfur. Further preferably, R4Is selected from
Figure BDA0002039788050000051
Figure BDA0002039788050000052
In some embodiments of the invention, R in formula I4Preferably selected from 6-to 10-membered bridged rings and 6-to 10-membered heterobridged rings, wherein the bridged rings and heterobridged rings can be substituted by m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-10 membered heterobridged ring are nitrogen, oxygen, sulfur. Further preferably, R4Is selected from
Figure BDA0002039788050000053
In some embodiments of the invention, each R in formula IdIndependently preferably from halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively independently preferably selected from hydrogen and C1～C6Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently preferably-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle. More preferably, each RdIndependently selected from halogen, cyano, C1～C4Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively and independently selected from hydrogen and C1～C4Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C4Alkyl, halogen substituted C1～C4An alkyl group; wherein R isa、RbAre respectively selected from hydrogen and C1～C4Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently selected from-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula I4Is preferably selected from-NRhRi(ii) a Wherein R ish、RiAre respectively independently preferably selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, wherein the cycloalkyl, heterocycle may be substituted with m RdAnd (4) substitution. More preferably, Rh、RiAre each independently selected from C1～C6Alkyl, 3-to 6-membered cycloalkyl, and 3-to 6-membered heterocycle. Further preferably, Rh、RiAre each independently selected from C1～C4An alkyl group, a 5-to 6-membered cycloalkyl group, a 5-to 6-membered heterocycle; wherein the heteroatom in the heterocycle is nitrogen, oxygen or sulfur.
In some embodiments of the invention, R in formula I4Preferably selected from-ORc、-SRc、-(CH2)rRc(ii) a Wherein R iscPreferably selected from 3-to 10-membered cycloalkyl and 3-to 10-membered heterocycle, wherein the cycloalkyl and heterocycle may be substituted by m RdAnd (4) substitution. More preferably, RcSelected from 3-6 membered cycloalkyl and 3-6 membered heterocycle. Further preferably, RcSelected from 5-6 membered cycloalkyl and 5-6 membered heterocycle; wherein the heteroatom in the heterocycle is nitrogen, oxygen or sulfur.
Further, the compound of formula I is represented by formula II:
Figure BDA0002039788050000061
wherein,
x is selected from O, S;
X1selected from N, CR2；
R、R1、R2Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, 3-to 10-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group, a 3-to 10-membered cycloalkyl group;
the B ring is selected from 4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
wherein when X is1Is CH,
Figure BDA0002039788050000062
Is composed of
Figure BDA0002039788050000063
When m is not 0.
In some embodiments of the invention, R in formula II is preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R is hydrogen, fluoro, chloro, bromo, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably isA trifluoromethyl group.
In some embodiments of the invention, R in formula II1Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R1Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula II2Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R2Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, the A ring in formula II is preferably selected from a benzene ring.
In some embodiments of the invention, the A ring in formula II is preferably selected from a 5-membered aromatic heterocycle. More preferably, the heteroatoms in the 5-membered aromatic heterocycle are nitrogen, oxygen,And (3) sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000071
Figure BDA0002039788050000072
In some embodiments of the invention, the a ring in formula II is preferably selected from a 6-membered heteroaromatic ring. More preferably, the heteroatoms in the 6-membered heteroaromatic ring are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000073
Figure BDA0002039788050000074
In some embodiments of the invention, the B ring in formula II is preferably selected from 4-10 membered cycloalkyl, wherein the cycloalkyl group may be substituted by m RdAnd (4) substitution. More preferably, the B ring is selected from 4-6 membered cycloalkyl.
In some embodiments of the invention, the B ring in formula II is preferably selected from 4-to 10-membered heterocyclic rings, wherein the heterocyclic ring may be substituted with m RdAnd (4) substitution. More preferably, the heteroatom in the 4-10 membered heterocycle is nitrogen, oxygen, sulfur. Further preferably, ring B is selected from
Figure BDA0002039788050000081
Figure BDA0002039788050000082
In some embodiments of the present invention, the ring B in formula II is preferably selected from 6-12 membered spirocyclic ring, 6-12 membered heterospirocyclic ring, wherein the spirocyclic ring and the heterospirocyclic ring may be substituted by m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-12 membered heterospirocycles are nitrogen, oxygen, sulfur. Further preferably, ring B is selected from
Figure BDA0002039788050000083
Figure BDA0002039788050000084
In some embodiments of the present invention, the ring B in formula II is preferably selected from 6-10 membered bridged rings, 6-10 membered heterobridged rings, wherein the bridged rings, heterobridged rings may be substituted with m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-10 membered heterobridged ring are nitrogen, oxygen, sulfur. Further preferably, ring B is selected from
Figure BDA0002039788050000085
In some embodiments of the invention, each R in formula IIdIndependently preferably from halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively independently preferably selected from hydrogen and C1～C6Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently preferably-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle. More preferably, each RdIndependently selected from halogen, cyano, C1～C4Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively and independently selected from hydrogen and C1～C4Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C4Alkyl, halogen substituted C1～C4An alkyl group; wherein R isa、RbAre respectively selected from hydrogen and C1～C4Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently selected from-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
Still further, the compound of formula II is:
Figure BDA0002039788050000091
Figure BDA0002039788050000101
further, the compound of formula I is represented by formula III:
Figure BDA0002039788050000102
wherein,
x is selected from O, S;
X1selected from N, CR2；
R、R1、R2And each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, 3-to 10-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group, a 3-to 10-membered cycloalkyl group;
the B ring is selected from 4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle.
In some embodiments of the invention, R in formula III is preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R is hydrogen, fluoro, chloro, bromo, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula III1Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R1Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula III2Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R2Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, each R in formula III3Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, each R3Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, ring a in formula III is preferably selected from a benzene ring.
In some embodiments of the invention, the A ring in formula III is preferably selected from a 5-membered aromatic heterocycle. More preferably, the heteroatoms in the 5-membered aromatic heterocycle are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000121
Figure BDA0002039788050000122
In some embodiments of the invention, the a ring in formula III is preferably selected from a 6-membered heteroaromatic ring. More preferably, the heteroatoms in the 6-membered heteroaromatic ring are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000123
Figure BDA0002039788050000124
In some of the present inventionIn embodiments, the B ring in formula III is preferably selected from 4-to 10-membered cycloalkyl groups, wherein the cycloalkyl group may be substituted with m RdAnd (4) substitution. More preferably, the B ring is selected from 4-6 membered cycloalkyl.
In some embodiments of the invention, the B ring in formula III is preferably selected from 4-to 10-membered heterocyclic rings, wherein the heterocyclic ring may be substituted with m RdAnd (4) substitution. More preferably, the heteroatom in the 4-10 membered heterocycle is nitrogen, oxygen, sulfur. Further preferably, ring B is selected from
Figure BDA0002039788050000125
Figure BDA0002039788050000126
In some embodiments of the present invention, the ring B in formula III is preferably selected from 6-12 membered spirocyclic ring, 6-12 membered heterospirocyclic ring, wherein the spirocyclic ring and the heterospirocyclic ring may be substituted by m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-12 membered heterospirocycles are nitrogen, oxygen, sulfur. Further preferably, ring B is selected from
Figure BDA0002039788050000131
Figure BDA0002039788050000132
In some embodiments of the present invention, the ring B in formula III is preferably selected from the group consisting of a 6-to 10-membered bridged ring, a 6-to 10-membered heterobridged ring, wherein the bridged ring, heterobridged ring may be substituted with m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-10 membered heterobridged ring are nitrogen, oxygen, sulfur. Further preferably, ring B is selected from
Figure BDA0002039788050000133
In some embodiments of the invention, each R in formula IIIdIndependently preferably from halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively independently preferably selected from hydrogen and C1～C6Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently preferably-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle. More preferably, each RdIndependently selected from halogen, cyano, C1～C4Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively and independently selected from hydrogen and C1～C4Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C4Alkyl, halogen substituted C1～C4An alkyl group; wherein R isa、RbAre respectively selected from hydrogen and C1～C4Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently selected from-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
Still further, the compound of formula III is:
Figure BDA0002039788050000134
Figure BDA0002039788050000141
Figure BDA0002039788050000151
Figure BDA0002039788050000161
Figure BDA0002039788050000171
further, the compound of formula I is represented by formula IV:
Figure BDA0002039788050000181
wherein,
x is selected from O, S;
R、R1and each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, 3-to 10-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group, a 3-to 10-membered cycloalkyl group;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted by 0 to c3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
Rh、Riare each independently selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted with m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group.
In some embodiments of the invention, R in formula IV is preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R is hydrogen, fluoro, chloro, bromo, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula IV1Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R1Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, each R in formula IV3Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, each R3Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, ring a in formula IV is preferably selected from a benzene ring.
In some embodiments of the invention, the ring a in formula IV is preferably selected from a 6-membered heteroaromatic ring. More preferably, the heteroatoms in the 6-membered heteroaromatic ring are nitrogen, oxygen, sulfur. IntoPreferably, ring A is selected from
Figure BDA0002039788050000191
Figure BDA0002039788050000192
In some embodiments of the invention, R in formula IVh、RiAre respectively independently preferably selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, wherein the cycloalkyl, heterocycle may be substituted with m RdAnd (4) substitution. More preferably, Rh、RiAre each independently selected from C1～C6Alkyl, 3-to 6-membered cycloalkyl, and 3-to 6-membered heterocycle. Further preferably, Rh、RiAre each independently selected from C1～C4An alkyl group, a 5-to 6-membered cycloalkyl group, a 5-to 6-membered heterocycle; wherein the heteroatom in the heterocycle is nitrogen, oxygen or sulfur.
Still further, the compound of formula IV is:
Figure BDA0002039788050000193
further, the compound of formula I is represented by formula V:
Figure BDA0002039788050000194
wherein,
x is selected from O, S;
R、R1and each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, 3-to 10-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbare each independently selected fromHydrogen, C1～C10An alkyl group, a 3-to 10-membered cycloalkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
Rcselected from 3-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group.
In some embodiments of the invention, R in formula V is preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R is hydrogen, fluoro, chloro, bromo, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen,C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula V1Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R1Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, each R in formula V3Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, each R3Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, ring A in formula V is preferably selected from the group consisting of phenyl rings.
In some embodiments of the invention, the ring a in formula V is preferably selected from a 6-membered heteroaromatic ring. More preferably, the heteroatoms in the 6-membered heteroaromatic ring are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000211
Figure BDA0002039788050000212
In some embodiments of the invention, R in formula VcPreferably selected from 3-to 10-membered cycloalkyl and 3-to 10-membered heterocycle, wherein the cycloalkyl and heterocycle may be substituted by m RdAnd (4) substitution. More preferably, RcSelected from 3-6 membered cycloalkyl and 3-6 membered heterocycle. Further preferably, RcSelected from 5-6 membered cycloalkyl and 5-6 membered heterocycle; wherein the heteroatom in the heterocycle is nitrogen, oxygen or sulfur.
In some embodiments of the invention, each R in formula VdIndependently preferably from halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively independently preferably selected from hydrogen and C1～C6Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently preferably-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle. More preferably, each RdIndependently selected from halogen, cyano, C1～C4Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively and independently selected from hydrogen and C1～C4Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C4Alkyl, halogen substituted C1～C4An alkyl group; wherein R isa、RbAre respectively selected from hydrogen and C1～C4Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently selected from-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
Still further, the compound of formula V is:
Figure BDA0002039788050000213
Figure BDA0002039788050000221
further, the compound of formula I is represented by formula VI:
Figure BDA0002039788050000222
in the formula,
x is selected from O, S;
R、R1and each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, 3-to 10-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group, a 3-to 10-membered cycloalkyl group;
R4selected from 4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle.
In some embodiments of the invention, R in formula VI is preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R is hydrogen, fluoro, chloro, bromo, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula VI1Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, R1Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, each R in formula VI3Preferably hydrogen, halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-to 6-membered cycloalkyl. More preferably, each R3Is hydrogen, fluorine, chlorine, bromine, cyano, C1～C4Alkyl, 3-to 4-membered cycloalkyl, -ORa、-NRaRbHalogen-substituted C1～C4An alkyl group; wherein R isa、RbAre respectively hydrogen and C1～C4An alkyl group, a 3-to 4-membered cycloalkyl group; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, ring a in formula VI is preferably selected from a benzene ring.
In some embodiments of the invention, ring a in formula VI is preferably selected from a 5-membered heteroaromatic ring. More preferably, the heteroatoms in the 5-membered aromatic heterocycle are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000231
Figure BDA0002039788050000232
In some embodiments of the invention, ring a in formula VI is preferably selected from a 6-membered heteroaromatic ring. More preferably, the heteroatoms in the 6-membered heteroaromatic ring are nitrogen, oxygen, sulfur. Further preferably, the A ring is selected from
Figure BDA0002039788050000233
Figure BDA0002039788050000234
In some embodiments of the invention, R in formula VI4Preferably 4-to 10-membered cycloalkyl, wherein the cycloalkyl may be substituted by m RdAnd (4) substitution. More preferably, R4Selected from 4-6 membered cycloalkyl.
In some embodiments of the invention, R in formula VI4Preferably 4-to 10-membered heterocycle, wherein the heterocycle may be substituted by m RdAnd (4) substitution. More preferably, the heteroatom in the 4-10 membered heterocycle is nitrogen, oxygen, sulfur. Further preferably, R4Is selected from
Figure BDA0002039788050000241
Figure BDA0002039788050000242
In some embodiments of the invention, R in formula VI4Preferably selected from 6-12 membered spirocyclic ring and 6-12 membered heterospirocyclic ring, wherein the spirocyclic ring and the heterospirocyclic ring can be substituted by m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-12 membered heterospirocycles are nitrogen, oxygen, sulfur. Further preferably, R4Is selected from
Figure BDA0002039788050000243
Figure BDA0002039788050000244
In some embodiments of the invention, R in formula VI4Preferably selected from 6-to 10-membered bridged rings and 6-to 10-membered heterobridged rings, wherein the bridged rings and heterobridged rings can be substituted by m RdAnd (4) substitution. More preferably, the heteroatoms in the 6-10 membered heterobridged ring are nitrogen, oxygen, sulfur. Further preferably, R4Is selected from
Figure BDA0002039788050000245
In some embodiments of the invention, each R in formula VIdIndependently preferably from halogen, cyano, C1～C6Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively independently preferably selected from hydrogen and C1～C6Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C6Alkyl, halogen radicalsSubstituted C1～C6An alkyl group; wherein R isa、RbAre preferably hydrogen and C, respectively1～C6Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently preferably-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle. More preferably, each RdIndependently selected from halogen, cyano, C1～C4Alkyl, 3-to 6-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 2RgSubstituted C1～C6Alkyl, halogen substituted C1～C6An alkyl group; wherein R ise、RfAre respectively and independently selected from hydrogen and C1～C4Alkyl, 3-to 6-membered cycloalkyl, substituted with 0 to 2RgSubstituted C1～C4Alkyl, halogen substituted C1～C4An alkyl group; wherein R isa、RbAre respectively selected from hydrogen and C1～C4Alkyl, 3-6 membered cycloalkyl; wherein each RgAre each independently selected from-ORa、-NRaRb5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein halogen is substituted C1～C4The alkyl group is preferably fluorine-substituted C1～C4An alkyl group; more preferably trifluoromethyl.
In some embodiments of the invention, R in formula VI4Is preferably selected from-NRhRi(ii) a Wherein R ish、RiAre respectively independently preferably selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, wherein the cycloalkyl, heterocycle may be substituted with m RdAnd (4) substitution. More preferably, Rh、RiAre each independently selected from C1～C6Alkyl, 3-to 6-membered cycloalkyl, and 3-to 6-membered heterocycle. Further preferably, Rh、RiAre each independently selected from C1～C4An alkyl group, a 5-to 6-membered cycloalkyl group, a 5-to 6-membered heterocycle; wherein the heteroatom in the heterocycle is nitrogen, oxygen or sulfur.
In some embodiments of the invention, R in formula VI4Preferably selected from-ORc、-SRc、-(CH2)rRc(ii) a Wherein R iscPreferably selected from 3-to 10-membered cycloalkyl and 3-to 10-membered heterocycle, wherein the cycloalkyl and heterocycle may be substituted by m RdAnd (4) substitution. More preferably, RcSelected from 3-6 membered cycloalkyl and 3-6 membered heterocycle. Further preferably, RcSelected from 5-6 membered cycloalkyl and 5-6 membered heterocycle; wherein the heteroatom in the heterocycle is nitrogen, oxygen or sulfur.
Still further, the compound of formula VI is:
Figure BDA0002039788050000251
the invention also provides the application of the compound or the stereoisomer thereof or the pharmaceutically acceptable salt thereof in preparing the HDAC inhibitor medicines.
Further, the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, inflammation, a neurodegenerative disease, or a viral disease.
Further, the cell proliferative disease is cancer.
Still further, the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, thyroid cancer.
Further, the HDAC is HDAC 6.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or the stereoisomer or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the preparation is an oral preparation, a transdermal absorption preparation or an injection preparation.
The invention also provides the application of the pharmaceutical composition in the preparation of HDAC inhibitor medicines.
