CN116253730A - PROTAC compound for targeted degradation of HDAC7 protein and preparation method and application thereof - Google Patents

PROTAC compound for targeted degradation of HDAC7 protein and preparation method and application thereof Download PDF

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CN116253730A
CN116253730A CN202310202287.5A CN202310202287A CN116253730A CN 116253730 A CN116253730 A CN 116253730A CN 202310202287 A CN202310202287 A CN 202310202287A CN 116253730 A CN116253730 A CN 116253730A
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董晓武
金宇恒
曹戟
蒋莉
车金鑫
何俏军
齐旭鑫
张竞宇
于晓丽
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Abstract

The invention discloses a PROTAC compound for targeted degradation of HDAC7 protein, a preparation method and application thereof. The PROTAC compound for degrading the HDAC7 protein in a targeted manner has the potential of degrading the HDAC7 on NB4 cells, has obvious proliferation inhibition activity on acute myeloid lymphoblastic leukemia and various diffuse large B lymphocyte lines, and has wide application prospects in the aspects of treating AML and DLBCL and exploring the biological functions of the HDAC7 as a tool molecule.

Description

PROTAC compound for targeted degradation of HDAC7 protein and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a target degradation HDAC7 protein PROTAC compound, a preparation method thereof and application thereof in the field of anti-tumor.
Background
HDAC (Histone Deacetylase) A full-name histone deacetylase belongs to an epigenetic regulatory factor, and has the main effect of deacetylating lysine residues on histones. Of the 11 classical HDACs that rely on zinc ion domains, are largely classified into 4 classes. Class I HDACs have HDACs 1,2,3,8; class IIa HDAC has HDAC4, HDAC5, HDAC7, HDAC9; class IIb HDAC has HDAC6, HDAC10; class IV HDACs have HDAC11. Class IIa HDACs regulate cellular and developmental processes primarily through enzymatic and non-enzymatic mechanisms.
Over the last 20 years, HDAC7 proteins have been extensively studied and have been shown to play a critical regulatory role in many physiological and pathological processes. Through a series of molecular, cellular, in vivo and disease-related studies, HDAC7 plays a key regulatory role in diseases such as immune system diseases, renal cancer, non-small cell lung cancer, colon cancer, gastric cancer, multiple myeloma and the like through various mechanisms. The HDAC7 protein controls functions of development, angiogenesis, immunoregulation, inflammation, metabolism and the like by regulating gene expression, cell proliferation, differentiation, survival and the like. In summary, HDAC7 has an inseparable relationship with cancer, inflammatory, metabolic and fibrotic diseases. However, the mechanism of action as an epigenetic metal catalytic enzyme is not clear for class IIa HDACs, and first, histones may not be their catalytic substrates. The literature shows that the deacetylation function of lysine on the histone of class IIa HDAC is about 1000-fold weaker than that of class I HDAC. Thus, some researchers suggested that class IIa HDAC may function as a chaperone for class I HDAC, or that it may exist as an undiscovered catalytic novel substrate. At present, small molecule inhibitors of IIa HDAC mainly comprise TMP269, TMP195, CHDI-390576, NVS-HD1 and other compounds, but the compounds cannot selectively inhibit HDAC7 protein, meanwhile, the proliferation inhibition effect at the cell level is generally weak, the ideal therapeutic effect is difficult to achieve, and further pharmaceutical research is impossible.
The action mechanism of the proteolytic targeting chimeric (PROTAC) is different from that of the traditional small molecule inhibitor, which can inhibit the function (occupying drive) of the target protein by combining with the active site of the target protein, and the target protein is degraded by mainly utilizing the inherent ubiquitin-proteinase system in vivo (event drive), so that the aim of treatment is fulfilled. PROTAC is a bifunctional molecule, and consists of three parts, namely a small molecule ligand of target protein, an E3 ubiquitin protein ligase ligand and a connecting chain for connecting the two. The degradation of the target protein by the PROTAC can not exert the kinase and non-kinase functions of the target protein, and has a great advantage compared with the small molecule inhibitor which can only inhibit the kinase function. No PROTAC molecule directly related to HDAC7 is reported. Therefore, there is a need to develop a PROTAC class of compounds that target degradation of HDAC7 proteins.
Disclosure of Invention
The invention aims to provide a PROTAC compound for targeted degradation of HDAC7 protein, a preparation method and application thereof, wherein the PROTAC compound for targeted degradation of HDAC7 protein has the capability of obviously degrading HDAC7 at the concentration of 1 mu M in NB4 cells and has a certain proliferation inhibition capability on NB4 cells. Can be used as potential acute myeloid lymphoblastic leukemia and diffuse large B-cell lymphoblastic leukemia drug for development, and has wide application prospect.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a PROTAC class compound targeted to degrade HDAC7 protein, the PROTAC class compound targeted to degrade HDAC7 protein having a structural formula shown in the following formula (I):
Figure BDA0004109444430000021
or a stereoisomer or a pharmaceutically acceptable salt thereof;
wherein:
linker is a linking group selected from one or more of the following groups: straight-chain or branched alkyl, alkoxy, alkylamino, alkenyl, alkynyl, alkenylene, alkynylene, alkynyloxy, alkynylamino, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, and cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, -CO (CH) 2 ) n -、-CO(CH 2 ) n O-、-(CH 2 ) n NH 2 -、-(CH 2 ) n NR 1 -、-CO(CH 2 ) n NH-、-CO(CH 2 ) n NR 1 -、-(CH 2 ) n CONH(CH 2 ) n -、-(CH 2 ) n CONH(CH 2 ) n NH- 、 -(CH 2 ) n CONH(CH 2 ) n NR 1 - 、-CO(CH 2 ) n NHCO(CH 2 ) n - 、 -CO(CH 2 ) n NHCO(CH 2 ) n NH- 、-CO(CH 2 ) n NHCO(CH 2 ) n NR 1 -、-CO(CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n -、-CO(CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NH-、-CO(CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NR 1 -、-CH 2 (CH 2 OCH 2 ) n CH 2 -、-CH 2 (CH 2 OCH 2 ) n CH 2 NH-、-CH 2 (CH 2 OCH 2 ) n CH 2 NR 1 -、-CH 2 (CH 2 OCH 2 ) n CH 2 O-、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NH-、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NR 1 - 、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NH- 、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NR 1 - 、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CO-、-CH 2 (CH 2 OCH 2 ) n CH 2 CO-or any combination thereof,
n represents a natural number of 1 to 20;
R 1 is H or C 1-10 An alkyl group.