Further, the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, inflammation, a neurodegenerative disease, or a viral disease.
Further, the cell proliferative disease is cancer.
Still further, the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, thyroid cancer.
Further, the HDAC is HDAC 6.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C1～C10Alkyl refers to having 1 to 10 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.
"cycloalkyl" refers to a saturated hydrocarbon ring having the indicated number of member atoms. Cycloalkyl groups may be monocyclic or fused. For example, a 4-10 membered cycloalkyl group refers to a cycloalkyl group having 4 to 10 member atoms, and a 3-10 membered cycloalkyl group refers to a cycloalkyl group having 3 to 10 member atoms. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. In one embodiment, a cycloalkyl group herein is cyclopropyl. In one embodiment, a cycloalkyl group herein is cyclobutyl. In one embodiment, a cycloalkyl group herein is cyclopentyl. In one embodiment, a cycloalkyl group herein is cyclohexyl.
"heterocycloalkyl", "heterocycle" refers to a saturated or unsaturated non-aromatic monocyclic, fused ring having the indicated number of member atoms, which carries heteroatoms such as nitrogen, oxygen, in place of one or more carbon atoms. The heterocycloalkyl group may be, in particular, a piperidinyl group, a tetrahydropyran group, a morpholinyl group, a piperazinyl group,
Figure BDA0002039788050000261
And the like.
"spirocycloalkyl" and "spirocyclic" refer to alicyclic hydrocarbon molecules in which two carbocyclic rings share a common carbon atom.
"Heterospirocycloalkyl", "heterospirocyclic" refers to an alicyclic hydrocarbon molecule in which two carbocyclic rings share a single carbon atom, with heteroatoms such as nitrogen, oxygen replacing one or more carbon atoms. The hetero-spirocycloalkyl group may be specifically:
Figure BDA0002039788050000271
Figure BDA0002039788050000272
and the like.
"bridged ring group", bridged ring "refers to a cyclic hydrocarbon in which any two rings share two carbon atoms which are not directly connected.
"Heterocyclyl", "heterobridged ring" refers to cyclic hydrocarbons in which any two rings share two carbon atoms not directly connected, with heteroatoms such as nitrogen, oxygen replacing one or more carbon atoms. The hetero-spirocycloalkyl group may be specifically:
Figure BDA0002039788050000273
and the like.
"aromatic ring" means a single or multiple ring having aromatic character, such as phenyl.
"heteroaryl ring" refers to a single or fused ring having aromatic character with one or more carbon atoms replaced by heteroatoms such as nitrogen and oxygen. The heteroaromatic ring may specifically be pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, isoxazoleA group, a1, 2, 4-triazolyl group, an imidazolyl group,
Figure BDA0002039788050000274
And the like.
"halogen" means fluorine, chlorine, bromine or iodine.
In the invention
Figure BDA0002039788050000275
Or
Figure BDA0002039788050000276
Represents R on the A ring4In the ortho position relative to the sulfonamide group.
In the present invention, "M" means mol/L; "mM" means mmol/L; "μ M" means μmol/L.
The term "room temperature" as used herein means 25. + -. 5 ℃.
The novel compound shown in the formula I shows good HDAC6 inhibition activity, and provides a new choice for clinically treating diseases related to abnormal HDAC6 activity.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
The specific embodiments of the present invention are described in the following short form: TEA is triethylamine; DCM is dichloromethane; DMF is N, N-dimethylformamide; EA is ethyl acetate; NaH: sodium hydride; MeOH: methanol; CH (CH)3CN: acetonitrile; TFA: trifluoroacetic acid; PE: stone (stone)Oleyl ether
Synthesis of intermediate 4a and intermediate 4b
Figure BDA0002039788050000281
Ethyl 6-bromobenzofuran-2-carboxylate (intermediate 2 a):
Figure BDA0002039788050000282
4-bromo-2-hydroxybenzaldehyde (20g,99.5mmol) and ethyl 2-bromoacetate (18.3g,109.4mmol) were dissolved in 100mL of DMF under nitrogen, potassium carbonate (41.3g,298.5mmol) was added, and the reaction was stirred at 100 ℃ for 18 hours. After cooling to room temperature, the reaction mixture was added to 500g of ice water and extracted 4 times with 500mL of ethyl acetate. The organic layers were combined and washed 1 time with 500mL of saturated sodium chloride. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50:1 to 20:1) to give intermediate 2a 6-bromobenzofuran-2-carboxylic acid ethyl ester (18.6g, yield 69.4%).
MS(ESI)m/z＝269.0,271.0[M+1].
Ethyl 5-bromobenzofuran-2-carboxylate (intermediate 2 b):
Figure BDA0002039788050000283
intermediate 2b ethyl 5-bromobenzofuran-2-carboxylate (42% yield) was obtained following the synthesis of intermediate 2a using 5-bromo-2-hydroxybenzaldehyde instead of 4-bromo-2-hydroxybenzaldehyde. MS (ESI) M/z 269.0,271.0[ M +1]
Ethyl 6- (benzylthio) benzofuran-2-carboxylate (intermediate 3 a):
Figure BDA0002039788050000291
ethyl 6-bromobenzofuran-2-carboxylate (18.6g,69.1mmol) was dissolved in 200mL of toluene under nitrogen, benzylthiol (10.3g,82.9mmol), N-diisopropylethylamine (26.8g,207.1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (4.0g,6.9mmol) and tris (dibenzylideneacetone) dipalladium (3.2g,3.5mmol) were added, air was replaced with nitrogen, and the reaction was warmed to reflux for 18 hours. After cooling to room temperature, 500mL of water was added, extraction was performed with ethyl acetate (300 mL. times.3), and the organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50:1 to 30:1) to give intermediate 3a 6- (benzylthio) benzofuran-2-carboxylic acid ethyl ester (19.5g, yield 90.3%).
MS(ESI)m/z＝313.1[M+1]。
Ethyl 5- (benzylthio) benzofuran-2-carboxylate (intermediate 3 b):
Figure BDA0002039788050000292
the procedure for the synthesis of intermediate 3a was followed, using ethyl 5-bromobenzofuran-2-carboxylate instead of ethyl 6-bromobenzofuran-2-carboxylate, to give intermediate 3b ethyl 5- (benzylthio) benzofuran-2-carboxylate (91% yield). MS (ESI) M/z 313.1[ M +1]
Ethyl 6- (chlorosulfonyl) benzofuran-2-carboxylate (intermediate 4 a):
Figure BDA0002039788050000293
ethyl 6- (benzylthio) benzofuran-2-carboxylate (19.5g,62.3mmol) was dissolved in 45mL of acetic acid and 15mL of water, N-chlorosuccinimide (33.3g,249.3mmol) was added in portions, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, 200mL of water was added. Ethyl acetate extraction (200 mL. times.3) and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 99:1 to 19:1) to give intermediate 4a 6- (chlorosulfonyl) benzofuran-2-carboxylic acid ethyl ester as a yellow solid, (11.0g, yield 61.1%).
1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.76(s,1H),7.75(d,J＝8.2Hz,1H),7.63(d,J＝8.2Hz,1H),4.36(q,J＝6.8Hz,2H),1.34(t,J＝6.8,3H).
Ethyl 5- (chlorosulfonyl) benzofuran-2-carboxylate (intermediate 4 b):
Figure BDA0002039788050000294
using ethyl 5- (benzylthio) benzofuran-2-carboxylate as a starting material instead of ethyl 6- (benzylthio) benzofuran-2-carboxylate, the synthesis of intermediate 4a was followed to give intermediate 4b ethyl 5- (chlorosulfonyl) benzofuran-2-carboxylate (62.0% yield). Synthesis of intermediate 7a and intermediate 7b
Figure BDA0002039788050000301
Methyl 6-bromobenzo [ b ] thiophene-2-carboxylate (intermediate 5 a):
Figure BDA0002039788050000302
4-bromo-2-fluorobenzaldehyde (10g,49.3mmol) and methyl 2-mercaptoacetate (12.0g,113.1mmol) were dissolved in 1.0L DMF, sodium hydride (59.2g,1.48mol, 60%) was added at 0 deg.C, after 3 hours of stirring reaction ice water (500L) was slowly added, ethyl acetate (200mL) was extracted 4 times, and the organic layers were combined and washed 1 time with saturated sodium chloride solution. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 99:1 to 19:1) to give intermediate 5a (10.9g, yield 81.5%). Ms (esi) M/z 271.0,273.0[ M +1].
5-Bromobenzo [ b ] thiophene-2-carboxylic acid methyl ester (intermediate 5 b):
Figure BDA0002039788050000303
the intermediate 5b 5-bromobenzo [ b ] thiophene-2-carboxylic acid methyl ester (yield 87%) was obtained according to the synthesis method of intermediate 5a using 5-bromo-2-fluorobenzaldehyde as a starting material instead of 4-bromo-2-fluorobenzaldehyde. Ms (esi) M/z 271.0,273.0[ M +1].
6-Benzylthenzo [ b ] thiophene-2-carboxylic acid methyl ester (intermediate 6 a):
Figure BDA0002039788050000304
methyl 6-bromobenzo [ b ] thiophene-2-carboxylate 5a (5.4g,19.7mmol) was dissolved in 100mL of toluene under nitrogen, benzylthiol (1.44g,23.6mmol), N-diisopropylethylamine (7.64g,59.1mmol,10.3mL), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (1.14g,1.97mmol) and tris (dibenzylideneacetone) dipalladium (902mg,985umol) were added, and the air was replaced with nitrogen, and the mixture was heated to reflux for 18 hours. After cooling to room temperature, 200mL of water was added, extraction was performed with ethyl acetate (200 mL. times.3), and the organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 80:1 to 30:1) to give intermediate 6a 6- (benzylthio) benzofuran-2-carboxylic acid methyl ester as a pale yellow solid (4.0g, yield 64.6%). Ms (esi) M/z 315.1[ M +1].
5-Benzylthenzo [ b ] thiophene-2-carboxylic acid methyl ester (intermediate 6 b):
Figure BDA0002039788050000311
the synthesis of 6a was performed using 5-bromobenzo [ b ] thiophene-2-carboxylic acid methyl ester 5b as the starting material instead of 6-bromobenzo [ b ] thiophene-2-carboxylic acid methyl ester 5a to give intermediate 6b 5-benzylsulfanylbenzo [ b ] thiophene-2-carboxylic acid methyl ester as a pale yellow solid (yield 76.0%).
Methyl 6- (chlorosulfonyl) benzo [ b ] thiophene-2-carboxylate (intermediate 7 a):
Figure BDA0002039788050000312
methyl 6- (benzylthio) benzo [ b ] thiophene-2-carboxylate 6a (3.6g,11.5mmol) was dissolved in 21mL of acetic acid and 7mL of water, N-chlorosuccinimide (6.2g,46.0mmol) was added in portions, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, 50mL of water was added. Ethyl acetate extraction (100 mL. times.3) and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give intermediate 7a methyl 6- (chlorosulfonyl) benzo [ b ] thiophene-2-carboxylate as a yellow solid (3.1g, 92.7% yield). The product was used in the next reaction without further purification.
Methyl 5- (chlorosulfonyl) benzo [ b ] thiophene-2-carboxylate (intermediate 7 b):
Figure BDA0002039788050000313
an oxidation reaction was carried out according to the synthesis method of 7a using 5-bromobenzo [ b ] thiophene-2-carboxylic acid methyl ester 6b as a starting material instead of 6- (benzylthio) benzo [ b ] thiophene-2-carboxylic acid methyl ester to give intermediate 7b (yield 91.5%).
Example 14- (3- (2- (Hydroxyloxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (Compound 1)
Figure BDA0002039788050000321
The first step is as follows: 4- (3-Nitropyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (1A)
N-Boc-4-piperidinol (697mg,3.47mmol) was dissolved in 10mL THF at room temperature, NaH (139mg,3.47mmol, 60%) was added and stirred for 30min, 2-chloro-3-nitropyridine (500mg,3.15mmol) was added and stirred at room temperature overnight. LCMS showed the reaction was complete, 30mL water and 50mL ethyl acetate were added, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate again (50mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and spun dry to give 4- (3-nitropyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester 1A as a brown oil (1.12g, 109.8%) which was used in the next reaction without further purification.
The second step is that: 4- (3-aminopyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (1B)
At room temperature, 4- (3-nitropyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester 1A (1.12g,3.47mmol) was dissolved in 20mL of MeOH, 10% Pd/C (200mg) was added, and the mixture was stirred under hydrogen atmosphere overnight. LCMS showed the reaction was complete, Pd/C was removed by filtration, and the filtrate was spin dried to give 4- (3-aminopyridin-2-oxy) piperidine-1-carboxylic acid tert-butyl ester 1B as a brown oil (1.02g, 87.4%) which was used in the next reaction without further purification.
The third step: 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (1C)
Tert-butyl 4- (3-aminopyridin-2-yloxy) piperidine-1-carboxylate 1B (500mg,1.7mmol) was dissolved in 10mL DCM, pyridine (0.41mL,5.1mmol) and intermediate 4a (542mg,1.88mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product tert-butyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonamido) pyridine-2-oxy) piperidine-1-carboxylate 1C (500mg, 53.8%) which was used directly in the next reaction.
The fourth step: 4- (3- (2- (Hydroxyloxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (Compound 1)
Tert-butyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-oxy) piperidine-1-carboxylate 1C (150mg,0.27mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.24mL,4.05mmol) was added, and an aqueous NaOH (54mg,1.35mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 1 as a white solid (5.7mg, 3.5%).
1H NMR(400MHz,DMSO-d6)δ7.95–7.85(m,3H),7.72–7.52(m,3H),6.98(ddd,J＝12.7,7.7,5.0Hz,1H),4.96–4.89(m,1H),3.31(dd,J＝11.2,7.0Hz,2H),3.18–3.04(m,2H),1.49(td,J＝8.7,4.1Hz,2H),1.39(s,9H).1.17-1.15(m,2H).LC-MS m/z(ESI)＝533[M+1].
Example 2N-hydroxy-6- (N- (2- (piperidin-4-yloxy) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 2)
Figure BDA0002039788050000331
The first step is as follows: 4- (3-Nitropyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (2A)
N-Boc-4-piperidinol (697mg,3.47mmol) was dissolved in 10mL THF at room temperature, NaH (139mg,3.47mmol, 60%) was added and stirred for 30min, 2-chloro-3-nitropyridine (500mg,3.15mmol) was added and stirred at room temperature overnight. LCMS showed the reaction was complete, 30mL water and 50mL ethyl acetate were added, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate again (50mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and spun dry to give 4- (3-nitropyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester 2A as a brown oil (1.12g, 109.8%) which was used in the next reaction without further purification.
The second step is that: 4- (3-aminopyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (2B)
At room temperature, 4- (3-nitropyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester 2A (1.12g,3.47mmol) was dissolved in 20mL of MeOH, 10% Pd/C (200mg) was added, and the mixture was stirred under hydrogen atmosphere overnight. LCMS showed the reaction was complete, Pd/C was removed by filtration, and the filtrate was spin dried to give 4- (3-aminopyridin-2-oxy) piperidine-1-carboxylic acid tert-butyl ester 2B as a brown oil (1.02g, 87.4%) which was used in the next reaction without further purification.
The third step: 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-oxy) piperidine-1-carboxylic acid tert-butyl ester (2C)
Tert-butyl 4- (3-aminopyridin-2-yloxy) piperidine-1-carboxylate 2B (500mg,1.7mmol) was dissolved in 10mL DCM, pyridine (0.41mL,5.1mmol) and intermediate 4a (542mg,1.88mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product tert-butyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonamido) pyridine-2-oxy) piperidine-1-carboxylate 2C (500mg, 53.8%) which was used directly in the next reaction.
The fourth step: 6- (N- (2- (piperidin-4-yloxy) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (2D)
Tert-butyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-oxy) piperidine-1-carboxylate 3C (400mg,0.733mmol) was dissolved in 10mL MeOH at room temperature, HCl/EA (4M,5mL) was added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and after spin-drying the reaction solution the product ethyl 6- (N- (2- (piperidin-4-yloxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 2D (400mg, 113.2%) was obtained as a light brown solid which was used directly in the next reaction.
The fifth step: n-hydroxy-6- (N- (2- (piperidin-4-yloxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 2)
Ethyl 6- (N- (2- (piperidin-4-yloxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 2D (200mg,0.415mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.37mL,6.23mmol) was added, and an aqueous NaOH (83mg,2.08mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 2 as a white solid (24mg, 11.9%).
1H NMR(400MHz,DMSO-d6)δ7.95–7.88(m,3H),7.72–7.59(m,2H),7.56(s,1H),6.99(ddd,J＝7.7,5.0,1.0Hz,1H),5.02(d,J＝5.4Hz,1H),3.20(t,J＝11.5Hz,2H),2.98(dd,J＝11.8,6.2Hz,2H),1.76(dt,J＝11.3,7.1Hz,2H),1.45(dd,J＝15.1,4.9Hz,2H).LC-MS m/z(ESI)＝433[M+1].