Linker is a linking group selected from one or more of the following groups such as polyhaloheterocycle, alkenyl, alkynyl, alkynyloxy, alkynylamino, polycycloalkyl, polyspirocyclic alkyl, polyspirocyclic cycloalkyl, polyspirocyclic, halogenated aromatic ring or any combination thereof, wherein the ring system combination is any combination of 1-4 ring systems, the ring system size is varied from four-membered ring to six-membered ring, and the ring system types include bridged ring, spiro ring and fused ring. Including but not limited to the following structures:
Figure BDA0004109444430000041
e3 ligand is an E3 ligase ligand selected from one of the following ligands:
Figure BDA0004109444430000042
further, the HDAC7-PROTAC compound provided by the invention is a compound shown in the following formula or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and the specific structure is shown in table 1.
TABLE 1 PROTAC class compound overview targeted to degradation of HDAC7 protein
Figure BDA0004109444430000051
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Figure BDA0004109444430000061
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Figure BDA0004109444430000071
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Figure BDA0004109444430000081
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Figure BDA0004109444430000091
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Figure BDA0004109444430000101
In a second aspect of the present invention, there is provided a pharmaceutical composition for treating acute myeloid lymphoblastic leukemia and diffuse large B-cell lymphoma, comprising the protoc compound targeted to degrade HDAC7 protein or a pharmacologically or physiologically acceptable stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions also include a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. The dosage forms of the pharmaceutical composition are mainly injection, oral administration and mucous membrane administration.
The pharmaceutical composition further comprises other medicines with the effect of treating or preventing acute myeloid leukemia or diffuse large B-cell lymphoma.
In a third aspect of the present invention, there is provided a method for preparing the protoc compound targeted to degrade HDAC7 protein, the method comprising:
the PROTAC compounds of the target degradation HDAC7 mutant protein are divided into A, B, C, D compounds, wherein,
the class A PROTAC compound is a compound shown in a general formula (I), linker is a piperidine formic acid derivative with different lengths and sizes, and E3 ligand is a 4-substituted amine derivative.
The class B PROTAC compound is a compound shown in a general formula (I), the Linker is a benzoic acid derivative with different lengths and sizes, and the E3 ligand is a 4-substituted amine derivative.
The C-class PROTAC compound is a compound shown in a general formula (I), the Linker is a nitrogenous heterocyclic derivative with different lengths and sizes, and the E3 ligand is a 4-substituted amine derivative.
4.D PROTAC compounds are compounds shown in a general formula (I), the linker is PEG chains with different degrees and sizes, and the E3 ligand is a 3-substituted amine derivative or VHL ligand.
The preparation route of class a PROTAC compounds is as follows:
Figure BDA0004109444430000111
dissolving the compound 8 in dichloromethane, adding trifluoroacetic acid to remove a Boc protecting group, and condensing with 1-Boc-4-piperidinecarboxylic acid under the conditions of HATU and DIPEA to obtain a compound 9, and removing Boc from the compound 9 under the condition of trifluoroacetic acid to obtain a compound 10. And carrying out nucleophilic reaction on the compound 11 and various nitrogen-containing heterocycles under the DIPEA condition to obtain 12a-d, and oxidizing the compound by using DMP to obtain 13a-d. And carrying out reductive amination on the compound 10 and the compounds 13a-d under the condition of sodium cyanoborohydride and glacial acetic acid to obtain four compounds A1-A4.
The preparation route of the class B PROTAC compound is as follows:
Figure BDA0004109444430000121
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Figure BDA0004109444430000131
dissolving the compound 8 in dichloromethane, adding trifluoroacetic acid to remove a Boc protecting group, and condensing with 1-Boc-4- (4-carboxyphenyl) piperidine or 1-Boc-4- (4-carboxyphenyl) piperazine under the condition of HATU and DIPEA to obtain compounds 14a-b, wherein the compounds 14a-b remove Boc under the condition of trifluoroacetic acid to obtain compounds 15a-b. The compounds 15a-B and the compounds 13a-d were subjected to reductive amination under sodium cyanoborohydride and glacial acetic acid to obtain four compounds B1-B4.
The preparation route of the class C PROTAC compound is as follows:
Figure BDA0004109444430000141
dissolving the compound 8 in dichloromethane, adding trifluoroacetic acid to remove a Boc protecting group, and then carrying out reductive amination on the Boc protecting group and an aldehyde derivative under the conditions of sodium cyanoborohydride and glacial acetic acid to obtain compounds 16a-d, and removing the Boc of the compounds 16a-d under the condition of trifluoroacetic acid to obtain compounds 17a-d. Carrying out reductive amination on the compounds 17a-d and the compounds 13a-d under the condition of sodium cyanoborohydride and glacial acetic acid to obtain five compounds C1-5; compound 11 is reacted with tert-butyl ester derivative under basic conditions to give compounds 18a-b, and the Boc protecting group is removed under trifluoroacetic acid conditions to give 19a-b. The compounds 17a-d and the compounds 19a-b undergo an acid amine condensation reaction under the conditions of HATU and DIPEA to obtain six compounds of C6-C11. The preparation route of class D PROTAC compounds is as follows:
Figure BDA0004109444430000151
and respectively removing Boc protecting groups from the compounds 20a-b and the compounds 21a-b, performing acid-amine condensation under the conditions of HATU and DIPEA to obtain a compound D1-2, respectively removing Boc protecting groups from the compounds 21c and the compounds 22, and performing acid-amine condensation under the conditions of HATU and DIPEA to obtain a compound D3.
The invention has the beneficial effects that:
a series of compounds are synthesized and screened, and the compounds are novel HDAC7-PROTAC degradation agents. The inventor proves that the novel HDAC7-PROTAC degradation agent provided by the invention has obvious degradation effect on HDAC7 in NB4 cells through a western blot experiment, further proves that the series of compounds effectively inhibit cell proliferation of NB4, DHL2 and Jeko-2 through a cell proliferation inhibition experiment, and the positive compound TMP269 has weaker or no obvious inhibition proliferation on the cells, so that the scope of indication is further developed, and the novel HDAC7-PROTAC has the potential of treating acute myeloid lymphoblastic leukemia and diffuse large B lymphoblastic leukemia.