Example 3N-hydroxy-6- (N- (2- (4-methylpiperidin-1-yl) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 3)
Figure BDA0002039788050000341
The first step is as follows: 2- (4-methylpiperidin-1-yl) -3-nitropyridine (3A)
2-chloro-3-nitropyridine (300mg,1.89mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.78mL,5.67mmol) and 4-methylpiperidine (200mg,2.02mmol) were added, and the reaction was allowed to react at 40 ℃ for 1 hour and monitored by LC-MS to show completion. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 2- (4-methylpiperidin-1-yl) -3-nitropyridine 3A as a yellow oil (390mg, 93.3%) which was used in the next reaction without further purification.
The second step is that: 2- (4-methylpiperidin-1-yl) pyridin-3-amine (3B)
2- (4-Methylpiperidin-1-yl) -3-nitropyridine 3A (380mg,1.72mmol) was dissolved in 10mL of MeOH at room temperature, 10% Pd/C (100mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration, and the filtrate was spin dried to give 2- (4-methylpiperidin-1-yl) pyridin-3-amine 3B as an off-white solid (300mg, 91.2%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4-methylpiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (3C)
2- (4-Methylpiperidin-1-yl) pyridin-3-amine 3B (300mg,1.57mmol) was dissolved in 10mL of DCM, pyridine (0.2mL,2.7mmol) and intermediate 4a (453mg,1.57mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and 100mL dichloromethane was added to the reaction, separated, washed with water (100mL), dried and spun to dryness to give the product 6- (N- (2- (4-methylpiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 3C (250mg, 35.9%) which was used directly in the next reaction. LC-MS M/z (esi) ═ 444[ M +1].
The fourth step: n-hydroxy-6- (N- (2- (4-methylpiperidin-1-yl) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 3)
Ethyl 6- (N- (2- (4-methylpiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 3C (125mg,0.282mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.31mL,5.22mmol) was added, and an aqueous NaOH solution (56mg,1.39mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) purified to give compound 3 as a white solid (12mg, 9.9%). LC-MS M/z (esi) ═ 431.1[ M +1].
Example 4N-hydroxy-6- (N- (2-morpholinopyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 4)
Figure BDA0002039788050000361
The first step is as follows: 4- (3-Nitropyridin-2-yl) morpholine (4A)
2-chloro-3-nitropyridine (300mg,1.89mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.78mL,5.67mmol) and morpholine (181mg,2.08mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate and spin-dried to give 4- (3-nitropyridin-2-yl) morpholine 4A as a yellow solid (376mg, 95%) which was used in the next reaction without further purification.
The second step is that: 2-morpholinylpyridin-3-amine (4B)
4- (3-Nitropyridin-2-yl) morpholine 4A (376mg,1.8mmol) was dissolved in 10mL MeOH at room temperature, 10% Pd/C (100mg) was added and the mixture was stirred overnight under hydrogen. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spun dry to give 2-morpholinopyridin-3-amine 4B as an off-white solid (300mg, 133%) which was used in the next reaction without further purification.
The third step: 6- (N- (2-Morpholinopyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (4C)
2-Morpholinylpyridin-3-amine 4B (80mg,0.447mmol) was dissolved in 10mL of DCM, and pyridine (0.1mL,1.34mmol) and intermediate 4a (142mg,0.492mmol) were added and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2-morpholinopyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 4C (150mg, 77.8%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (2-morpholinylpyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 4)
Ethyl 6- (N- (2-morpholinopyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 4C (150mg,0.348mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.31mL,5.22mmol) was added, and an aqueous NaOH (56mg,1.39mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS display reverseTo completion, 1M HCl was added to adjust pH to 8, spin dried, and the residue was subjected to prep-HPLC (0.5% TFA in CH)3CN/H2O) purified to give compound 4 as a white solid (4mg, 2.8%).
1H NMR(400MHz,DMSO-d6)δ8.08–8.00(m,2H),7.95(q,J＝9.1,7.8Hz,1H),7.70(dd,J＝8.3,1.5Hz,1H),7.58(s,1H),7.38–7.17(m,1H),6.91(dd,J＝7.8,4.8Hz,1H),3.52(t,J＝4.6Hz,4H),2.98–2.86(m,4H).LC-MS m/z(ESI)＝419[M+1].
Example 56- (N- (2-Cyclohexylpyridin-3-yl) aminosulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 5)
Figure BDA0002039788050000371
The first step is as follows: 2- (cyclohexen-1-yl) -3-nitropyridine (5A)
Dissolving 2-chloro-3-nitropyridine (300mg,1.89mmol) in 20mL 1, 4-dioxane, adding 1-cyclohexenylboronic acid pinacol ester (472mg,2.27mmol), Pd (dppf) Cl2(138mg,0.189mmol) and Na in sequence under the protection of nitrogen2CO3(601mg,5.67mmol), the reaction was refluxed overnight and monitored by LC-MS to show completion of the reaction. Insoluble matter was removed by filtration, and the filtrate was dried by rotary chromatography on silica gel (PE: EA ═ 8:1) to give 2- (cyclohexen-1-yl) -3-nitropyridine 5A (320mg, 82.8%) as a product and a yellow oil.
The second step is that: 2-Cyclohexylpyridin-3-amine (5B)
2- (cyclohexen-1-yl) -3-nitropyridine 5A (160mg,0.784mmol) was dissolved in 10mL MeOH at room temperature, 10% Pd/C (80mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spin dried to give 2-cyclohexylpyridin-3-amine 5B as a colorless oil (130mg, 94%) which was used in the next reaction without further purification.
The third step: 6- (N- (2-Cyclohexylpyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (5C)
2-Cyclohexylpyridin-3-amine 5B (130mg,0.739mmol) was dissolved in 10mL DCM, and pyridine (292mg,3.7mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (256mg,0.886mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2-cyclohexylpyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 5C (300mg, 120%) as a yellow oil which was used directly in the next reaction.
The fourth step: 6- (N- (2-Cyclohexylpyridin-3-yl) aminosulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 5)
Ethyl 6- (N- (2-cyclohexylpyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 5C (300mg,0.7mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.625mL,10.5mmol) was added, an aqueous NaOH (140mg,3.5mmol) solution was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 5 as a white solid (34mg, 11.5%).
1H NMR(400MHz,DMSO-d6)δ8.44(dd,J＝5.2,1.5Hz,1H),7.99–7.87(m,3H),7.63–7.50(m,2H),7.57(s,1H),2.63(dt,J＝12.2,3.2Hz,1H),1.47(t,J＝15.4Hz,3H),1.24(tt,J＝13.2,7.0Hz,2H),1.02(t,J＝12.3Hz,1H),0.93(s,1H),0.91(s,3H).LC-MS m/z(ESI)＝416[M+1].
Example 6N-hydroxy-6- (N- (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 6)
Figure BDA0002039788050000381
The first step is as follows: 2- (4-Methoxypiperidin-1-yl) -3-nitropyridine (6A)
2-chloro-3-nitropyridine (300mg,1.89mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.52mL,3.78mmol) and 4-methoxypiperidine (240mg,2.08mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), and the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 2- (4-methoxypiperidin-1-yl) -3-nitropyridine 6A as a yellow oil (500mg, 111.37%) which was used in the next reaction without further purification.
The second step is that: 2- (4-Methoxypiperidin-1-yl) pyridin-3-amine (6B)
2- (4-Methoxypiperidin-1-yl) -3-nitropyridine 6A (500mg,2.11mmol) was dissolved in 10mL of MeOH at room temperature, 10% Pd/C (200mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration, and the filtrate was spin-dried to give 2- (4-methoxypiperidin-1-yl) pyridin-3-amine 6B as a black oil (410mg, 93.9%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (6C)
2- (4-Methoxypiperidin-1-yl) pyridin-3-amine 6B (410mg,1.98mmol) was dissolved in 10mL of DCM, and pyridine (0.48mL,5.94mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (560mg,1.98mmol) were added, followed by stirring at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product 6- (N- (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 6C (909mg, 100%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 6)
Ethyl 6- (N- (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 6C (909mg,1.98mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (1.2mL,19.8mmol) was added, and an aqueous NaOH solution (320mg,7.92mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 6 as a white solid (116mg, 12.9%).
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.99–7.92(m,2H),7.71–7.63(m,1H),7.58(s,1H),7.29(dd,J＝7.8,1.7Hz,1H),6.90(dd,J＝7.8,5.4Hz,1H),3.44–3.28(m,3H),3.21(s,3H),3.03–2.92(m,2H),1.82(tt,J＝7.1,3.3Hz,2H),1.48(dtd,J＝12.7,8.8,3.6Hz,2H)).LC-MS m/z(ESI)＝447[M+1].
Example 7N-hydroxy-6- (N- (2- (4-methanesulfonylpiperazin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 7)
Figure BDA0002039788050000401
The first step is as follows: 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (7A)
Tert-butyl 4- (3-aminopyridin-2-yl) piperazine-1-carboxylate (1g,3.6mmol) was dissolved in 30mL of DCM, pyridine (0.87mL,10.8mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (1.56g,5.4mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product tert-butyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridin-2-yl) piperazine-1-carboxylate 7A (1.14g, 59.6%) which was used directly in the next reaction.
The second step is that: 6- (N- (2- (piperazin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (7B)
Tert-butyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridin-2-yl) piperazine-1-carboxylate 7A (1.14g,2.15mmol) was dissolved in 5mL MeOH at room temperature, HCl in EA (4M,20mL) was added, and the mixture was stirred at room temperature overnight. LCMS monitoring indicated completion of the reaction and the solvent was spun dry to give the product ethyl 6- (N- (2- (piperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate (950mg, 94.7%) as a white solid which was used directly in the next reaction.
The third step: 6- (N- (2- (4-Methanesulfonylpiperazin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (7C)
Ethyl 6- (N- (2- (piperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 7B (50mg,0.117mmol) was dissolved in 10mL DCM at room temperature, pyridine (25mg,0.321mmol) and methanesulfonyl chloride (15mg,0.118mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction was complete as monitored by LCMS and washed with water (50mL), dried and spun to give the product ethyl 6- (N- (2- (4-methanesulfonylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 7C (54mg, 91.4%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (2- (4-methanesulfonylpiperazin-1-yl) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 7)
Ethyl 6- (N- (2- (4-methanesulfonylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 7C (54mg,0.107mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.047mL,1.6mmol) was added, and an aqueous NaOH (21mg,0.53mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 7 as a white solid (6mg, 11.4%).
1H NMR(400MHz,DMSO-d6)δ8.09–7.99(m,2H),7.95(d,J＝8.3Hz,1H),7.68(dd,J＝8.2,1.6Hz,1H),7.58(s,1H),7.42(dd,J＝7.9,1.7Hz,1H),6.98(dd,J＝7.9,5.0Hz,1H),3.09–3.00(m,8H),2.81(s,3H).LC-MS m/z(ESI)＝496[M+1].
Example 8N-hydroxy-6- (N- (2- (tetrahydropyran-4-oxy) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 8)
Figure BDA0002039788050000411
The first step is as follows: 3-Nitro-2- (tetrahydropyran-4-oxy) pyridine (8A)
Tetrahydropyran-4-ol (142mg,1.39mmol) was dissolved in 10mL THF at room temperature, NaH (56mg,1.39mmol, 60%) was added and stirred for 30min, 2-chloro-3-nitropyridine (200mg,1.26mmol) was added and stirred at room temperature overnight. LCMS showed the reaction was complete, 30mL water and 50mL ethyl acetate were added, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and spin dried to give 3-nitro-2- (tetrahydropyran-4-oxy) pyridine 8A as a brown oil (282mg, 100%) which was used in the next reaction without further purification.
The second step is that: 2- (tetrahydropyran-4-oxy) pyridin-3-amine (8B)
3-Nitro-2- (tetrahydropyran-4-oxy) pyridine 8A (282mg,1.26mmol) was dissolved in 10mL MeOH at room temperature, 10% Pd/C (100mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spin dried to give 2- (tetrahydropyran-4-oxy) pyridin-3-amine 8B (180mg, 73.7%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (tetrahydropyran-4-oxy) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (8C)
2- (tetrahydropyran-4-oxy) pyridin-3-amine 8B (180mg,0.93mmol) was dissolved in 10mL DCM, pyridine (0.22mL,2.79mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (268mg,0.93mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2- (tetrahydropyran-4-oxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 8C (380mg, 91.8%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (2- (tetrahydropyran-4-oxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 8)
Ethyl 6- (N- (2- (tetrahydropyran-4-oxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 8C (380mg,0.93mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.76mL,12.8mmol) was added, and an aqueous NaOH (170mg,4.25mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) purification to give compound 8 as a white solid (90mg, 23.4%).
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.89(dt,J＝6.7,1.8Hz,2H),7.64(ddt,J＝17.0,8.3,1.7Hz,2H),7.55(s,1H),6.95(dd,J＝7.6,4.9Hz,1H),4.87(tq,J＝8.1,3.9Hz,1H),3.60(dq,J＝11.8,4.0Hz,2H),3.26(ddt,J＝11.4,8.8,2.5Hz,2H),1.61–1.50(m,2H),1.16(dtt,J＝12.5,8.3,3.4Hz,2H).LC-MS m/z(ESI)＝434[M+1].
Example 96- (N- (2- (4-Benzylpiperazin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxy-benzofuran 2-carboxamide (Compound 9)
Figure BDA0002039788050000421
The first step is as follows: 4- (3-Acetylaminopyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (9A)
Tert-butyl 4- (3-aminopyridin-2-yl) piperazine-1-carboxylate (200mg,0.72mmol) was dissolved in 5mL of pyridine at room temperature, acetic anhydride (147mg,1.44mmol) was added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, 30mL water and 50mL ethyl acetate were added, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate again (50mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and spun dry to give 4- (3-acetamidopyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 9A as a brown solid (270mg, 117.3%) which was used in the next reaction without further purification.
The second step is that: n- (2- (piperazin-1-yl) pyridin-3-yl) acetamide (9B)
Tert-butyl 4- (3-acetamidopyridin-2-yl) piperazine-1-carboxylate 9A (270mg,0.84mmol) was dissolved in 5mL of meoh at room temperature, HCl in EA (4M,10mL) was added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the solvent was spin dried under reduced pressure to give the product, N- (2- (piperazin-1-yl) pyridin-3-yl) acetamide 9B (280mg, 99.4%) which was used in the next reaction without further purification.
The third step: n- (2- (4-Benzylpiperazin-1-yl) pyridin-3-yl) acetamide (9C)
N- (2- (piperazin-1-yl) pyridin-3-yl) acetamide 9B (185mg,0.84mmol) was dissolved in 10mL of tetrahydrofuran, triethylamine (0.35mL,2.52mmol) and benzyl bromide (287mg,1.68mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, 30mL water and 50mL ethyl acetate were added to the reaction, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and spun to give N- (2- (4-benzylpiperazin-1-yl) pyridin-3-yl) acetamide 9C (60mg, 23%) which was used in the next reaction without further purification.
The fourth step: 2- (4-Benzylpiperazin-1-yl) pyridin-3-amine (9D)
N- (2- (4-benzylpiperazin-1-yl) pyridin-3-yl) acetamide 9C (60mg, 0.19mmol) was dissolved in 10mM MyOH at room temperature, NaOH (39mg,0.97mmol) was added and the reaction heated to reflux for 4 h and was monitored by LCMS to show completion. The reaction was spun down, pH adjusted to about 5 with 1M HCl, extracted with ethyl acetate (30mLx3), the organic layers combined, dried over anhydrous sodium sulfate and spun down to give 2- (4-benzylpiperazin-1-yl) pyridin-3-amine 9D (51mg, 98%) which was used in the next reaction without further purification.
The fifth step: 6- (N- (2- (4-Benzylpiperazin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (9E)
2- (4-Benzylpiperazin-1-yl) pyridin-3-amine 9D (51mg,0.19mmol) was dissolved in 10mL DCM, pyridine (0.053mL,0.57mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (55mg,0.19mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2- (4-benzylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 9E (180mg, 182%) which was used directly in the next reaction.
And a sixth step: 6- (N- (2- (4-Benzylpiperazin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxy-benzofuran-2-carboxamide (Compound 9)
Ethyl 6- (N- (2- (4-benzylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 9E (180mg,0.35mmol) was dissolved in 5mL MeOH at room temperature, an aqueous hydroxylamine solution (0.31mL,5.19mmol) was added, and an aqueous NaOH (70mg,1.75mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 9 as a white solid (25mg, 19%).
1H NMR(400MHz,DMSO-d6)δ8.06(s,2H),7.93-7.91(m,1H),7.70-7.68(m,1H),7.50-7.49(m,6H),7.39-7.38(m,1H),6.99-6.97(m,1H),4.30-4.28(m,2H),3.235-3.28(m,4H),3.03-2.99(m,4H).LC-MS m/z(ESI)＝508[M+1].
Example 106- (N- (2-cyclohexylethylamine) pyridin-3-yl) aminosulfonyl) -N-hydroxy-benzofuran-2-carboxamide (Compound 10)
Figure BDA0002039788050000441
The first step is as follows: N-cyclohexyl-N-ethyl-3-nitropyridin-2-amine (10A)
2-chloro-3-nitropyridine (200mg,1.26mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.52mL,3.78mmol) and N-ethylcyclohexylamine (177mg,1.39mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give N-cyclohexyl-N-ethyl-3-nitropyridin-2-amine 10A as a yellow oil (314mg, 100%) which was used in the next reaction without further purification.
The second step is that: n is a radical of2-cyclohexyl-N2-ethyl-pyridine-2, 3-diamine (10B)
N-cyclohexyl-N-ethyl-3-nitropyridin-2-amine 10A (314mg,1.26mmol) was dissolved in 10mL MeOH at room temperature, 10% Pd/C (100mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS shows that the reaction is finished, Pd/C is removed by filtration, and N is obtained after filtrate is dried by rotation2-cyclohexyl-N2Ethyl-pyridine-2, 3-diamine 10B, a black oil (190mg, 68.8%), was used in the next reaction without further purification.
The third step: 6- (N- (2-cyclohexylethylamine) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (10C)
Will N2-cyclohexyl-N2-Ethyl-pyridine-2, 3-diamine 10B (190mg,0.868mmol) was dissolved in 10mL DCM, and pyridine (0.0.21mL,2.6mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (250mg,0.868mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2-cyclohexylethylamine) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 10C (409mg, 100%) which was used directly in the next reaction.
The fourth step: 6- (N- (2-cyclohexylethylamine) pyridin-3-yl) aminosulfonyl) -N-hydroxy-benzofuran-2-carboxamide (10)
Ethyl 6- (N- (2-cyclohexylethylamine) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 10C (180mg,0.35mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.31mL,5.19mmol) was added, and an aqueous NaOH (70mg,1.75mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 10 as a white solid (25mg, 14%).
1H NMR(400MHz,DMSO-d6)δ8.08–7.92(m,3H),7.67(tq,J＝6.3,1.5Hz,1H),7.59(d,J＝2.7Hz,1H),7.27(ddd,J＝8.3,5.7,1.7Hz,1H),6.90(dd,J＝7.9,5.4Hz,1H),3.58(s,1H),3.42–3.34(m,2H),1.67(dd,J＝23.2,12.6Hz,4H),1.50(d,J＝12.3Hz,1H),1.32(d,J＝12.8Hz,2H),1.06(dq,J＝52.5,12.8Hz,3H),0.83(qd,J＝6.5,6.0,3.2Hz,3H).LC-MS m/z(ESI)＝459[M+1].
Example 11N-hydroxy-6- (N- (2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 11)
Figure BDA0002039788050000451
The first step is as follows: 2- (4-Ethoxypiperidin-1-yl) -3-nitropyridine (11A)
2-chloro-3-nitropyridine (200mg,1.26mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.52mL,3.78mmol) and 4-ethoxypiperidine hydrochloride (250mg,1.51mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), and the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 2- (4 ethoxypiperidin-1-yl) -3-nitropyridine 11A as a yellow oil (316mg, 100%) which was used in the next reaction without further purification.
The second step is that: 2- (4-ethoxypiperidin-1-yl) pyridin-3-amine (11B)
2- (4-ethoxypiperidin-1-yl) -3-nitropyridine 11A (316mg,1.26mmol) was dissolved in 10mL MeOH at room temperature, 10% Pd/C (100mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spin dried to give 2- (4-ethoxypiperidin-1-yl) pyridin-3-amine 11B (330mg, 118%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (11C)
2- (4-ethoxypiperidin-1-yl) pyridin-3-amine 11B (278mg,1.26mmol) was dissolved in 10mL DCM, and pyridine (0.3mL,3.78mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (264mg,1.26mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 11C (570mg, 95.8%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (11)
Ethyl 6- (N- (2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 11C (570mg,1.20mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (1.07mL,18.1mmol) was added, and an aqueous NaOH solution (240mg,6mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 11 as a white solid (114mg, 20.4%).
1H NMR(400MHz,DMSO-d6)δ8.05–7.94(m,3H),7.72(dd,J＝8.4,1.6Hz,1H),7.61(s,1H),7.32(dd,J＝7.9,1.7Hz,1H),6.89(dd,J＝7.8,5.0Hz,1H),3.49–3.27(m,5H),2.83(ddd,J＝12.8,9.7,2.9Hz,2H),1.80(dq,J＝12.5,3.7Hz,2H),1.48(ddt,J＝13.2,8.9,4.5Hz,2H),1.10(t,J＝7.0Hz,3H).LC-MS m/z(ESI)＝461[M+1].
Example 126- (N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxy-benzofuran 2-carboxamide (Compound 12)
Figure BDA0002039788050000471
The first step is as follows: n- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) acetamide (12A)
N- (2- (piperazin-1-yl) pyridin-3-yl) acetamide 9B (300mg,0.895mmol) was dissolved in 10mL of tetrahydrofuran, triethylamine (0.37mL,2.69mmol) and 2-iodopropane (152mg,0.895mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, 30mL water and 50mL ethyl acetate were added to the reaction, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and spun to dryness to give N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) acetamide 12A (100mg, 28%) which was used in the next reaction without further purification.
The second step is that: 2- (4-Isopropylpiperazin-1-yl) pyridin-3-amine (12B)
N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) acetamide 12A (100mg, 0.352mmol) was dissolved in 10mL MeOH at room temperature, NaOH (46mg,1.14mmol) was added and heated to reflux for 16 h and LCMS monitoring indicated completion of the reaction. The reaction was spun down, pH adjusted to about 5 with 1M HCl, extracted with ethyl acetate (30mLx3), the organic layers combined, dried over anhydrous sodium sulfate and spun down to give 2- (4-isopropylpiperazin-1-yl) pyridin-3-amine 12B (84mg, 100%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (12C)
2- (4-Isopropylpiperazin-1-yl) pyridin-3-amine 12B (84mg,0.382mmol) was dissolved in 10mL DCM, pyridine (0.1mL,1.146mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (110mg,0.382mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 12C (180mg, 100%) which was used directly in the next reaction.
The fourth step: 6- (N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) aminosulfonyl) -N-hydroxy-benzofuran 2-carboxamide (12)
Ethyl 6- (N- (2- (4-isopropylpiperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 12C (180mg,0.382mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.34mL,5.78mmol) was added, and an aqueous NaOH (76mg,1.91mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to afford compound 12 as a white solid (19mg, 9%).
1H NMR(400MHz,DMSO-d6)δ8.11–8.03(m,2H),7.97(d,J＝8.3Hz,1H),7.74(d,J＝8.2Hz,1H),7.59(s,1H),7.46(d,J＝7.9Hz,1H),7.01(dd,J＝8.0,4.8Hz,1H),3.51–3.29(m,5H),3.10–2.92(m,4H),1.24(d,J＝6.4Hz,6H).LC-MS m/z(ESI)＝460[M+1].
Example 134- (3- (2- (hydroxylamine carbonyl) benzofuran-6-sulfonylamino) pyridin-2-yl) piperazine-1-carboxylic acid isobutyl ester (Compound 13)
Figure BDA0002039788050000481
The first step is as follows: 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridin-2-yl) piperazine-1-carboxylic acid isobutyl ester (13A)
Ethyl 6- (N- (2- (piperazin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 7B (100mg,0.233mmol) was dissolved in 10mL DCM at room temperature, pyridine (0.1mL,1.165mmol) and isobutyl chloroformate (32mg,0.233mmol) were added in that order, and the mixture was stirred at room temperature overnight. The reaction was complete as monitored by LCMS, and the reaction was washed with water (50mL), dried and spun dry to give the product isobutyl 4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonamido) pyridin-2-yl) piperazine-1-carboxylate 13A (123mg, 100%) which was used directly in the next reaction.
The second step is that: 4- (3- (2- (hydroxylamine carbonyl) benzofuran-6-sulfonylamino) pyridin-2-yl) piperazine-1-carboxylic acid isobutyl ester (13)
4- (3- (2- (ethoxycarbonyl) benzofuran-6-sulfonylamino) pyridine-2-one at room temperatureYl) piperazine-1-carboxylic acid isobutyl ester 13A (200mg,0.377mmol) was dissolved in 10mL MeOH, aqueous hydroxylamine solution (0.34mL,5.66mmol) was added, and an aqueous solution of NaOH (75mg,1.86mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to afford compound 13 as a white solid (22mg, 11%).
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.67(s,1H),8.07(dd,J＝4.8,1.7Hz,1H),8.01–7.94(m,2H),7.71(dd,J＝8.2,1.6Hz,1H),7.59(s,1H),7.41(dd,J＝7.8,1.7Hz,1H),6.95(dd,J＝7.8,4.7Hz,1H),3.79(d,J＝6.5Hz,2H),3.34(s,2H)2.92–2.84(m,4H),1.86(hept,J＝6.7Hz,1H),0.88(d,J＝6.7Hz,6H).LC-MS m/z(ESI)＝518[M+1].
EXAMPLE 14N-hydroxy-6- (N- (5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 14)
Figure BDA0002039788050000491
The first step is as follows: 5-chloro-2- (4-methoxypiperidin-1-yl) -3-nitropyridine (14A)
2, 5-dichloro-3-nitropyridine (200mg,1.04mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.43mL,3.12mmol) and 4-methoxypiperidine (143mg,1.24mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), and the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 5-chloro-2- (4-methoxypiperidin-1-yl) -3-nitropyridine 14A as a yellow oil (290mg, 103%) which was used in the next reaction without further purification.
The second step is that: 5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-amine (14B)
5-chloro-2- (4-methoxypiperidin-1-yl) -3-nitropyridine 14A (500mg,2.11mmol) was dissolved in 20mL of MeOH, Raney's nickel (300mg) was added, and hydrazine hydrate (1mL) was slowly added dropwise with cooling in an ice bath, followed by reaction for 1 hour in an ice bath. LCMS showed the reaction was complete, the catalyst was removed by filtration and the filtrate was spin dried to give 5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-amine 14B as a yellow oil (258mg, 100%) which was used in the next reaction without further purification.
The third step: 6- (N- (5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (14C)
5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-amine 14B (230mg,1.07mmol) was dissolved in 10mL of DCM, and pyridine (0.26mL,3.21mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (310mg,1.07mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 14C (100mg, 21.3%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (14)
Ethyl 6- (N- (5-chloro-2- (4-methoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 14C (100mg,0.2mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.18mL,3.0mmol) was added, and an aqueous NaOH (40mg,1.0mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 14 as a white solid (1.15mg, 1.2%).
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),9.46(s,1H),8.10–7.95(m,3H),7.73(d,J＝8.4Hz,1H),7.61(s,1H),7.35(d,J＝2.4Hz,1H),3.27–3.12(m,6H),2.68(dd,J＝22.4,2.9Hz,2H),1.73(tt,J＝7.5,3.4Hz,2H),1.39(dtd,J＝12.8,9.2,3.6Hz,2H).LC-MS m/z(ESI)＝481.0[M+1].
Example 15N-hydroxy-6- (N- (5-chloro-2- (piperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 15)
Figure BDA0002039788050000501
The first step is as follows: 5-chloro-2- (piperidin-1-yl) -3-nitropyridine (15A)
2, 5-dichloro-3-nitropyridine (200mg,1.04mmol) was dissolved in 10mL 1, 4-dioxane at room temperature, TEA (0.43mL,3.12mmol) and piperidine (106mg,1.24mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 5-chloro-2- (piperidin-1-yl) -3-nitropyridine 15A as a yellow oil (270mg, 107.5%) which was used in the next reaction without further purification.
The second step is that: 5-chloro-2- (piperidin-1-yl) pyridin-3-amine (15B)
5-chloro-2- (piperidin-1-yl) -3-nitropyridine 15A (270mg,1.12mmol) was dissolved in 20mL of MeOH, Raney-Ni (300mg) was added, and hydrazine hydrate (1mL) was slowly added dropwise with cooling in an ice bath, and the reaction was carried out for 1 hour in an ice bath. LCMS showed the reaction was complete, the catalyst was removed by filtration and the filtrate was spin dried to give 5-chloro-2- (piperidin-1-yl) pyridin-3-amine 15B as a yellow oil (236mg, 100%) which was used in the next reaction without further purification.
The third step: 6- (N- (5-chloro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (15C)
5-chloro-2- (piperidin-1-yl) pyridin-3-amine 15B (233mg,1.1mmol) was dissolved in 10mL DCM, and pyridine (0.27mL,3.3mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (318mg,1.1mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (5-chloro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 15C (50mg, 9.8%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (5-chloro-2- (piperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (15)
Ethyl 6- (N- (5-chloro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 15C at room temperature(50mg,0.108mmol) was dissolved in 5mL MeOH, an aqueous hydroxylamine solution (0.1mL,1.62mmol) was added, and an aqueous NaOH (22mg,0.54mmol) solution was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 15(5.0mg, 8.12%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.10–7.98(m,2H),7.97(dd,J＝8.3,2.8Hz,1H),7.71(dd,J＝8.2,1.8Hz,1H),7.59(d,J＝2.8Hz,1H),7.29(dd,J＝5.3,2.6Hz,1H),,2.87(t,J＝4.2Hz,4H),1.41(s,6H).LC-MS m/z(ESI)＝451.0[M+1].
Example 16N-hydroxy-6- (N- (5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 16)
Figure BDA0002039788050000521
The first step is as follows: 5-fluoro-2- (4, 4-difluoropiperidin-1-yl) -3-nitropyridine (16A)
2-chloro-3-nitro-5-fluoropyridine (150mg,0.85mmol) was dissolved in 10mL of acetonitrile at room temperature, potassium carbonate (235mg,1.7mmol) and 4, 4-difluoropiperidine hydrochloride (147mg,0.94mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), and the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 5-fluoro-2- (4-methoxypiperidin-1-yl) -3-nitropyridine 16A as a yellow oil (190mg, 85.6%) which was used in the next reaction without further purification.
The second step is that: 5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-amine (16B)
5-fluoro-2- (4, 4-difluoropiperidin-1-yl) -3-nitropyridine 16A (190mg,0.73mmol) was dissolved in 10mL of MeOH at room temperature, 10% Pd/C (100mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spin dried to give 5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-amine 16B as a yellow oil (140mg, 83.2%) which was used in the next reaction without further purification.
The third step: 6- (N- (5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (16C)
5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-amine 16B (140mg,0.61mmol) was dissolved in 10mL DCM, and pyridine (0.15mL,1.83mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (176mg,0.61mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 16C (210mg, 68%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (16)
Ethyl 6- (N- (5-fluoro-2- (4, 4-difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 16C (210mg,0.435mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.39mL,6.52mmol) was added, an aqueous NaOH solution (87mg,2.18mmol) was added dropwise with stirring, and stirring was carried out at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 16(23mg, 9%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.94(s,1H),9.45(s,1H),8.14–8.04(m,2H),7.99(d,J＝8.3Hz,1H),7.79(dd,J＝8.3,1.6Hz,1H),7.62–7.49(m,2H),2.80(t,J＝5.5Hz,4H),1.97(tt,J＝14.1,5.5Hz,4H).LC-MS m/z(ESI)＝471.0[M+1].
Example 17N-hydroxy-6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 17)
Figure BDA0002039788050000531
The first step is as follows: 5-fluoro-2- (piperidin-1-yl) -3-nitropyridine (17A)
2-chloro-3-nitro-5-fluoropyridine (150mg,0.85mmol) was dissolved in 10mL of acetonitrile at room temperature, and potassium carbonate (352mg,2.55mmol) and piperidine (86.9mg,1.02mmol) were added to react at room temperature for 1 hour, and LC-MS monitored to show completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.1), the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 5-fluoro-2- (4-methoxypiperidin-1-yl) -3-nitropyridine 17A as a yellow oil (190mg, 99.2%) which was used in the next reaction without further purification.
The second step is that: 5-fluoro-2- (piperidin-1-yl) pyridin-3-amine (17B)
5-fluoro-2- (piperidin-1-yl) -3-nitropyridine 17A (190mg,0.84mmol) was dissolved in 10mL of MeOH at room temperature, 10% Pd/C (19mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spin dried to give 5-fluoro-2- (piperidin-1-yl) pyridin-3-amine 17B as a yellow oil (140mg, 85.4%) which was used in the next reaction without further purification.
The third step: 6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (17C)
5-fluoro-2- (piperidin-1-yl) pyridin-3-amine 17B (140mg,0.717mmol) was dissolved in 10mL DCM, pyridine (0.78mL,7.17mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (207mg,0.717mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product 6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 17C (240mg, 74.8%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (17)
Ethyl 6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 17C (240mg,0.54mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.48mL,8.12mmol) was added, and an aqueous NaOH solution (108mg,2.7mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, 1M HCl adjusted pH to 8, spin dried, and residue prep-HPLC(0.5％TFA in CH3CN/H2O) to give compound 17(55mg, 23.6%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.51(s,2H),8.12(s,1H),8.06(d,J＝2.8Hz,1H),7.97(d,J＝8.3Hz,1H),7.78(dd,J＝8.3,1.6Hz,1H),7.59(s,1H),7.44(dd,J＝9.6,2.8Hz,1H),2.67(t,J＝5.1Hz,4H),1.52–1.36(m,6H).LC-MS m/z(ESI)＝435[M+1].