Drawings
FIG. 1: proliferation inhibition of compounds of the invention on SU-DHL4 cells;
fig. 2: proliferation inhibition of compounds of the invention on SU-DHL2 cells;
fig. 3: preliminary pharmacokinetics of the compounds of the invention in ICR mice.
Detailed Description
The following detailed description of some embodiments of the invention is provided merely as an example and is intended to provide a detailed illustration of the invention in order to facilitate an understanding of the invention and is not to be construed as limiting the invention.
Throughout the description of the examples, the materials, methods, and terms of art used are those which are recognized in the art and unless otherwise indicated, the description of the invention will take place in the presence of an ambiguity. The various raw materials, reagents, instruments, equipment, etc. used in the present invention are commercially available or available by existing methods unless otherwise specified.
The specific synthesis mode and related biological evaluation data of the examples are used for explaining the novel PROTAC compound targeted to degrade the HDAC7 protein, the preparation method thereof and the application thereof in acute myeloid lymphoblastic leukemia and diffuse large B-lymphoblastic leukemia in detail.
Example 1
Synthesis of POI Targeted molecule 1
Figure BDA0004109444430000171
Step one: preparation of 3- (N-hydroxyureido) benzoic acid (Compound 2)
3-Cyanobenzoic acid (Compound 1,20.0g,0.1 mol) was dissolved in 1000mL of ethanol solution, aqueous solution (150 mL) of hydroxylamine hydrochloride (19.0 g,0.3 mol), aqueous solution (150 mL) of sodium carbonate (24.0 g,0.2 mol), 8-hydroxyquinoline (100.0 mg,0.7 mmol) were added sequentially, reflux-stirring was performed at 80℃for 4 hours, the spin-dried solvent was diluted with water, 2N HCl was added to acidify to pH 3 or so, precipitation of a white solid was seen, washing with water and acetone was performed sequentially, and drying under reduced pressure was performed to obtain a white solid of 18.2g, yield: 76%; ESI-MS 179.1[ M-H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ9.77(s,1H),8.28(t,J＝1.8Hz,1H),7.95(dt,J＝7.7,1.5Hz,1H),7.90(dt,J＝7.8,1.5Hz,1H),7.51(t,J＝7.8Hz,1H),5.94(s,2H)。
Step two: preparation of 3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzoic acid (Compound 3)
3- (N-hydroxyureido) benzoic acid (compound 2,5.0g,27.8 mmol) is dissolved in 100mL of anhydrous pyridine solution, cooled to 0 ℃, and trifluoromethyl acetic anhydride (11.6 mL,83.4 mmol) is slowly added dropwise, the temperature is raised to 50 ℃ after the addition is finished, the reaction is carried out for 3 hours, 2N HCl is added under the ice bath condition, the pH value is acidified to 3-4, water is added for dilution, the ethyl acetate is used for multiple extraction, an organic layer is combined, silica gel is mixed, a spin-dry solvent is used, PE is used for purifying through a column according to EA=3:1, and 3.5g of white solid is obtained, and the yield is 49%; ESI-MS 257.1[ M-H ]] - ； 1 H NMR(500MHz,DMSO-d6)δ13.46(s,1H),8.57(q,J＝1.8Hz,1H),8.35–8.28(m,1H),8.22(dq,J＝7.8,1.5Hz,1H),7.78(m,1H)。
Step three: preparation of 2- (4-phenylthiazol-2-yl) acetonitrile (Compound 5)
Sequentially dissolving 2-cyanothioacetamide (compound 4,10.1g,0.1 mol) and 2-bromoacetophenone (20.0 g,0.1 mol) in 400mL of absolute ethanol, refluxing at 80 ℃ for 4 hours, adding saturated sodium bicarbonate aqueous solution, adjusting pH to be alkaline, extracting with EA for multiple times, combining organic layers, mixing the organic layers with silica gel, spin-drying the solvent, purifying PE with EA=10:1 by column to obtain yellow solid with 18.9g, yield of 95%；ESI-MS:201.1[M+H] + ； 1 H NMR(500MHz,DMSO-d6)δ8.14(s,1H),8.03–7.93(m,2H),7.49–7.43(m,2H),7.41–7.33(m,1H),4.65(s,2H)。
Step four: preparation of tert-butyl 4-cyano-4- (4-phenylthiazol-2-yl) piperidine-1-carboxylate (Compound 6)
2- (4-phenylthiazol-2-yl) acetonitrile (Compound 5,5.0g,25.0 mmol) was dissolved in anhydrous DMF, sodium hydride (1.8 g,75.0 mmol) was added under ice-bath conditions, reacted at room temperature for 1h, tert-butyl bis (2-chloroethyl) carbamate (9.0 g,37.5 mmol) was added, reacted at 80℃for 3h, diluted with saturated ammonium chloride solution, extracted multiple times with EA, combined organic layers, stirred silica gel, spin-dried solvent, PE: ea=5:1, to yield 3.8g of pale yellow solid in 41%; ESI-MS 370.2[ M+H ]] + ； 1 H NMR(500MHz,Chloroform-d)δ7.79–7.74(m,2H),7.34(s,1H),7.29(dd,J＝8.3,6.8Hz,2H),7.24–7.18(m,1H),4.12(d,J＝26.0Hz,2H),3.13(s,2H),2.21(dq,J＝13.6,2.9Hz,2H),2.08(m,2H),1.38(s,9H).