EXAMPLE 18N-hydroxy-6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 18)
Figure BDA0002039788050000541
The first step is as follows: 5-chloro-2- (4 ethoxypiperidin-1-yl) -3-nitropyridine (18A)
2, 5-dichloro-3-nitropyridine (250mg,1.3mmol) was dissolved in 10mL of 1, 4-dioxane at room temperature, TEA (0.54mL,3.9mmol) and 4-ethoxypiperidine hydrochloride (236mg,1.42mmol) were added, the reaction was refluxed for 1 hour, and LC-MS monitoring indicated completion of the reaction. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), and the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 5-chloro-2- (4-ethoxypiperidin-1-yl) -3-nitropyridine 18A as a yellow oil (430mg, 116%) which was used in the next reaction without further purification.
The second step is that: 5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine (18B)
5-chloro-2- (4-ethoxypiperidin-1-yl) -3-nitropyridine 18A (430mg,1.5mmol) was dissolved in 20mL of MeOH, Raney-Ni (300mg) was added, and hydrazine hydrate (1mL) was slowly added dropwise with cooling in an ice bath, and the reaction was carried out for 1 hour in an ice bath. LCMS showed the reaction was complete, the catalyst was removed by filtration and the filtrate was spin dried to give 5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine 18B as a yellow solid (320mg, 83.1%) which was used in the next reaction without further purification.
The third step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (18C)
5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine 18B (320mg,1.25mmol) was dissolved in 5mL of pyridine, and 6-chlorosulfonyl-benzofuran-2-carboxylic acid ethyl ester (361mg,1.25mmol) was added, followed by stirring at 80 ℃ overnight. LCMS shows that the reaction is finished, 30mL of water and 50mL of ethyl acetate are added to the reaction solution to dissolve the residue, an ethyl acetate layer is separated, an aqueous layer is extracted by ethyl acetate again (50mL multiplied by 2), organic layers are combined, and the mixture is dried by anhydrous sodium sulfate and then is dried in a rotary manner to obtain the product, namely 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 18C (453mg, 67.7%) which is directly used for the next reaction. The fourth step: n-hydroxy-6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (18)
Ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 18C (453mg,0.892mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.8mL,13.4mmol) was added, an aqueous solution of NaOH (179mg,4.47mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 18(34mg, 7.4%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.10–8.00(m,2H),7.97(d,J＝8.3Hz,1H),7.71(d,J＝8.4Hz,1H),7.59(s,1H),7.29(d,J＝2.4Hz,1H),3.38(q,J＝7.0Hz,2H),3.31(dq,J＝8.5,4.3Hz,1H),3.18(dt,J＝12.3,4.3Hz,2H),2.66(ddd,J＝12.8,9.8,2.9Hz,2H),,1.70(dq,J＝12.3,3.7Hz,2H),1.42–1.29(m,2H),1.05(t,J＝7.0Hz,3H).LC-MS m/z(ESI)＝495[M+1].
Example 19N-hydroxy-6- (N- (3-trifluoromethylpiperidin-1-yl) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 19)
Figure BDA0002039788050000561
The first step is as follows: 3-Nitro-2- (3-trifluoromethylpiperidin-1-yl) pyridine (19A)
2-chloro-3-nitropyridine (317mg,2.0mmol) was dissolved in 20mL of 1, 4-dioxane at room temperature, TEA (607mg,6.0mmol) and 3-trifluoromethylpiperidine (320mg,2.09mmol) were added, and the reaction was heated at 60 ℃ for 1 hour and monitored by LC-MS to show completion. The reaction mixture was concentrated to remove the solvent, 30mL of water and 50mL of ethyl acetate were added to dissolve the residue, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate and then spin-dried to give 3-nitro-2- (3-trifluoromethylpiperidin-1-yl) pyridine 19A as a yellow oil (550mg, 99.9%) which was used in the next reaction without further purification.
The second step is that: 2- (3-Trifluoromethylpiperidin-1-yl) pyridin-3-amine (19B)
3-Nitro-2- (3-trifluoromethylpiperidin-1-yl) pyridine 19A (550mg,2.0mmol) was dissolved in 30mL MeOH at room temperature, 10% Pd/C (50mg) was added, and the mixture was stirred overnight under hydrogen protection. LCMS showed the reaction was complete, Pd/C was removed by filtration and the filtrate was spin dried to give 2- (3-trifluoromethylpiperidin-1-yl) pyridin-3-amine 19B (500mg, 102%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (3-trifluoromethyl) -piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (19C)
2- (3-Trifluoromethylpiperidin-1-yl) pyridin-3-amine 19B (500mg,2mmol) was dissolved in 10mL of DCM, and pyridine (0.48mL,6mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (584mg,2mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product 6- (N- (2- (3-trifluoromethyl) -piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 19C (430mg, 42.4%) which was used directly in the next reaction.
The fourth step: n-hydroxy-6- (N- (3-trifluoromethylpiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (19)
Ethyl 6- (N- (2- (3-trifluoromethyl) -piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 19C (430mg,0.865mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.77mL,13mmol) was added, and an aqueous NaOH solution (173mg,4.33mmol) was added dropwise with stirring at room temperatureStirred for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 19(130mg, 30.1%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.07(s,1H),7.99–7.87(m,3H),7.76(dd,J＝8.2,1.6Hz,1H),7.54(s,1H),7.46(dd,J＝8.3,4.5Hz,1H),4.14(t,J＝12.2Hz,1H),3.92(td,J＝12.7,3.2Hz,1H),3.74(d,J＝11.8Hz,1H),3.65–3.56(m,1H),3.41(ddq,J＝12.4,8.8,4.1Hz,1H),2.31(qt,J＝13.5,3.9Hz,1H),1.97(d,J＝12.6Hz,1H),1.89(d,J＝14.3Hz,1H),1.66
(qd,J＝12.9,4.1Hz,1H).LC-MS m/z(ESI)＝485[M+1].
Example 20N-hydroxy-6- (N- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 20)
Figure BDA0002039788050000571
The first step is as follows: 6- (N- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (20A)
Ethyl 6- (N- (2- (piperidin-4-yloxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate (82mg,0.20mmol) was dissolved in 10mL of methanol at room temperature, and 35-40% formaldehyde solution (82mg,1.0mmol), glacial acetic acid (12mg,0.2mmol) and anhydrous sodium sulfate (574mg,4.0mmol) were added, followed by sodium triacetoxyborohydride (214mg,1.0mmol), and the reaction was stirred at room temperature for 5 h. 20mL of water was added, extracted with 50mL of dichloromethane (50 mL. times.2), the organic layers combined, dried over anhydrous sodium sulfate and dried by spin-drying to give ethyl 6- (N- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 20A as a pale yellow solid (75mg, 80.8%) which was used in the next reaction without further purification. LC-MS M/z (esi) ═ 460.3[ M +1].
The second step is that: n-hydroxy-6- (N- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 20)
At room temperature, 6- (N- (2- ((1-)Methylpiperidin-4-yl) oxy) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 20A (430mg,0.865mmol) was dissolved in 10mL MeOH, an aqueous hydroxylamine solution (0.77mL,13mmol) was added, an aqueous solution of NaOH (173mg,4.33mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 20(130mg, 30.1%) as a white solid. LC-MS M/z (ESI) ═ 447.1[ M +1].
Example 21N-hydroxy-6- (N- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxamide (Compound 21)
Figure BDA0002039788050000581
The first step is as follows: 2- (3-Nitropyridin-2-yl) octahydrocyclopenta [ c ] pyrrole (21A)
2-fluoro-3-nitropyridine (282mg,2.0mmol) was dissolved in 10mL DMF at room temperature and cesium carbonate (1.29mg,3.97mmol) and octahydrocyclopenta [ c ] pyrrole (221mg,2.0mmol) were added and the reaction was allowed to react for 2 h at room temperature with TLC monitoring showing completion. 30mL of water was added, extraction was performed with 50mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, 100 mL. times.2 was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying to give 21A as a yellow oil (400mg, 86.4%) which was used in the next reaction without further purification.
The second step is that: 2- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) pyridin-3-amine (21B)
To 2- (3-nitropyridin-2-yl) octahydrocyclopenta [ C ] pyrrole 21A (400mg,1.71mmol) was added 10mL of MeOH and 10mL of dichloromethane, 10% Pd/C (40mg) at room temperature, and the reaction was stirred under a hydrogen atmosphere overnight. TLC monitoring indicated completion of the reaction, the catalyst was removed by filtration and the filtrate was dried by spinning to give 21B (320mg, 91.8%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (hexahydrocyclopenta [ C ] pyrrol-2 (1H) -yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (21C)
2- (Hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) pyridin-3-amine 21B (200mg,0.98mmol) was dissolved in 10mL DCM, pyridine (389mg,4.92mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (426mg,1.48mmol) were added, and the mixture was stirred at room temperature overnight. TLC monitoring indicated completion of the reaction. The reaction mixture was added with 100mL of dichloromethane, washed with water (50mL × 2), the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1:6 to 1:4) to give 21C as a pale yellow solid (400mg, 89.3%). LC-MS M/z (esi) ═ 456.2[ M +1].
The fourth step: n-hydroxy-6- (N- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-3-yl) aminesulfonyl) benzofuran-2-carboxamide (Compound 21)
Reacting 6- (N- (2- (hexahydrocyclopenta [ c ]) at room temperature]Pyrrol-2 (1H) -yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 21C (400mg,0.878mmol) was dissolved in 10mL MeOH, an aqueous hydroxylamine solution (0.580mg,8.78mmol) was added, and a solution of NaOH (105mg,2.63mmol) in water (0.5mL) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 21 as a white solid (165mg, 42.5%).
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.07(s,1H),7.99(d,J＝8.2Hz,1H),7.95(dd,J＝5.3,1.7Hz,1H),7.87(s,1H),7.63(dd,J＝8.3,1.4Hz,1H),6.86(d,J＝7.1Hz,1H),6.56(s,1H),3.80-3.66(m,1H),3.34(d,J＝10.4Hz,2H),2.69-2.57(m,2H),1.74(dt,J＝14.1,7.1Hz,2H),1.68-1.59(m,1H),1.59-1.46(m,1H),1.42-1.30(m,2H).LC-MS m/z(ESI)＝443.1[M+1].
Example 22N-hydroxy-6- (N- (2- (4- (2-hydroxyprop-2-yl) piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (Compound 22)
Figure BDA0002039788050000591
The first step is as follows: 2- (1- (3-Nitropyridin-2-yl) piperidin-4-yl) propan-2-ol (22A)
2-fluoro-3-nitropyridine (300mg,2.0mmol) was dissolved in 10mL DMF at room temperature, cesium carbonate (1.29mg,3.97mmol) and 2- (piperidin-4-yl) propan-2-ol (333mg,2.32mmol) were added and the reaction was allowed to react for 2 hours at room temperature with TLC monitoring indicating completion. 30mL of water was added, extraction was performed with 50mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, 100 mL. times.2 was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying to give 22A as a yellow oil (500mg, 89.3%) which was used in the next reaction without further purification.
The second step is that: 2- (1- (3-Aminopyridin-2-yl) piperidin-4-yl) propan-2-ol (22B)
To 2- (1- (3-nitropyridin-2-yl) piperidin-4-yl) propan-2-ol 22A (500mg,1.88mmol) were added 10mL of DMEOH and 10mL of dichloromethane, 10% Pd/C (100mg) at room temperature, and the reaction was stirred under a hydrogen atmosphere overnight. TLC monitoring indicated completion of the reaction, the catalyst was removed by filtration and the filtrate was dried by spinning to give 22B (400mg, 90.2%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4- (2-hydroxypropan-2-yl) piperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (22C)
2- (1- (3-Aminopyridin-2-yl) piperidin-4-yl) propan-2-ol 22B (400mg,1.7mmol) was dissolved in 15mL DCM, pyridine (672mg,8.5mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (490mg,1.7mmol) were added, and the mixture was stirred at room temperature overnight. TLC monitoring indicated completion of the reaction. The reaction mixture was added with 100mL of dichloromethane, washed with water (50mL × 2), the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1:6 to 1:4) to give 22C as a white solid (600mg, 72.4%).1H NMR(400MHz,CDCl3)δ8.10(s,1H),8.06(d,J＝3.8Hz,1H),7.88(dd,J＝8.1,1.4Hz,1H),7.83-7.75(m,2H),7.53(d,J＝0.8Hz,1H),7.03(s,1H),4.46(q,J＝7.2Hz,2H),2.83-2.60(m,4H),1.86-1.73(m,2H),1.49-1.35(m,3H),1.44(t,J＝7.2Hz,3H),1.24(s,6H).
The fourth step: n-hydroxy-6- (N- (2- (4- (2-hydroxyprop-2-yl) piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxamide (compound 22)
Reacting 6- (N- (2- (4- (2-hydroxypropane-))2-Yl) piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 22C (600mg,1.23mmol) was dissolved in 15mL MeOH, an aqueous hydroxylamine solution (0.813mg,12.3mmol) was added, and a solution of NaOH (148mg,3.7mmol) in water (0.5mL) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 22 as a white solid (300mg, 51.4%).
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),9.56(s,1H),8.03(dd,J＝4.9,1.7Hz,1H),7.99(s,1H),7.95(d,J＝8.3Hz,1H),7.70(dd,J＝8.3,1.5Hz,1H),7.58(s,1H),7.33(dd,J＝7.8,1.7Hz,1H),6.87(dd,J＝7.8,4.9Hz,1H),3.46(d,J＝11.7Hz,2H),2.58-2.42(m,2H),1.57(d,J＝9.1Hz,2H),1.25-1.14(m,3H),0.99(s,6H).LC-MS m/z(ESI)＝475.2[M+1].
Example 236- (N- (2- (4, 4-Difluoropiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 23)
Figure BDA0002039788050000611
The first step is as follows: 2- (4, 4-Difluoropiperidin-1-yl) -3-nitropyridine (23A)
2-fluoro-3-nitropyridine (300mg,2.1mmol) was dissolved in 10mL DMF at room temperature, cesium carbonate (2.06mg,6.33mmol) and 4, 4-difluoropiperidine (331mg,2.1mmol) were added and the reaction was allowed to react for 10 h at room temperature with TLC monitoring indicating completion. 30mL of water was added, extraction was performed with 50mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, 100 mL. times.2 was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying to give 23A as a yellow oil (500mg, 97.4%) which was used in the next reaction without further purification.
The second step is that: 2- (4, 4-Difluoropiperidin-1-yl) pyridin-3-amine (23B)
To 2- (4, 4-Difluoropiperidin-1-yl) -3-nitropyridine 23A (500mg,2.06mmol) was added 10mL of MeOH and 10mL of dichloromethane, 10% Pd/C (100mg) at room temperature, and the reaction was stirred under a hydrogen atmosphere overnight. TLC monitoring indicated completion of the reaction, the catalyst was removed by filtration and the filtrate was dried by spinning to give 23B (400mg, 91.3%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4, 4-Difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (23C)
2- (4, 4-Difluoropiperidin-1-yl) pyridin-3-amine 23B (400mg,1.88mmol) was dissolved in 15mL DCM, pyridine (742mg,9.38mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (542mg,1.88mmol) were added, and the mixture was stirred at room temperature overnight. TLC monitoring indicated completion of the reaction. The reaction mixture was added with 100mL of dichloromethane, washed with water (50mL × 2), the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1:6 to 1:4) to give 23C as a white solid (600mg, 72.4%).
1H NMR(400MHz,CDCl3)δ8.10(d,J＝1.0Hz,1H),8.06(dd,J＝4.8,1.7Hz,1H),7.86(dd,J＝8.1,1.6Hz,1H),7.80(d,J＝1.0Hz,2H),7.54(d,J＝0.9Hz,1H),7.43(s,1H),7.05(dd,J＝7.2,4.8Hz,1H),4.46(q,J＝7.2Hz,2H),2.93-2.80(m,4H),2.10-2.00(m,4H),1.44(t,J＝7.2Hz,3H),1.24(s,6H).
The fourth step: 6- (N- (2- (4, 4-Difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxybenzofuran-2-carboxamide (Compound 23)
Ethyl 6- (N- (2- (4, 4-difluoropiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 23C (400mg,1.40mmol) was dissolved in 15mL MeOH at room temperature, an aqueous hydroxylamine solution (0.923mg,14.0mmol) was added, and a solution of NaOH (167mg,4.2mmol) in water (0.5mL) was added dropwise with stirring and stirred at room temperature for 4 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 23 as a white solid (400mg, 63.3%).
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.71(s,1H),8.05(dd,J＝4.8,1.7Hz,1H),8.00(s,1H),7.97(d,J＝8.3Hz,1H),7.73(dd,J＝8.3,1.5Hz,1H),7.59(s,1H),7.41(dd,J＝7.9,1.6Hz,1H),6.95(dd,J＝7.9,4.8Hz,1H),3.10-2.96(m,4H),2.05-1.86(m,4H).LC-MS m/z(ESI)＝453.1[M+1].
Example 246- (N- (2- (1, 1-difluoro-5-aza [2.5] octan-5-yl) pyridin-3-yl) sulfamoyl) -N-hydroxybenzofuran-2-carboxamide (Compound 24)
Figure BDA0002039788050000621
The first step is as follows: 1, 1-difluoro-5- (3-nitropyridin-2-yl) -5-azaspiro [2.5] octane (24A)
2-fluoro-3-nitropyridine (130mg,0.914mmol) was dissolved in 10mL of DMF at room temperature, and cesium carbonate (893mg,2.74mmol) and 1, 1-difluoro-5-azaspiro [2.5] octane hydrochloride (135mg,0.914mmol) were added and reacted at room temperature for 10 hours with TLC monitoring showing completion of the reaction. 30mL of water was added and extracted with 50mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, 100 mL. times.2 was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying to give 24A as a yellow oil (100mg, 40.6%) which was used in the next reaction without further purification.
The second step is that: 2- (1, 1-difluoro-5-azaspiro [2.5] octan-5-yl) pyridin-3-amine (24B)
5mL of MeOH and 5mL of dichloromethane and 10% Pd/C (20mg) were added to 1, 1-difluoro-5- (3-nitropyridin-2-yl) -5-azaspiro [2.5] octane 24A (100mg,371umol) at room temperature, and the reaction was stirred overnight under a hydrogen atmosphere. TLC monitoring indicated completion of the reaction, the catalyst was removed by filtration and the filtrate was dried by spinning to give 24B (80mg, 90.0%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (1, 1-difluoro-5-aza [2.5] oct-5-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (24C)
2- (1, 1-difluoro-5-azaspiro [2.5] octan-5-yl) pyridin-3-amine 24B (80mg,334umol) was dissolved in 15mL DCM, pyridine (132mg,1.67mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (96.5mg,334umol) were added, and the mixture was stirred at room temperature overnight. TLC monitoring indicated completion of the reaction. The reaction mixture was added with 100mL of dichloromethane, washed with water (50mL × 2), the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1:6 to 1:4) to give 24C as a pale yellow solid (85mg, 51.7%).
The fourth step: 6- (N- (2- (1, 1-difluoro-5-aza [2.5] oct-5-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 24)
Reacting 6- (N- (2- (1, 1-difluoro-5-aza [2.5 ]) at room temperature]Octane-5-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester 24C (80mg,163umol) was dissolved in 10mL MeOH, an aqueous hydroxylamine solution (108mg,1.63mmol) was added, a solution of NaOH (20mg,488umol) in water (0.3mL) was added dropwise with stirring, and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 24 as a white solid (20mg, 25.7%).
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.44(s,1H),8.00(s,1H),7.96(dd,J＝8.3,1.3Hz,1H),7.59(s,1H),7.21(dd,J＝8.3,1.4Hz,1H),6.82(dd,J＝7.7,4.8Hz,1H),3.19(d,J＝12.3Hz,1H),3.10-2.97(m,3H),1.69-1.60(m,3H),1.58-1.52(m,1H),0.86-0.82(m,2H).LC-MSm/z(ESI)＝479.1[M+1].
Example 256- (N- (2- (4-ethoxypiperidin-1-yl) -5-fluoropyridin-3-yl) aminesulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 25)
Figure BDA0002039788050000641
The first step is as follows: 2- (4-ethoxypiperidin-1-yl) -5-fluoro-3-nitropyridine (25A)
2-chloro-5-fluoro-3-nitropyridine (250mg,1.42mmol) was dissolved in 10mL DMF at room temperature, cesium carbonate (1.39mg,4.26mmol) and 4-ethoxypiperidine hydrochloride (235mg,1.42mmol) were added and the reaction was allowed to react for 5 hours at room temperature with TLC monitoring showing completion. 30mL of water was added and extracted with 50mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, 100 mL. times.2 was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then spun dry to give 25A as a yellow oil (300mg, 78.2%) which was used in the next reaction without further purification. The second step is that: 2- (4-ethoxypiperidin-1-yl) -5-fluoropyridin-3-amine (25B)
10mM LEOH, Raney nickel (20mg) was added to 2- (4-ethoxypiperidin-1-yl) -5-fluoro-3-nitropyridine 25A (300mg,371umol) under ice-bath, and hydrazine hydrate (179mg,5.57mmol) was added dropwise under nitrogen protection. TLC monitoring indicated completion of the reaction, the catalyst was removed by filtration and the filtrate was dried by spinning to give 25B (250mg, 93.8%) which was used in the next reaction without further purification.
The third step: 6- (N- (2- (4-ethoxypiperidin-1-yl) -5-fluoropiperidin-3-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (25C)
2- (4-ethoxypiperidin-1-yl) -5-fluoropyridin-3-amine 25B (250mg,1.04mmol) was dissolved in 15mL DCM, pyridine (826mg,10.5mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (301.6mg,1.04mmol) were added, and the mixture was stirred at room temperature overnight. TLC monitoring indicated completion of the reaction. The reaction mixture was added with 100mL of dichloromethane, washed with water (50mL × 2), the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1:6 to 1:4) to give 25C as a pale yellow solid (200mg, 39.0%).
The fourth step: 6- (N- (2- (4-ethoxypiperidin-1-yl) -5-fluoropyridin-3-yl) sulfamoyl) -N-hydroxybenzofuran-2-carboxamide (Compound 25)
Ethyl 6- (N- (2- (4-ethoxypiperidin-1-yl) -5-fluoropiperidin-3-yl) sulfamoyl) benzofuran-2-carboxylate 25C (200mg,407umol) was dissolved in 10mL MeOH at room temperature, 50% aqueous hydroxylamine solution (4.07mmol) was added, and a solution of NaOH (49mg,1.2mmol) in water (0.2mL) was added dropwise with stirring and stirred at room temperature for 4 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 25 as a white solid (20mg, 25.7%).
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.47(s,1H),8.12(s,1H),8.05(d,J＝2.5Hz,1H),7.98(d,J＝8.2Hz,1H),7.79(d,J＝8.2Hz,1H),7.59(s,1H),7.44(dd,J＝9.5Hz,J＝2.5Hz,1H),3.47-3.40(m,3H),2.93-2.90(m,2H),2.57–2.51(m,2H),1.75–1.72(m,2H),1.51–1.44(m,2H),1.09(t,J＝7.2Hz,3H).LC-MS m/z(ESI)＝479.1[M+1].
Example 266- (N- (5-cyano-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 26)
Figure BDA0002039788050000651
The first step is as follows: 6- (4-ethoxypiperidin-1-yl) -5-nitronicotinonitrile (26A)
6-chloro-5-nitronicotinonitrile (250mg,1.36mmol) was dissolved in 10mL DMF at room temperature, cesium carbonate (1.33mg,4.08mmol) and 4-ethoxypiperidine hydrochloride (225mg,1.42mmol) were added and the reaction was allowed to react for 5h at room temperature with TLC monitoring showing completion. 30mL of water was added and extracted with 50mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, 100 mL. times.2 was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying to give 26A as a yellow oil (300mg, 78.2%) which was used in the next reaction without further purification.
The second step is that: 5-amino-6- (4-ethoxypiperidin-1-yl) nicotinonitrile (26B)
Under ice bath, 10mL of LEOH, Raney nickel (20mg) was added to 6- (4-ethoxypiperidin-1-yl) -5-nitronicotinonitrile 26A (330mg,1.19mmol), and hydrazine hydrate (191mg,5.97mmol) was added dropwise under nitrogen. TLC monitoring indicated completion of the reaction, the catalyst was removed by filtration and the filtrate was dried by spinning to give 26B (280mg, 95.2%) which was used in the next reaction without further purification.
The third step: 6- (N- (5-cyano-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (26C)
5-amino-6- (4-ethoxypiperidin-1-yl) nicotinonitrile 26B (250mg,1.01mmol) was dissolved in 15mL DCM, pyridine (803mg,10.2mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (293mg,1.01mmol) were added, and the mixture was stirred at room temperature overnight. TLC monitoring indicated completion of the reaction. The reaction mixture was added with 100mL of dichloromethane, washed with water (50mL × 2), the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1:6 to 1:4) to give 26C as a pale yellow solid (250mg, 49.4%).
The fourth step: 6- (N- (5-cyano-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 26)
Ethyl 6- (N- (5-cyano-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 26C (250mg,501umol) was dissolved in 10mL MeOH at room temperature, 50% aqueous hydroxylamine solution (5.01mmol) was added, and a solution of NaOH (60mg,1.50mmol) in water (0.3mL) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 26 as a white solid (8mg, 3.3%).
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.91(s,1H),8.41(d,J＝2.1Hz,1H),8.00(d,J＝8.3Hz,1H),7.92(s,1H),7.62–7.60(m,2H),7.17(d,J＝2.1Hz,1H),3.85(dd,J＝8.6,5.3Hz,2H),3.43-3.41(m,3H),3.17-3.14(m,2H),1.83–1.73(m,2H),1.42–1.35(m,2H),1.09(t,J＝6.8Hz,3H).LC-MS m/z(ESI)＝486.2[M+1].
Example 276- (N- (5-chloro-2- (4-cyclopropylmethoxypiperidin-1 yl) pyridin-3-yl) aminosulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 27)
Figure BDA0002039788050000671
The first step is as follows: 4-Cyclopropylmethoxypiperidine-1-carboxylic acid tert-butyl ester (27A)
Tert-butyl 4-hydroxypiperidine-1-carboxylate (1g,4.98mmol) was dissolved in 20mL of N, N-dimethylformamide, cooled in an ice bath under nitrogen, and NaH (60% in content, 219mg,5.48mmol) was added in portions, and stirred in an ice bath for 30 minutes, at which time cyclopropylmethyl bromide (1g,7.46mmol) was added, slowly warmed to room temperature and reacted overnight. LC-MS monitoring indicated completion of the reaction, the reaction was poured into water, extracted 3 times with 20mL ethyl acetate, the ethyl acetate layers were combined, dried and spun dry, and purified by silica gel column chromatography (PE: EA ═ 20:1) to give the product tert-butyl 4-cyclopropylmethoxypiperidine-1-carboxylate (870mg,68.. 5%) as a yellow oil.
The second step is that: 4-Cyclopropylmethoxypiperidine (27B)
Tert-butyl 4-cyclopropylmethoxypiperidine-1-carboxylate 27A (870mg,3.41mmol) was dissolved in 20mL of dichloromethane, 5mL of trifluoroacetic acid was added and the reaction was allowed to proceed overnight at room temperature, as monitored by LC-MS. The reaction solution was made basic with aqueous sodium carbonate, extracted 3 times with 20mL of dichloromethane, the dichloromethane layers were combined, dried and spin dried to give the product 4-cyclopropylmethoxypiperidine 27B (530mg, 100%) as a yellow oil.
The third step: 5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) -3-nitropyridine 27C)
2, 5-dichloro-3-nitropyridine (193mg,1.00mmol) was dissolved in 10mL of 1, 4-dioxane, and 4-cyclopropylmethoxypiperidine (170mg,1.10mmol) and triethylamine (0.41mL,3.00mmol) were added to the solution, and the mixture was reacted at room temperature overnight. LC-MS monitoring indicated completion of the reaction. The solvent was spun dry, 30mL of water and 20mL of ethyl acetate were added to the residue, the organic layer was separated, the aqueous phase was extracted 2 times with 20mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate and spun dry to give the product 5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) -3-nitropyridine 27C (480mg, 155%) as a yellow oil.
The fourth step: 5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) pyridin-3-amine (27D)
5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) -3-nitropyridine 27C (480mg,1.2mmol) was dissolved in 10mL of MeOH at room temperature, Raney-Ni (200mg) was added, and hydrazine hydrate (0.3mL,6.0mmol) was added dropwise with cooling on an ice bath. After the dripping, stirring was continued for 1 hour under ice bath. LCMS showed the reaction was complete, Raney-Ni was removed by filtration and the filtrate was spin dried to give 5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) pyridin-3-amine 27D (337mg, 77%) which was used directly in the next step.
The fifth step: 6- (N- (5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzofuran-2-carboxylic acid ethyl ester (27E)
5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) pyridin-3-amine 27D (337mg,1.2mmol) was dissolved in 10mL of 1, 2-dichloroethane, and pyridine (0.39mL,4.8mmol) and ethyl 6-chlorosulfonyl-benzofuran-2-carboxylate (693mg,2.4mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water (50mL), dried and spun dry to give the product ethyl 6- (N- (5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 27E (600mg, 94%) as a yellow oil which was used directly in the next reaction.
And a sixth step: 6- (N- (5-chloro-2- (4-cyclopropylmethoxypiperidin-1 yl) pyridin-3-yl) aminesulfonyl) -N-hydroxybenzofuran-2-carboxamide (Compound 27)
Ethyl 6- (N- (5-chloro-2- (4-cyclopropylmethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) benzofuran-2-carboxylate 27E (600mg,1.12mmol) was dissolved in 10mL of methanol at room temperature, an aqueous hydroxylamine solution (1mL,16.9mmol) was added, and an aqueous solution of sodium hydroxide (224mg,5.6mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed the reaction was complete, 1M HCl was added to adjust pH to 8, the solvent was dried and the residue was purified by prep-HPLC to give the product compound 27(198mg, 33%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.11–8.05(m,1H),8.03–7.92(m,2H),7.69(dd,J＝8.3,1.6Hz,1H),7.60–7.55(m,1H),7.29(d,J＝2.4Hz,1H),3.34(tt,J＝8.6,3.9Hz,1H),3.16(t,J＝6.2Hz,3H),2.65(ddd,J＝12.7,9.8,2.9Hz,2H),2.01(s,1H),1.69(d,J＝11.7Hz,2H),1.41–1.27(m,2H),0.90(dddd,J＝14.8,6.9,3.2,2.0Hz,1H),0.46–0.35(m,2H),0.15–0.04(m,2H).LC-MS m/z(ESI)＝521.2[M+1].
Examples 28 to 60
Examples 28-60 were prepared according to the synthetic method of example 14.
Figure BDA0002039788050000681
Figure BDA0002039788050000691
Figure BDA0002039788050000701
Figure BDA0002039788050000711
Figure BDA0002039788050000721
Figure BDA0002039788050000731
Figure BDA0002039788050000741
Figure BDA0002039788050000751
Example 626- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxy-furo [3,2-c ] pyridine-2-carboxamide (Compound 62)
Figure BDA0002039788050000752
The first step is as follows: 6-chloro-4-hydroxynicotinaldehyde (62A)
6-chloro-4-methoxypyridine-3-carbaldehyde (1g,4.98mmol) was added to 50mL of concentrated hydrochloric acid, and the mixture was heated to reflux for 18 hours. TLC monitoring indicated completion of the reaction, cooling to room temperature, pouring the reaction into 100mL of water, extracting 5 times with 200mL of dichloromethane, combining the organic layers, drying and spin-drying to give the product 6-chloro-4-hydroxynicotinaldehyde 61A (520mg, 28.3%) as a white solid.
The second step is that: 6-chloro-furo [3,2-c ] pyridine-2-carboxylic acid ethyl ester (62B)
6-chloro-4-methoxypyridine-3-carbaldehyde 62A (405mg,2.57mmol) was dissolved in 20mL of DMF, ethyl bromoacetate (537mg,3.22mmol) and potassium carbonate (1.07,7.72mmol) were added, and the reaction was allowed to warm at room temperature for 2 hours overnight. After cooling to room temperature, the reaction mixture was introduced into 100mL of water, and 3 times with 100mL of ethyl acetate, the organic layers were combined, dried and spun to dryness, and the residue was purified by silica gel column chromatography (15% ethyl acetate/dichloromethane) to give ethyl 6-chloro-furo [3,2-c ] pyridine-2-carboxylate (300mg, 51.7%) as a white solid. LC-MS M/z (esi) ═ 226.0[ M +1].
The third step: 6-Benzylthio-furo [3,2-C ] pyridine-2-carboxylic acid ethyl ester (62C)
Reacting 6-chloro-furo [3,2-c ]]Pyridine-2-carboxylic acid ethyl ester (418mg,185mmol), benzylthiol (345mg,2.78mmol) were dissolved in 15mL toluene, N-diisopropylethylamine (718mg,5.55mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (214mg,370mmol), and tris (dibenzylideneacetone) dipalladium 43mg,185umol were added, air was replaced with nitrogen, and the mixture was heated to reflux for 18 hours. After cooling to room temperature, 50mL of water was added, extraction was performed with ethyl acetate (100 mL. times.2), and the organic layers were combined and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50:1 to 30:1) to obtain 6-benzylthio-furo [3, 2-c)]Pyridine-2-carboxylic acid ethyl ester (250mg, yield 43.1%). MS (ESI) M/z 314.1[ M +1]].1HNMR(400MHz,DMSO)δ8.96(s,1H),7.82(d,J＝0.9Hz 1H),7.78(s,1H),7.45(m,2H),7.35-7.28(m,2H),7.27-7.21(m,1H),4.49(s,2H),4.37(q,J＝7.1Hz,2H),1.33(t,J＝6.8,J＝7.1Hz,3H).