Step five: preparation of tert-butyl 4-aminomethyl-4- (4-phenylthiazol-2-yl) piperidine-1-carboxylate (Compound 7)
Tert-butyl 4-cyano-4- (4-phenylthiazol-2-yl) piperidine-1-carboxylate (compound 6,5.0g,13.6 mmol) was dissolved in 60mL of dry tetrahydrofuran solution, lithium aluminum hydride (1.0 g,26.3 mmol) was slowly added, reacted for 3h at room temperature, slowly added dropwise with water under ice bath until no more bubbles were generated, diluted with water, extracted with DCM multiple times, the organic layers were combined, silica gel stirred, spin-dried solvent, dichloromethane: methanol=30:1, to yield 2.8g of pale yellow liquid with 55%; ESI-MS 374.2[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.93(d,J＝7.9Hz,2H),7.42(t,J＝7.6Hz,2H),7.34(t,J＝7.2Hz,1H),3.73(d,J＝13.4Hz,2H),3.01(s,2H),2.80(s,2H),2.12(d,J＝13.9Hz,2H),1.84–1.72(m,2H),1.40(s,9H).
Step six: preparation of tert-butyl 4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidine-1-carboxylate (Compound 8)
3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzoic acid (Compound 3,3.0g,11.6 mmol) was reacted with 4-AmmoniaMethyl-4- (4-phenylthiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 7,5.6g,15.0 mmol) was dissolved in DCM, HOBt (2.6 g,17.4 mmol), EDCI (3.3 g,17.4 mmol), DIPEA (6.2 mL,34.8 mmol) was added, reacted at room temperature for 3h, diluted with water, extracted multiple times with DCM, the organic layers combined, anhydrous Na 2 SO 4 Drying, mixing with silica gel, spin-drying the solvent, purifying with PE: EA=5:1 column to obtain white solid 5.1g with a yield of 71%; ESI-MS 614.2[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ8.79(t,J＝6.5Hz,1H),8.45(p,J＝1.8Hz,1H),8.18(dq,J＝7.9,1.6Hz,1H),8.12–8.03(m,2H),7.94(dt,J＝8.2,1.6Hz,2H),7.68(td,J＝7.8,2.5Hz,1H),7.38(t,J＝7.6Hz,2H),7.29(td,J＝7.3,1.5Hz,1H),3.84(d,J＝13.3Hz,2H),3.65–3.54(m,2H),2.97(d,J＝12.6Hz,2H),2.36–2.21(m,2H),1.88(m,2H),1.38(s,9H).
Example 2
Synthesis of HDAC7-PROTAC molecule A1
Figure BDA0004109444430000191
Figure BDA0004109444430000201
Step one: preparation of tert-butyl 4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidine-1-carbonyl piperidine-1-carboxylate (Compound 9)
Tert-butyl 4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzoylamino) methyl piperidine-1-carboxylate (compound 8,250.0mg,0.4 mmol) was dissolved in 20mL DCM, 2mL trifluoroacetic acid was added, reacted at room temperature for 1h, the solvent was dried by spin-drying, 20mL DMF solution was added, 1- (tert-butoxycarbonyl) piperidine-4-carboxylate (121.0 mg,0.5 mmol), HATU (230.0 mg,0.6 mmol), DIPEA (0.2 mL,1.2 mmol) was added, stirred at room temperature for 2h, diluted with water, EA was extracted multiple times, and the organic layer was combined, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, purifying with a column by using methylene dichloride methanol=40:1 to obtain white solid 120mg with the yield of 41%;ESI-MS:725.3[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ8.83(t,J＝6.3Hz,1H),8.48(t,J＝1.8Hz,1H),8.23–8.17(m,1H),8.12–8.06(m,2H),8.00–7.94(m,2H),7.69(t,J＝7.8Hz,1H),7.40(dd,J＝8.3,7.1Hz,2H),7.35–7.28(m,1H),4.22(d,J＝13.1Hz,1H),4.09–3.82(m,3H),3.72–3.54(m,2H),3.41(s,2H),3.24(t,J＝12.0Hz,1H),2.93–2.74(m,4H),2.40(d,J＝13.5Hz,1H),2.29(d,J＝13.5Hz,1H),2.02–1.84(m,2H),1.66–1.53(m,2H),1.40(s,9H)。
step two: preparation of N- ((4- (4-phenylthiazol-2-yl) -1- (piperidine-4-carbonyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound 10)
4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidine-1-carbonyl) piperidine-1-carboxylic acid tert-butyl ester (Compound 9,250.0mg,0.3 mmol) was dissolved in 20mL of DCM, 2mL of trifluoroacetic acid was added and reacted at room temperature for 1h, and the solvent was dried to give 215mg of oily liquid which was used directly in the next reaction without purification. The yield is 100 percent; ESI-MS 625.3[ M+H ]] + 。
Step three: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4-hydroxypiperidin-1-yl) isoindoline-1, 3-dione (Compound 12 a)
2- (2, 6-Dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (Compound 11,276.0mg,1.0 mmol) was dissolved in 20mL of DMSO, 4-hydroxypiperidine hydrochloride (206.0 mg,1.5 mmol), DIPEA (0.5 mL,3.0 mmol) were added, reacted at 90℃for 4h, diluted with water, extracted with EA multiple times, combined with organic solution, washed multiple times with water, anhydrous Na 2 SO 4 Drying, mixing the sample with silica gel, spin-drying, and purifying with dichloromethane: methanol=40:1, to obtain yellow solid 200mg with a yield of 56%; ESI-MS 358.1[ M+H ]] + ； 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.65(d,J＝8.5Hz,1H),7.32(d,J＝2.4Hz,1H),7.24(dd,J＝8.7,2.4Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),4.78(d,J＝4.1Hz,1H),3.82(m,2H),3.75(m,1H),3.25–3.18(m,2H),2.94–2.83(m,1H),2.63–2.52(m,2H),2.28(t,J＝7.4Hz,1H),2.07–1.97(m,1H),1.81(m,2H),1.50(q,J＝7.2,6.7Hz,1H)。
Step four: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione (Compound 13 a)