The fourth step: 6-Chlorosulfonyl-furo [3,2-c ] pyridine-2-carboxylic acid ethyl ester (62D)
Ethyl 6-benzylthio-furo [3,2-c ] pyridine-2-carboxylate (450mg,1.44mmol) was suspended in 10mL of acetic acid and 5mL of water, N-chlorosuccinimide (575mg,4.31mmol) was added in portions, and the reaction was stirred at room temperature for 10 hours. After the reaction was complete, 50mL of water was added. Ethyl acetate extraction (100 mL. times.3) and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give ethyl 6-chlorosulfonyl-furo [3,2-c ] pyridine-2-carboxylate as a pale yellow solid, (250mg, yield 61.1%). LC-MSm/z (esi) 290.0[ M +1].
The fifth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -furo [3,2-c ] pyridine-2-carboxylic acid ethyl ester (62E)
5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine (221mg,0.863mmol) was dissolved in 10mL of 1, 2-dichloroethane, and pyridine (0.39mL,4.8mmol) and ethyl 6-chlorosulfonyl-furo [3,2-c ] pyridine-2-carboxylate (250mg,0.863mmol) were added and stirred at room temperature overnight. LCMS indicated the reaction was complete and the reaction was washed with water (50mL), dried and spin dried to give the product ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -furo [3,2-c ] pyridine-2-carboxylate (100mg, 22.8%) as a pale yellow solid which was used in the next reaction without further purification.
And a sixth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxy-furo [3,2-c ] pyridine-2-carboxamide (62)
Ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -furo [3,2-c ] pyridine-2-carboxylate (100mg,0.196mmol) was dissolved in 10mL of methanol at room temperature, an aqueous hydroxylamine solution (0.12mL,2.03mmol) was added, and an aqueous solution of sodium hydroxide (24mg,5.6mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed the reaction was complete, 1M HCl was added to adjust pH to 8, the solvent was dried and the residue was purified by prep-HPLC to give example compound 62(6.5mg, 6.7%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.33(s,1H),8.00(d,J＝2.4Hz,1H),7.70(s,1H),7.58(d,J＝2.4Hz,1H),3.39(q,J＝7.0Hz,1H),3.28(m,1H),2.73(t,J＝10.24Hz,2H),1.78-1.74(m,2H),1.38-1.34(m,2H),1.05(t,J＝10.24Hz,3H).LC-MS m/z(ESI)＝496.2[M+1].
Example 636- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxybenzo [ b ] thiophene-2-carboxamide (Compound 63)
Figure BDA0002039788050000771
The first step is as follows: 6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzo [ b ] thiophene-2-carboxylic acid methyl ester (63A)
5-fluoro-2- (piperidin-1-yl) pyridin-3-amine (200mg,1.02mmol) was dissolved in 5mL of 1, 2-dichloroethane, and pyridine (0.576mL,7.15mmol) and methyl 6- (chlorosulfonyl) benzo [ b ] thiophene-2-carboxylate (1.04mg,3.58mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was washed with water (50mL), dried and spun, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50:1 to 30:1) to give methyl 6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) benzo [ b ] thiophene-2-carboxylate (339mg, 73.8%) as a pale yellow solid. LC-MS M/z (esi) 450.1[ M +1].
The second step is that: 6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxybenzo [ b ] thiophene-2-carboxamide (63)
6- (N- (5-fluoro-2- (piperidin-1-yl) pyridin-3-yl) aminosulfonyl) benzo [ b ] at room temperature]Thiophene-2-carboxylic acid methyl ester (170mg,0.377mmol) was dissolved in 5mL MeOH, 50% aqueous hydroxylamine solution (186.7mg,5.66mmol) was added, and 0.5mL aqueous NaOH (45mg,1.13mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1MHCl, spin dried, and residue by prep-HPLC (CH with 0.5% TFA)3CN/H2O) to give compound 63 as a white solid (57.4mg, 33.4%).
1H NMR(400MHz,Methanol-d4)δ8.60–8.55(m,1H),8.05(d,J＝8.5Hz,1H),7.95(d,J＝2.8Hz,1H),7.91(s,1H),7.83(dd,J＝8.5,1.7Hz,1H),7.69(dd,J＝9.5,2.9Hz,1H),2.64(t,J＝5.3Hz,4H),1.60(q,J＝5.2Hz,4H),1.55–1.48(m,2H).LC-MS m/z(ESI)＝451.0[M+1].
Examples 64 to 66
Compounds 64-66 were prepared according to the synthetic procedure of example 63.
Figure BDA0002039788050000781
Figure BDA0002039788050000791
Example 676- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -7-fluoro-N-hydroxybenzofuran-2-carboxamide (Compound 67)
Figure BDA0002039788050000792
The first step is as follows: 4-bromo-3-fluoro-2-methoxybenzaldehyde (67A)
To a solution of 4-bromo-2, 3-difluorobenzaldehyde (4.83g,21.85mmol) in 125mL of methanol was added sodium methoxide (1.77g,32.78mmol) at room temperature. The reaction was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, 100mL of ethyl acetate and 50mL of water were added to the mixture, the layers were separated, the aqueous phase was extracted 2 times with 100mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to give 4-bromo-3-fluoro-2-methoxybenzaldehyde as a pale yellow solid (5.09mg, 91.79%). LC-MSm/z (esi) 233.0,235.0[ M +1].
The second step is that: 4-bromo-3-fluoro-2-hydroxybenzaldehyde (67B)
To 4-bromo-3-fluoro-2-methoxybenzaldehyde (4.67g,20.06mmol) was added 30mL hydrobromic acid (48%) at room temperature. The reaction was heated to reflux for 18 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was diluted with 100mL of water, ethyl acetate (100mL) was added and extracted 2 times, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 20:1 to 10:1) to obtain 4-bromo-3-fluoro-2-hydroxybenzaldehyde (2.8g, 63.7%) as a product, and a pale yellow solid. LC-MS M/z (esi) ═ 219.0,221.0[ M +1].
The third step: 6-bromo-7-fluorobenzofuran-2-carboxylic acid ethyl ester (67C)
To a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (2.83g,12.9mmol) in 30ml of DMF at room temperature were added ethyl bromoacetate (3.45g,20.7mmol) and potassium carbonate (5.35g,38.8 mmol). The reaction was heated to 90 ℃ for 18 hours. After the reaction is finished, the reaction solution is concentrated under reduced pressure to remove the solvent, the residue is diluted by 100mL of water, ethyl acetate 100mL of ethyl acetate is added for extraction for 2 times, organic phases are combined, dried by anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 200: 1-100: 1) to obtain a product, namely 6-bromo-7-fluorobenzofuran-2-carboxylic acid ethyl ester (1.81g, 48.8%) and light yellow solid. LC-MS M/z (esi) ═ 287.0,289.0[ M +1].
The fourth step: 6- (benzylthio) -7-fluorobenzofuran-2-carboxylic acid ethyl ester (67D)
Ethyl 6-bromo-7-fluorobenzofuran-2-carboxylate (1.81g,6.30mmol), benzylthiol (940mg,7.57mmol) were dissolved in 30mL of toluene, N-diisopropylethylamine (2.44g,18.9mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (365mg, 630. mu. mol) and tris (dibenzylideneacetone) dipalladium (289mg, 315. mu. mol) were added, air was replaced with nitrogen, and the mixture was heated to reflux and reacted for 18 hours. After cooling to room temperature, 50mL of water was added, extraction was performed with ethyl acetate (100 mL. times.2), and the organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 100:1 to 20:1) to give ethyl 6- (benzylthio) -7-fluorobenzofuran-2-carboxylate (1.65g, yield 79.2%). Ms (esi) M/z 331.0[ M +1].
The fifth step: 6- (Chlorosulfonyl) -7-fluorobenzofuran-2-carboxylic acid ethyl ester (67E)
Ethyl 6- (benzylsulfanyl) -7-fluorobenzofuran-2-carboxylate (1.65g,4.99mmol) is suspended in 18mL of acetic acid and 6mL of water. N-chlorosuccinimide (2.67mg,20.0mmol) was added in portions at 0 ℃ and the reaction was stirred at room temperature for 10 hours. After the reaction was complete, 50mL of water was added. Ethyl acetate extraction (100 mL. times.3) and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give ethyl 6- (chlorosulfonyl) -7-fluorobenzofuran-2-carboxylate as a pale yellow solid, (250mg, 61.1% yield). The reaction mixture was used in the next reaction without further purification.
And a sixth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -7-fluorobenzofuran-2-carboxylic acid ethyl ester (67F)
5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine (210mg,0.819mmol) was dissolved in 10mL of 1, 2-dichloroethane, and pyridine (0.46mL,5.7mmol) and ethyl 6- (chlorosulfonyl) -7-fluorobenzofuran-2-carboxylate (879mg,2.87mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was washed with water (50mL), dried and spun dry, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 49: 1-10:1) to give the product ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) -7-fluorobenzofuran-2-carboxylate (234mg, 54.3%) as an off-white solid. LC-MS M/z (esi) ═ 526.1[ M +1].
The seventh step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -7-fluoro-N-hydroxybenzofuran-2-carboxamide (67)
Ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -7-fluorobenzofuran-2-carboxylate (117mg,0.222mmol) was dissolved in 10mL of methanol at room temperature, an aqueous hydroxylamine solution (110mg,3.34mmol) was added, and 0.3mL of an aqueous solution of sodium hydroxide (27mg,6.7mmol) was added dropwise with stirring and stirred at room temperature for 2 hours. LCMS showed the reaction was complete, 1M HCl was added to adjust pH to 8, the solvent was spun off, and the residue was purified by prep-HPLC to give example compound 67 as an off-white solid (54.5mg, 46.9%).
1H NMR(400MHz,Methanol-d4)δ8.02(d,J＝2.4Hz,1H),7.73(dd,J＝8.3,5.5Hz,1H),7.70–7.65(m,2H),7.61(d,J＝2.7Hz,1H),3.54(q,J＝7.0Hz,2H),3.42(tt,J＝8.5,3.9Hz,1H),3.14(dt,J＝9.9,4.1Hz,2H),2.74(ddd,J＝12.7,9.9,2.9Hz,2H),1.87(dq,J＝12.5,3.8Hz,2H),1.54(dtd,J＝12.9,9.4,3.6Hz,2H),1.20(t,J＝7.0Hz,3H).LC-MS m/z(ESI)＝513.1[M+1].
Examples 68 to 69
Compounds 68-69 were prepared according to the synthetic procedure of example 67.
Figure BDA0002039788050000811
Examples 70 to 87
Examples 70-87 were prepared according to the synthetic method of example 18.
Figure BDA0002039788050000812
Figure BDA0002039788050000821
Figure BDA0002039788050000831
Figure BDA0002039788050000841
Example 886- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -7-fluoro-N-hydroxybenzofuran-2-carboxamide (Compound 88)
Figure BDA0002039788050000842
The first step is as follows: 1-cyclohexyl-3-methyl-1H-pyrazol-5-amine (88A)
To a solution of cyclohexylhydrazine hydrochloride (500mg,3.32mmol) in 15mL of ethanol was added 3-oxobutanenitrile (414mg,4.98mmol) at room temperature. The reaction was heated to reflux for 18 hours. LCMS showed the reaction was complete, 50mL water was added, extracted with ethyl acetate (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent to give 1-cyclohexyl-3-methyl-1H-pyrazol-5-amine as a brown solid (590mg, 99.2%). LC-MS M/z (esi) 180.1[ M +1].
The second step is that: 6- (N- (1-cyclohexyl-3-methyl-1H-pyrazol-5-yl) sulfamoyl) benzofuran-2-carboxylic acid ethyl ester (88B)
1-cyclohexyl-3-methyl-1H-pyrazol-5-amine (300mg,1.67mmol) was dissolved in 15mL of 1, 2-dichloroethane, and pyridine (662mg,8.4mmol) and ethyl 6- (chlorosulfonyl) -7-fluorobenzofuran-2-carboxylate (483mg,1.67mmol) were added, followed by stirring at room temperature overnight. LCMS showed the reaction was complete, the reaction was washed with water (50mL), dried and spun dry, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 49:1 to 10:1) to give the product ethyl 6- (N- (1-cyclohexyl-3-methyl-1H-pyrazol-5-yl) sulfamoyl) benzofuran-2-carboxylate (600mg, 83.3%) as an off-white solid. LC-MS M/z (esi) ═ 432.1[ M +1].
The third step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -7-fluoro-N-hydroxybenzofuran-2-carboxamide (88)
Ethyl 6- (N- (1-cyclohexyl-3-methyl-1H-pyrazol-5-yl) sulfamoyl) benzofuran-2-carboxylate (600mg,1.39mmol) was dissolved in 10mL of methanol at room temperature, an aqueous hydroxylamine solution (919mg,13.9mmol) was added, and 1mL of an aqueous solution of sodium hydroxide (167mg,4.17mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete, adjusted to pH8 with 1M HCl and extracted with dichloromethane (200mL × 4). The organic phases are combined, dried over anhydrous sodium sulfate, 20mL of dichloromethane are added to the residue, slurried with stirring at room temperature for 1 hour, and filtered under reduced pressure. The above slurry operation was repeated on the filter cake, suction filtered and the filter cake was dried to give example compound 88 as an off-white solid (550mg, 94.6%).
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.40(s,1H),9.44(s,1H),8.00(d,J＝8.3,1H),7.93(s,1H),7.68(d,J＝8.3Hz,1H),7.61(s,1H),5.52(s,1H),3.87-3.73(m,1H),2.01(s,3H),1.68-1.57(m,2H),1.57-1.45(m,3H),1.35-1.20(m,2H),1.14-0.97(m,3H).LC-MS m/z(ESI)＝419.0[M+1].
Examples 89 to 97
Compounds 89-97 were prepared according to the synthetic procedure of example 88.
Figure BDA0002039788050000851
Figure BDA0002039788050000861
Example 986- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) -N-hydroxy-3-methylbenzofuran-2-carboxamide (Compound 98)
Figure BDA0002039788050000862
The first step is as follows: 6-bromo-3-methylbenzofuran-2-carboxylic acid ethyl ester (98A)
1- (4-bromo-2-hydroxy-phenyl) ethanone (2.0g,9.30mmol) was dissolved in 30mL of DMF at room temperature, potassium carbonate (3.85g,27.9mmol) and ethyl bromoacetate (1.86g,11.2mmol) were added, the mixture was heated to 90 ℃ for reaction for 3 hours, and LC-MS monitoring indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was added to 100g of ice water and the residue was dissolved in 100mL of ethyl acetate, the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (100mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and then spun, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 99:1 to 49:1) to give 98A pale yellow solid (2.63g, 22.0%). LC-MS M/z (esi) ═ 282.9,284.9[ M +1].
The second step is that: 6- (benzylthio) -3-methylbenzofuran-2-carboxylic acid ethyl ester (98B)
Ethyl 6-bromo-3-methylbenzofuran-2-carboxylate (580mg,2.05mmol), benzylthiol (150mg,2.46mmol) were dissolved in 15mL of toluene, N-diisopropylethylamine (794.3mg,6.15mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (237mg,410umol) and tris (dibenzylideneacetone) dipalladium (188mg,205umol) were added, air was replaced with nitrogen, and the mixture was heated to reflux for 18 hours. After cooling to room temperature, 50mL of water was added, extraction was performed with ethyl acetate (100 mL. times.2), and the organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50:1-30:1) to give ethyl 6- (benzylthio) -3-methylbenzofuran-2-carboxylate as an off-white solid (300mg, yield 44.9%). LC-MS M/z (esi) 327.2[ M +1].
The third step: 6- (Chlorosulfonyl) -3-methylbenzofuran-2-carboxylic acid ethyl ester (98C)
Ethyl 6- (benzylthio) -3-methylbenzofuran-2-carboxylate (200mg,613umol) was suspended in 6mL of acetic acid and 2mL of water, and N-chlorosuccinimide (327mg,2.45mmol) was added in portions, and the reaction was stirred at room temperature for 5 hours. After the reaction was complete, 50mL of water was added. Ethyl acetate extraction (100 mL. times.3) and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give ethyl 6- (chlorosulfonyl) -3-methylbenzofuran-2-carboxylate 98C as a pale yellow solid, (177mg, 95.4% yield). Used in the next step without further purification.
The fourth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -3-methylbenzofuran-2-carboxylic acid ethyl ester (98D)
Ethyl 6- (chlorosulfonyl) -3-methylbenzofuran-2-carboxylate (177mg,0.585mmol) was dissolved in 10mL of DCM, and pyridine (139mg,1.75mmol) and 5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine 18B (150mg,0.585mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete, 100mL dichloromethane was added, the layers were separated, the organic phase was washed with water (50mL), dried and spun dry. Ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -3-methylbenzofuran-2-carboxylate as a pale yellow solid (200mg, 65.5%) was used directly in the next reaction. LC-MS M/z (esi) ═ 522.2[ M +1].