2- (2, 6-Dioxopiperidin-3-yl) -5- (4-hydroxypiperidin-1-yl) isoindoline-1, 3-dione (Compound 12a,357.0mg,1.0 mmol) was dissolved in 20mL of DCM, DMP (848.0 mg,2.0 mmol) was added, stirred at room temperature for 2h, celite was filtered off with suction, DCM was washed multiple times, anhydrous Na 2 SO 4 Drying, spin-drying the solvent gave 355mg of yellow liquid, which was used directly in the next reaction. The yield is 100 percent; ESI-MS 356.1[ M+H ]] + 。
Step five: preparation of N- ((1- (1 '- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) - [1,4' -bipiperidin ] -4-carbonyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5-trifluoromethyl-1, 2, 4-oxadiazol-3-yl) benzamide (Compound A1)
N- ((4- (4-phenylthiazol-2-yl) -1- (piperidin-4-carbonyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (compound 10,321.0mg,0.5 mmol) was dissolved in 20mL of DCM, sodium cyanoborohydride (94.0 mg,1.5 mmol) was added dropwise glacial acetic acid to bring the pH of the system to 3-5, stirred for 5h at room temperature, diluted with water, EA was extracted multiple times, the organic layers were combined, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, and purifying with dichloromethane: methanol=35:1 to obtain yellow solid 150mg with a yield of 30%; ESI-MS 964.3[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ11.08(s,1H),8.78(t,J＝6.4Hz,1H),8.43(d,J＝1.9Hz,1H),8.19(dt,J＝7.8,1.4Hz,1H),8.09(s,1H),8.04(dt,J＝7.9,1.5Hz,1H),7.96–7.90(m,2H),7.72–7.63(m,2H),7.39(t,J＝7.6Hz,2H),7.34–7.28(m,2H),7.24(dd,J＝8.7,2.3Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.18(d,J＝13.4Hz,1H),4.07(d,J＝12.8Hz,2H),3.91(d,J＝13.5Hz,1H),3.58(t,J＝7.1Hz,2H),3.19(t,J＝12.2Hz,1H),3.03–2.76(m,7H),2.62–2.52(m,3H),2.31(dd,J＝52.8,13.8Hz,4H),2.00(m,2H),1.94–1.75(m,5H),1.67–1.52(m,4H)。
Example 3
The synthesis of HDAC7-PROTAC molecule A2-4 is carried out by taking compound 11 as raw material, nucleophilic reacting with 4-piperidinemethanol hydrochloride, 4-piperidineethanol and 3-methoxyazetidine hydrochloride under alkaline condition to obtain intermediate 12b-d (12 b:2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione, 12c:2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxyethyl) piperidin-1-yl) isoindoline-1, 3-dione, 12d:2- (2, 6-dioxopiperidin-3-yl) -5- (3- (hydroxymethyl) azetidin-1-dione), and oxidizing by DMP to obtain intermediate 13b-d (13 b:1- (2, 6-dioxopiperidin-3-yl) -1, 3-dione, 13c: 1- (2, 6-dioxopiperidin-1-yl) -5- (4- (hydroxyethyl) isoindoline-1, 3-dione, 12d:2- (2, 6-dioxopiperidin-3-yl) -5- (3-yl) isoindoline-1, 3-dione, 6-dioxopiperidine-3-yl) -1, 3-diketone isoindoline-5-yl) azetidine-3-formaldehyde, and then respectively carrying out acid-amine condensation reaction with a compound 10 to obtain a compound A2-A4. The structural formulas of the series of compounds are shown in the following table.
Figure BDA0004109444430000221
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Figure BDA0004109444430000231
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Figure BDA0004109444430000241
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Figure BDA0004109444430000251
Example 4
Synthesis of HDAC7-PROTAC molecule B1
Figure BDA0004109444430000261
Step one: preparation of tert-butyl 4- (4- (4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide) methyl) piperidine-1-carbonyl) phenyl) piperidine-1-carboxylate (compound 14 a)
Tert-butyl 4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzoylamino) methyl) piperidine-1-carboxylate (compound 8,250.0mg,0.4 mmol) was dissolved in DCM, 2mL of trifluoroacetic acid was added, reacted at room temperature for 1h, the solvent was dried by spin-drying, 20mL of DMF solution was added, 4- (1- (tert-butoxycarbonyl) piperidin-4-yl) benzoic acid (162.0 mg,0.5 mmol), HATU (230.0 mg,0.6 mmol), DIPEA (0.2 mL,1.2 mmol) was added, stirred at room temperature for 2h, diluted with water, EA was extracted multiple times, the organic layer was combined, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, purifying with a column by using methylene dichloride methanol=35:1 to obtain 180mg of white solid with the yield of 56%; ESI-MS 801.3[ M+H ]] + . 1 H NMR(500MHz,DMSO-d6)δ8.81(t,J＝6.4Hz,1H),8.46(t,J＝1.8Hz,1H),8.19(m,1H),8.12–8.05(m,2H),7.98–7.91(m,2H),7.69(t,J＝7.8Hz,1H),7.39(dd,J＝8.3,7.0Hz,2H),7.34–7.27(m,5H),4.31(s,1H),4.09(s,2H),3.62(d,J＝5.6Hz,3H),3.26–3.02(m,2H),2.74(d,J＝3.5Hz,2H),2.70(h,J＝3.4Hz,1H),2.33(d,J＝43.5Hz,2H),1.97(d,J＝38.0Hz,2H),1.80–1.70(m,2H),1.51(m,2H),1.42(s,9H).
Step two: preparation of N- ((4- (4-phenylthiazol-2-yl) -1- (4- (piperidin-4-yl) benzoyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound 15 a)
4- (4- (4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide) methyl) piperidine-1-carbonyl)Phenyl) piperidine-1-carboxylic acid tert-butyl ester (Compound 14a,400.0mg,0.5 mmol) was dissolved in 30mL DCM, 2mL trifluoroacetic acid was added and reacted at room temperature for 1h, the solvent was dried by spinning to give 350mg of oily liquid which was used directly in the next reaction without purification. The yield is 100 percent; ESI-MS 701.3[ M+H ]] + .
Step three: preparation of N- ((1- (4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) benzoyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound B1)
N- ((4- (4-phenylthiazol-2-yl) -1- (4- (piperidin-4-yl) benzoyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (compound 15a,350.0mg,0.5 mmol) was dissolved in 30mL of DCM, sodium cyanoborohydride (94.0 mg,1.5 mmol) was added dropwise glacial acetic acid to bring the pH of the system to 3-5, stirred for 5h at room temperature, diluted with water, EA multiple extractions, combined with the organic layer, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, and purifying with dichloromethane: methanol=35:1 to obtain 180mg of yellow solid with yield of 34%; ESI-MS 1054.4[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ11.09(s,1H),8.78(t,J＝6.4Hz,1H),8.44(d,J＝1.8Hz,1H),8.19(dt,J＝7.7,1.5Hz,1H),8.11–8.03(m,2H),7.98–7.91(m,2H),7.72–7.63(m,2H),7.38(dd,J＝8.3,7.0Hz,2H),7.34–7.27(m,6H),7.22(dd,J＝8.8,2.3Hz,1H),5.08(dd,J＝12.9,5.4Hz,1H),4.30(s,1H),4.04(d,J＝12.8Hz,2H),3.62(d,J＝6.3Hz,3H),3.09(s,2H),3.01–2.85(m,5H),2.64–2.52(m,3H),2.40–2.15(m,4H),2.06–1.73(m,11H),1.71–1.60(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.93,173.25,170.56,169.58,168.57,168.12,167.43,166.29,155.48,154.23,136.19,134.78,134.52,134.35,131.76,130.35,130.07,129.07,128.27,127.46,127.13,126.81,126.49,125.46,125.03,118.04,117.85,114.98,108.19,54.62,49.75,49.23,47.73,45.70,33.17,31.47,30.14,22.69。
Example 5
Synthesis of HDAC7-PROTAC molecules B2-B4
The operation process is the synthesis of the compound B1, and the compound 15a is taken as a raw material and is subjected to reductive amination with the compound 13d to obtain a compound B2; compound 8 after removal of the Boc protecting group under acidic conditions was acid amine condensed with 4- (4- (t-butoxycarbonyl) piperazin-1-yl) benzoic acid under HATU, DIPEA conditions to give compound 14b (4- (4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide) methyl) piperidine-1-carbonyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester and removal of the Boc protecting group under trifluoroacetic acid conditions to give compound 15b (N- ((4- (4-phenylthiazol-2-yl) -1- (4- (piperazin-1-yl) benzoyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide. The compound 15B and the compound 13B are subjected to reductive amination to obtain a compound B3; the compound 15B and the compound 13d are subjected to reductive amination to obtain a compound B4. The structural formulas of the series of compounds are shown in the following table.
Figure BDA0004109444430000281
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Figure BDA0004109444430000291
Example 6
Synthesis of HDAC7-PROTAC molecule C1
Figure BDA0004109444430000301
Step one: preparation of tert-butyl 4- (2- (4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidin-1-yl) ethyl) piperidine-1-carboxylate (compound 16 a)
4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzoylamino) methyl piperidine-1-carboxylic acid tert-butyl ester (compound 8,250.0mg,0.4 mmol) was dissolved in DCM, 2mL of trifluoroacetic acid was added, reacted at room temperature for 1h, the solvent was dried by spin-drying, 20mL of DCM solution was added, 4- (2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester (120.0 mg,0.5 mmol) was added, sodium cyanoborohydride (78.0 mg,1.2 mmol), glacial acetic acid was added dropwise to bring the pH of the system to 3-5, stirred at room temperature for 2h, water was added for dilution, EA was extracted multiple times, the organic layer was combined, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, purifying with a column by using methylene dichloride methanol=40:1 to obtain 175mg of white solid with the yield of 60%; ESI-MS 725.3[ M+H ]] + . 1 H NMR(500MHz,Chloroform-d)δ8.49(d,J＝1.8Hz,1H),8.22(d,J＝7.8Hz,1H),7.99(dt,J＝7.9,1.5Hz,1H),7.88–7.84(m,2H),7.60–7.55(m,2H),7.42–7.32(m,4H),4.21–3.82(m,5H),3.66–3.39(m,3H),3.03(s,2H),2.64(d,J＝15.3Hz,4H),2.45(s,2H),1.97(s,2H),1.76–1.59(m,5H),1.44(s,9H).
Step two: preparation of N- ((4- (4-phenylthiazol-2-yl) -1- (2- (piperidin-4-yl) ethyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound 17 a)
4- (2- (4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidin-1-yl) ethyl) piperidine-1-carboxylic acid tert-butyl ester (Compound 16a,362.0mg,0.5 mmol) was dissolved in 30mL of DCM, 2mL of trifluoroacetic acid was added and reacted at room temperature for 1h, the solvent was dried to give 312mg as an oily liquid which was used directly in the next reaction without purification. The yield is 100 percent; ESI-MS 625.3[ M+H ]] + .
Step three: preparation of N- ((1- (2- (1 '- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) - [1,4' -bispiperidin ] -4-yl) ethyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound C1)
N- ((4- (4-phenylthiazol-2-yl) -1- (2- (piperidin-4-yl) ethyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound 17a,312.0mg,0.5 mmol) was dissolved in 30mL of DCM, sodium cyanoborohydride (94.0 mg,1.5 mmol) was added, glacial acetic acid was added dropwise to bring the pH of the system to 3-5, stirred at room temperature for 5h, diluted with water, EA multiple times extracted, the organic layer was combined with anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, and purifying with dichloromethane: methanol=35:1 to obtain yellow solid 200mg with yield of 41%; ESI-MS 964.4[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ11.08(s,1H),8.85–8.72(m,1H),8.44(s,1H),8.22–8.17(m,1H),8.12–8.02(m,2H),7.96–7.91(m,2H),7.68(dt,J＝10.4,8.0Hz,2H),7.39(t,J＝7.7Hz,2H),7.31(dd,J＝16.6,9.3Hz,2H),7.25(d,J＝9.0Hz,1H),5.07(dd,J＝12.7,5.5Hz,1H),4.12(s,3H),3.78–3.38(m,4H),3.21–2.68(m,9H),2.65–2.52(m,3H),2.46–1.82(m,14H),1.66(d,J＝28.2Hz,3H).