The fifth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxy-3-methylbenzofuran-2-carboxamide (98)
Ethyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -3-methylbenzofuran-2-carboxylate 98D (200mg,0.383mmol) was dissolved in 10mL MeOH at room temperature, an aqueous hydroxylamine solution (0.4mL,6.93mmol) was added, 0.3mL of an aqueous NaOH (86mg,2.16mmol) was added dropwise with stirring, and stirring was carried out at room temperature for 2 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 98 as a white solid (50mg, 25.6%). LC-MS M/z (ESI) ═ 509.1[ M +1].
Example 996- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminesulfonyl) -N-hydroxy-3-methoxybenzo [ b ] thiophene-2-carboxamide (Compound 99)
Figure BDA0002039788050000881
The first step is as follows: 6-bromo-3-hydroxybenzo [ b ] thiophene-2-carboxylic acid methyl ester (99A)
Methyl 4-bromo-2-fluorobenzoate (2.0g,8.58mmol) was dissolved in 20mL of DMF at room temperature, lithium hydroxide (411mg,17.2mmol) and ethyl thioglycolate (911mg,8.58mmol) were added, the reaction was stirred for 13 hours, and LC-MS monitoring indicated completion of the reaction. Cooled to room temperature, 1M hydrochloric acid was added dropwise to neutralize the reaction and precipitate, which was filtered to give 99A, a white solid (1.57g, 63.7%).
The second step is that: 6-bromo-3-methoxybenzo [ B ] thiophene-2-carboxylic acid methyl ester (99B)
Methyl 6-bromo-3-hydroxybenzo [ b ] thiophene-2-carboxylate (1.57g,5.47mmol) was dissolved in 15mL of DMF at room temperature, and potassium carbonate (1.51g,10.9mmol) and iodomethane (1.55g,10.9mmol) were added to react at room temperature for 18 hours. 100mL of water was added, extraction was performed with ethyl acetate (100 mL. times.2), and the organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 100:1-10:1) to give methyl 6- (benzylthio) -3-methylbenzo [ b ] thiophene-2-carboxylate as a yellow solid (1.90g, yield 80.6%). LC-MS M/z (esi) ═ 301.0,303.0[ M +1].
The third step: 6- (benzylthio) -3-methoxybenzo [ b ] thiophene-2-carboxylic acid methyl ester (99C)
Methyl 6-bromo-3-methoxybenzo [ b ] thiophene-2-carboxylate (1.90g,6.30mmol), benzylthiol (460mg,7.56mmol) were dissolved in 15mL of toluene, N-diisopropylethylamine (2.44g,18.9mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (729mg,1.26mmol), and tris (dibenzylideneacetone) dipalladium (576mg, 630. mu. mol) were added, the air was replaced with nitrogen, and the mixture was heated to reflux for 18 hours. After cooling to room temperature, 50mL of water was added, extraction was performed with ethyl acetate (100 mL. times.2), and the organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 20:1-10:1) to give methyl 6- (benzylthio) -3-methoxybenzo [ b ] thiophene-2-carboxylate as a yellow solid (500mg, yield 23.0%). LC-MS M/z (esi) ═ 344.9[ M +1].
The fourth step: 6- (Chlorosulfonyl) -3-methoxybenzo [ b ] thiophene-2-carboxylic acid methyl ester (99D)
Methyl 6- (benzylthio) -3-methoxybenzo [ b ] thiophene-2-carboxylate 99C (200mg, 581. mu. mol) was suspended in 6mL of acetic acid and 2mL of water, and N-chlorosuccinimide (310mg,2.32mmol) was added in portions, and the reaction was stirred at room temperature for 5 hours. After the reaction was complete, 50mL of water was added. Ethyl acetate extraction (100 mL. times.3) and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give methyl 6- (chlorosulfonyl) -3-methoxybenzo [ b ] thiophene-2-carboxylate 99D as a pale yellow solid, (186mg, 99.9% yield). Used in the next step without further purification.
The fifth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -3-methoxybenzo [ b ] thiophene-2-carboxylic acid methyl ester (99E)
Methyl 6- (chlorosulfonyl) -3-methoxybenzo [ B ] thiophene-2-carboxylate 99D (167mg,0.520mmol) was dissolved in 10mL of DCM, and pyridine (150mg,1.89mmol) and 5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-amine 18B (133mg,0.52mmol) were added and stirred at room temperature overnight. LCMS showed the reaction was complete, 100mL dichloromethane was added, the layers were separated, the organic phase was washed with water (50mL), dried and spun dry. Methyl 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -3-methoxybenzo [ b ] thiophene-2-carboxylate as a pale yellow solid (170mg, 60.5%) was used directly in the next reaction. LC-MS M/z (esi) 540.1[ M +1].
And a sixth step: 6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) sulfamoyl) -N-hydroxy-3-methoxybenzo [ b ] thiophene-2-carboxamide (99)
6- (N- (5-chloro-2- (4-ethoxypiperidin-1-yl) pyridin-3-yl) aminosulfonyl) -3-methoxybenzo [ b ] at room temperature]Thiophene-2-carboxylic acid methyl ester 99E (170mg,0.315mmol) was dissolved in 10mL MeOH, 50% aqueous hydroxylamine solution (300mg,6.8mmol) was added, 0.2mL aqueous NaOH (50mg,1.25mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction completion, pH8 adjusted with 1M HCl, spin dried, residue by prep-HPLC (0.5% TFA in CH)3CN/H2O) to give compound 99 as a white solid (32mg, 18.8%). LC-MS M/z (ESI) ═ 541[ M +1]].
The following test examples specifically illustrate the advantageous effects of the present invention:
test example 1 acetylation Activity of alpha-tubulin
HCT116 cells in logarithmic growth phase were seeded in 96-well clear-bottom blackboards (Corning # 3340). After overnight cell culture, compounds were added at different concentrations to treat the cells, with final concentrations of 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003uM, and DMSO controls were provided, with 3 replicates for each compound. The cell culture plate was placed in a carbon dioxide incubator for an additional 6 hours.
After 6 hours of compound treatment, the well plates were discarded and 200ul of 4% (w/v) PFA (dissolved in PBS buffer (aMRESCO # E404-200TABS) and pH adjusted to 7.4) was added to immobilize the cells and incubated at room temperature for 15 minutes. PFA was discarded, 200ul of 0.1% (v/v) TritonX-100 (dissolved in PBS buffer) was added to permeabilize the cells, and incubated for 15 minutes at room temperature. TritonX-100 was discarded and 100ul of 1% (w/v) blocking solution (Roche #11096176001, dissolved in TBS solution (20mM Tris-HCl, 150mM NaCl, pH 8.0)) was added to each well. Incubate 30 minutes at room temperature with shaking at 300 rpm. The acetylated tubulin antibody (Sigma-Aldrich # T6793) was diluted 1% (w/v) in blocking solution at a 1:2000 dilution ratio, 50ul of the diluted antibody was pipetted into all wells of the cell plate and incubated overnight at 4 ℃. The following day 200ul wash (0.05% PBST) was pipetted into each well and the plate was washed 4 times. Goat anti-mouse fluorescent secondary antibody (Invitrogen # F-2761) was diluted with 1% (w/v) blocking solution at a 1:500 dilution and DAPI (Themolfisher #62247) at a 1:2000 dilution. 50ul of diluted antibody was pipetted into all wells of the cell plate and incubated with shaking at 300rpm in the dark at room temperature for 120 minutes. Pipette 200ul of wash solution (0.05% PBST) into each well and repeat the plate wash 4 times. And (5) wrapping the plate with tin foil paper to prevent light to be detected after the plate is washed.
Data were acquired using a high content imaging analysis system In Cell Analyzer (GE #2200) and data analysis was performed using In Cell Analyzer work software. Normalized cell grey values obtained after treatment at each concentration of each compound (intensity (N + C) divided by normalized cell grey values after negative control (DMSO treatment) (intensity (N + C), respectively, to obtain fold-changes in acetylated tubulin relative to negative control after treatment with different compounds, and EC relative to log concentration was fitted and calculated in GraphPad Prism software50。
The acetylation activity of α -tubulin of HCT116 cells was measured for the compounds prepared in the previous examples according to the above-described method, and the results of the test are shown in Table 1, in which the EC of each compound was determined50Classified as per the description.
TABLE 1 acetylation activity of compounds on alpha-tubulin
Figure BDA0002039788050000901
Figure BDA0002039788050000911
Note: "+" indicates EC50More than 1uM and less than 100 uM; "+ +" indicates EC50Greater than 300nM and less than 1000 nM; "+ + + +" denotes EC50Less than 300 nM.
Test results show that the compound has good deacetylase inhibitory activity on tubulin, and can be effectively used for treating diseases related to tubulin action and diseases related to histone deacetylase 6 abnormity.
Test example 2 acetylation Activity of Histone3
HCT116 cells in logarithmic growth phase were seeded in 96-well clear-bottom blackboards (Corning # 3340). After overnight cell culture, compounds were added at different concentrations to treat the cells, with final concentrations of 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003uM, and DMSO controls were provided, with 3 replicates for each compound. The cell culture plate was placed in a carbon dioxide incubator for further 24 hours.
After 24 hours of compound treatment, the plate was discarded, 200ul of pre-cooled methanol fixed cells were added and incubated for 15 minutes at room temperature. Methanol was discarded, 200ul of 0.1% (v/v) TritonX-100 (dissolved in PBS buffer) was added to permeabilize the cells, and incubated for 15 minutes at room temperature. TritonX-100 was discarded and 100ul of 1% (w/v) blocking solution (Roche #11096176001, dissolved in TBS solution (20mM Tris-HCl, 150mM NaCl, pH 8.0)) was added to each well. Incubate 30 minutes at room temperature with shaking at 300 rpm. The acetylated histone H3 antibody (Abcam # ab47915) was diluted with 1% (w/v) blocking solution at a dilution ratio of 1:1000, 50ul of the diluted antibody was pipetted into all wells of the cell plate and incubated overnight at 4 ℃. The following day 200ul wash (0.05% PBST) was pipetted into each well and the plate was washed 4 times. Goat anti-rabbit fluorescent secondary antibody (Invitrogen # A11034) was diluted with 1% (w/v) blocking solution at A1: 500 dilution ratio and DAPI (Themolfisher #62247) at A1: 2000 dilution ratio. 50ul of diluted antibody was pipetted into all wells of the cell plate and incubated with shaking at 300rpm in the dark at room temperature for 120 minutes. Pipette 200ul of wash solution (0.05% PBST) into each well and repeat the plate wash 4 times. And (5) wrapping the plate with tin foil paper to prevent light to be detected after the plate is washed.
Data were acquired using a high content imaging analysis system In Cell Analyzer (GE #2200) and data analysis was performed using In Cell Analyzer work software. Normalized cellular gray values obtained after treatment at each concentration of each compound (intensity (N + C) divided by normalized cellular gray values after negative control (DMSO treatment) (intensity (N + C), respectively, were obtained as fold changes of acetylated histone H3 relative to negative control after treatment with different compounds, and EC50 relative to log concentration was fitted and calculated in GraphPad Prism software.
The acetylation activity of Histone3 of HCT116 cells was measured for the compounds prepared in the previous examples according to the method described above, and the results are shown in Table 1, in which the EC of each compound was determined50Classified as per the description.
Figure BDA0002039788050000921
Figure BDA0002039788050000931
The test result shows that the compound has weaker deacetylase inhibitory activity on histone3, so that the compound has higher selectivity on HDAC6, and can avoid or reduce toxic effects related to histone while effectively treating diseases.

Claims (18)

1. A compound represented by formula I, or a pharmaceutically acceptable salt thereof:
Figure FDA0003454681440000011
wherein,
x is selected from O, S;
X1selected from N, CR2；
R is respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORaHalogen-substituted C1～C10An alkyl group;
R1each independently selected from hydrogen, halogen, cyano, nitro;
R2each independently selected from hydrogen;
each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group;
R4is selected from-NRhRi、-ORc、-SRc、-(CH2)rRc4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
r is 0, 1,2 or 3;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
Rh、Riare each independently selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, wherein the cycloalkyl, heterocycle may be substituted with m RdSubstitutionEach RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, ═ O, -ORe、-NReRf0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
Rcselected from 3-10 membered cycloalkyl and 3-10 membered heterocycle, wherein the cycloalkyl and heterocycle can be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, ═ O, -ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
wherein when X is1Is CH, ring A is
Figure FDA0003454681440000021
R4Is composed of
Figure FDA0003454681440000022
When n and m are not 0 at the same time.
2. The compound of claim 1, wherein: a compound of formula I is represented by formula II:
Figure FDA0003454681440000023
wherein,
x is selected from O, S;
X1selected from N, CR2；
R is respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORaHalogen-substituted C1～C10An alkyl group;
R1each independently selected from hydrogen, halogen, cyano, nitro;
R2each independently selected from hydrogen;
each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group;
the B ring is selected from 4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
wherein when X is1Is CH,
Figure FDA0003454681440000031
Is composed of
Figure FDA0003454681440000032
When m is not 0.
3. The compound of claim 2, wherein: the compound of formula II is:
Figure FDA0003454681440000033
Figure FDA0003454681440000041
4. the compound of claim 1, wherein: a compound of formula I is represented by formula III:
Figure FDA0003454681440000042
wherein,
x is selected from O, S;
X1selected from N, CR2；
R is respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORaHalogen-substituted C1～C10An alkyl group;
R1each independently selected from hydrogen, halogen, cyano, nitro;
R2each independently selected from hydrogen;
each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group;
the B ring is selected from 4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle.
5. The compound of claim 4, wherein: the compound of formula III is:
Figure FDA0003454681440000051
Figure FDA0003454681440000061
Figure FDA0003454681440000071
Figure FDA0003454681440000081
Figure FDA0003454681440000091
6. the compound of claim 1, wherein: a compound of formula I is represented by formula IV:
Figure FDA0003454681440000092
wherein,
x is selected from O, S;
r is respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORaHalogen-substituted C1～C10An alkyl group;
R1each independently selected from hydrogen, halogen, cyano, nitro;
each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
Rh、Riare each independently selected from C1～C10Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycle, wherein the cycloalkyl, heterocycle may be substituted with m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, ═ O, -ORe、-NReRf0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group.
7. The compound of claim 6, wherein: the compound of formula IV is:
Figure FDA0003454681440000101
8. the compound of claim 1, wherein: a compound of formula I is represented by formula V:
Figure FDA0003454681440000102
wherein,
x is selected from O, S;
r is respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORaHalogen-substituted C1～C10An alkyl group;
R1each independently selected from hydrogen, halogen, cyano, nitro;
each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle;
Rcselected from 3-10 membered cycloalkyl and 3-10 membered heterocycle, wherein the cycloalkyl and heterocycle can be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, ═ O, -ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group.
9. The compound of claim 8, wherein: the compound of formula V is:
Figure FDA0003454681440000111
10. the compound of claim 1, wherein: a compound of formula I is represented by formula VI:
Figure FDA0003454681440000112
in the formula,
x is selected from O, S;
r is respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORaHalogen-substituted C1～C10An alkyl group;
R1each independently selected from hydrogen, halogen, cyano, nitro;
each R3Are respectively and independently selected from hydrogen, halogen, cyano, nitro and C1～C10Alkyl, -ORa、-NRaRbHalogen-substituted C1～C10An alkyl group;
the ring A is selected from a 5-10-membered aromatic ring and a 5-10-membered aromatic heterocycle;
n is 0, 1,2 or 3;
Ra、Rbeach independently selected from hydrogen and C1～C10An alkyl group;
R4selected from 4-10 membered cycloalkyl, 3-10 membered heterocycle, 6-12 membered spirocycle, 6-12 membered heterospirocycle, 6-10 membered bridged ring, 6-10 membered heterobridged ring, wherein the cycloalkyl, heterocycle, spirocycle, heterospirocycle, bridged ring, heterobridged ring may be substituted by m RdSubstituted, each RdIndependently selected from halogen, cyano, nitro, C1～C10Alkyl, 3-to 10-membered cycloalkyl, ═ O ORe、-NReRf、-OC(O)Ra、-NRaC(O)Rb、-NRaS(O)2Rb、-S(O)2Rb、-S(O)2NRaRb、-C(O)Rb、-C(O)ORb、-C(O)NRaRb0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
m is 0, 1,2 or 3;
Re、Rfare respectively and independently selected from hydrogen and C1～C10Alkyl, 3-to 10-membered cycloalkyl, substituted with 0 to 3RgSubstituted C1～C10Alkyl, halogen substituted C1～C10An alkyl group;
each RgAre each independently selected from-ORa、-NRaRb5-10 membered aromatic ring, 5-10 membered aromatic heterocycle.
11. The compound of claim 10, wherein: the compound of formula VI is:
Figure FDA0003454681440000121
12. use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the HDAC inhibitor class.
13. Use according to claim 12, characterized in that: the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
14. Use according to claim 13, characterized in that: the cell proliferative disease is cancer.
15. Use according to claim 14, characterized in that: the cancer is selected from colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, and thyroid cancer.
16. Use according to any one of claims 12 to 15, characterized in that: the HDAC is HDAC 6.
17. A pharmaceutical composition characterized by: the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials.
18. The composition of claim 17, wherein: the preparation is an oral preparation, a transdermal absorption preparation or an injection preparation.
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