Example 7
Synthesis of HDAC7-PROTAC molecule C2-C5
The operation process is the same as the synthesis of the compound C1, and the compound 17a is taken as a raw material to be respectively subjected to reductive amination with the compound 13b and the compound 13C to obtain a compound C2 and a compound C3; the compound 8 is subjected to reductive amination under acidic conditions with tert-butyl 3- (2-oxoethyl) azetidine-1-carboxylate, tert-butyl 3-formylazetidine-1-carboxylate, sodium cyanoborohydride and glacial acetic acid to obtain the compound 16c-d (16 c: tert-butyl 3- (2- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide) methyl) piperidin-1-yl) ethyl) azetidine-1-carboxylate, 16d:3- ((4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide) methyl) piperidin-1-yl) methyl) azetidine-1-carboxylate; removing the Boc protecting group from the compound 16c-d under trifluoroacetic acid conditions gives the compound 17c-d (17 c: N- ((1- (2- (azetidin-3-yl) ethyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide; 17d: N- ((1- (2- (azetidin-3-yl) methyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide). Performing reductive amination on the compound 17C and the compound 13d to obtain a compound C4; the compound 17d and the compound 13d are subjected to reductive amination to obtain a compound C4. The structural formulas of the series of compounds are shown in the following table.
Figure BDA0004109444430000321
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Figure BDA0004109444430000331
Example 8
Synthesis of HDAC7-PROTAC molecule C6
Figure BDA0004109444430000341
Step one: preparation of tert-butyl 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carboxylate (Compound 18 a)
2- (2, 6-Dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (Compound 11,276.0mg,1.0 mmol) was dissolved in 20mL of DMSO solution, tert-butyl 4-piperidinecarboxylate (130.0 mg,0.7 mmol) DIPEA (0.3 mL,1.5 mmol) was added, reacted at 90℃for 3h, diluted with water, extracted with EA multiple times, the organic layers were combined, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying solvent, and purifying with column chromatography with methanol=80:1 to obtain yellow solid 200mg with yield of 45%; ESI-MS 442.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ11,10(s,1H),7,61(d,J＝8.5Hz,1H),7.35(s,1H),7.21(d,J＝8.6Hz,1H),5.05(dd,J＝12.9,5.3Hz,1H),3.92(d,J＝13.3Hz,2H),3.03(t,J＝11.4Hz,2H),2.95-2.80(m,1H),2.54(d,J＝15.6Hz,2H),2.00(d,J＝5.4Hz,1H),1.82(d,J＝10.9Hz,2H).1.53(d,J＝10.2Hz,2H).1.42(s,9H).
Step two: preparation of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carboxylic acid (Compound 19 a)
1- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-5-yl) piperidine-4-carboxylic acid tert-butyl ester (Compound 18a,441.0mg,1.0 mmol) was dissolved in 20mL DCM, 2mL trifluoroacetic acid was added, the reaction was carried out at room temperature for 1h, the solvent was dried, 385mg of yellow liquid was obtained, and the next step was directly added without purification. The yield is 100 percent; ESI-MS 386.2[ M+H ]] + .
Step three: preparation of N- ((1- (2- (1- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-carbonyl) piperidin-4-yl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound C6)
N- ((4- (4-phenylthiazol-2-yl) -1- (2- (piperidin-4-yl) ethyl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound 17a,312.0mg,0.5 mmol) was dissolved with 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carboxylic acid (Compound 19a,308.0mg,0.8 mmol) in 30mL DMF, HATU (285.0 mg,0.8 mmol), DIPEA (0.3 mL,1.5 mmol) was added and reacted for 2h at room temperature, diluted with water, EA multiple extractions, combined organic layers, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying solvent, and purifying with column chromatography with methanol=40:1 to obtain yellow solid 120mg with yield of 24%; ESI-MS 992.4[ M+H ]] + . 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),8.75(t,J＝6.5Hz,1H),8.45(d,J＝1.8Hz,1H),8.19(d,J＝7.7Hz,1H),8.09–8.03(m,2H),7.96–7.91(m,2H),7.72–7.63(m,2H),7.39(t,J＝7.6Hz,2H),7.32–7.28(m,2H),7.22(dd,J＝8.8,2.3Hz,1H),5.08(dd,J＝10.8,5.4Hz,1H),4.33(d,J＝12.6Hz,1H),4.07–4.00(m,2H),3.96(d,J＝13.1Hz,1H),3.56(d,J＝6.2Hz,2H),3.12–2.74(m,8H),2.64–2.53(m,2H),2.46(d,J＝12.9Hz,1H),2.30(t,J＝18.1Hz,4H),2.14–1.94(m,5H),1.75–1.54(m,7H),1.52–1.45(m,1H),1.35(q,J＝7.3Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ173.26,172.26,170.55,168.58,168.07,167.42,166.13,155.28,154.21,136.24,134.86,134.51,131.73,130.31,130.07,129.07,128.22,126.80,126.44,125.46,125.03,118.05,114.72,108.23,55.80,50.18,49.22,47.18,45.30(d,J＝24.5Hz),41.84,37.34,34.24,33.37,32.17,31.46,27.97,22.67.
Example 9
Synthesis of HDAC7-PROTAC molecule C7-C11
Procedure analogous to the synthesis of compound C6 compound 11 was reacted with azetidine-3-carboxylic acid tert-butyl ester hydrochloride under DMSO, DIPEA conditions to give 18b (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-4-carboxylic acid tert-butyl ester) and deboc under trifluoroacetic acid conditions to give 19b (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carboxylic acid. Condensing the compound 17d with the compound 19b acid amine to obtain C7; condensing the compound 17C with the compound 19b acid amine to obtain C8; condensing the compound 17b with a compound 19a acid amine to obtain a compound C9; condensing the compound 17b with a compound 19b acid amine to obtain a compound C10; the compound 17a is condensed with the amine acid of the compound 19b to obtain a compound C11. The structural formulas of the series of compounds are shown in the following table.
Figure BDA0004109444430000361
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Figure BDA0004109444430000371
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Figure BDA0004109444430000381
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Figure BDA0004109444430000391
Example 10
Synthesis of HDAC7-PROTAC molecule D1
Figure BDA0004109444430000401
Step one: preparation of tert-butyl (2- (2- (2- (4- (4-phenylthiazol-2-yl) -4- (3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidin-1-yl) ethoxy) ethyl) carbamate (Compound 21 a)
Tert-butyl 4- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzoylamino) methyl piperidine-1-carboxylate (compound 8,250.0mg,0.4 mmol) was dissolved in DCM, 2mL of trifluoroacetic acid was added, reacted at room temperature for 1h, spin-dried solvent was added, 20mL of DMF solution was added, potassium carbonate (69.0 mg,0.5 mmol) was added, reacted at room temperature for 2h, diluted with water was added, and EA was extracted multiple times, the organic layer was combined, anhydrous Na was used 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, and purifying with a column with methanol=45:1 to obtain 180mg of white solid, namely, YIeld:57%; ESI-MS 789.3[ M+H ]] + . 1 H NMR(500MHz,DMSO-d6)δ8.47(s,1H),8.25–8.01(m,4H),7.94(d,J＝7.7Hz,2H),7.70(t,J＝7.9Hz,1H),7.40(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),5.12(td,J＝10.7,5.3Hz,1H),3.49(d,J＝20.8Hz,22H),2.00(dd,J＝13.2,4.1Hz,2H),1.61(t,J＝12.0Hz,2H),1.36(s,9H).
Step two: preparation of N- ((1- (15- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -13-oxo-3, 6, 9-trioxa-12-aza-pentadecyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl) -3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide (Compound D1)
Compound 20b (464.0 mg,1.2 mmol), compound 21a (788.0 mg,1.0 mmol) were dissolved in 30mL of DCM, 2mL of trifluoroacetic acid was added, stirring was performed at room temperature for 2h, after spinning the solvent, DMF solutions were added separately, the reaction solutions were combined, HATU (570.0 mg,1.5 mmol), DIPEA (0.5 mL,3 mmol) were added, stirring was performed at room temperature for 2h, dilution with water was added, EA was extracted multiple times, the organic layers were combined, anhydrous Na 2 SO 4 Drying, stirring with silica gel, spin-drying the solvent, purifying with a column by using methylene dichloride methanol=30:1 to obtain 457mg of yellowish green solid with the yield of 45%; ESI-MS 1016.3[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ11.10(s,1H),8.78(s,1H),8.45(d,J＝2.0Hz,1H),8.21–8.16(m,1H),8.07(q,J＝4.7,3.5Hz,3H),7.96–7.91(m,2H),7.69(t,J＝7.8Hz,1H),7.58(dd,J＝8.6,7.0Hz,1H),7.38(t,J＝7.6Hz,2H),7.29(t,J＝7.3Hz,1H),7.12(d,J＝8.7Hz,1H),7.03(d,J＝7.1Hz,1H),6.71(t,J＝6.0Hz,1H),5.05(dd,J＝12.8,5.5Hz,1H),3.57–3.44(m,17H),3.20(q,J＝5.8Hz,3H),2.89(m,2H),2.62–2.52(m,3H),2.42(t,J＝6.5Hz,3H),2.37–2.30(m,3H),2.06–1.97(m,3H). 13 C NMR(126MHz,DMSO-d 6 )δ173.22,171.01,170.47,169.26,168.59,167.75,166.17,154.25,146.64,136.70,136.21,134.83,132.65,131.73,130.33,130.06,129.06,128.24,126.80,126.46,125.03,117.62,114.82,111.02,109.78,70.10(d,J＝9.8Hz),69.55,50.29,49.04,35.22,31.46,22.64.
Example 11
Synthesis of HDAC7-PROTAC molecules D2-D3
The process is the same as the synthesis of compound D1, and after Boc removal of tert-butyl ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycine) of compound 20a, tert-butyl ((2- (2- (2-oxo-2- (4- (4-phenylthiazol-2-yl) -4- ((3- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamide) methyl) piperidin-1-yl) ethoxy) ethyl) carbamate of compound 21b, an acid amine condensation reaction is carried out under HATU, DIPEA conditions to give compound D2; the compound 21c (1- (4-phenylthiazol-2-yl) -4- (3- (5-trifluoromethyl) -1,2, 4-oxadiazol-3-yl) benzamido) methyl) piperidin-1-yl) -3,6,9, 12-tetraoxapentadecane-15-oic acid tert-butyl ester was each Boc removed and subjected to acid amine condensation under HATU, DIPEA conditions with compound 22 ((S) -1- ((2S, 4R) -4-hydroxy-2- (4- (4-methylthiazol-5-yl) benzylcarbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester to give compound D3. The structural formulas of the series of compounds are shown in the following table.
Figure BDA0004109444430000421
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Figure BDA0004109444430000431
Example 12
In vitro enzyme Activity of the Compounds of the invention
1. Experimental method
Instrument: microplate reader TECAN SPARK (TECAN, switzerland)
Materials: HDAC7 protein purified from SF9 cells; substrate Ac-Leu-Lys (TFAc) -AMC
Sample processing: the sample is dissolved by DMSO, stored at low temperature and diluted in a gradient way, and the concentration of the DMSO in a final system is controlled within a range which does not influence the enzyme activity detection. The positive compound used in the experiment was TMP269.
2. The experimental procedure is as follows: 100nM HDAC7 protein and 50. Mu.M substrate were dissolved in kinase reaction buffer (500mM NaCl,50mM Tris,PH8.0). 0.3. Mu.M, 3. Mu.M of compound was added to the reaction system (100. Mu.L) and the non-dosing group, positive compound (TMP 269, 0.3. Mu.M and 3. Mu.M) and blank group were set simultaneously, and 2 sub-wells were set for each concentration of each sample. After sufficient lysis, the system was transferred to a 96-well plate and 100. Mu.l of 10mg/ml of trypsin was added and incubated at 37 ℃. Fluorescence values (absorption light 460nm, excitation light 390 nm) were detected by an enzyme-labeled instrument to indicate the release of AMC. And calculating the enzyme activity inhibition rate of the sample according to the sample reading, wherein the calculation formula is as follows: (RFU non-dosing-RFU compound)/RFU non-dosing x100%. The results are shown in Table 1.
3. Experimental results:
the experimental results can be obtained: the compound of the invention, which is modified by taking TMP269 as a target, has weak binding capacity with HDAC7 protein, and shows that the compound of the invention has the potential to exert a PROTAC degradation mechanism and exert drug effects independent of target-end strong inhibition.
TABLE 1 inhibition of enzyme activity of the compounds of the invention at a concentration of 1. Mu.M
Figure BDA0004109444430000441
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Figure BDA0004109444430000451
"A" represents >75%; "B" represents 50% to 75%; "C" represents 15% to 50%; "D" represents <15% of example 13
Degradation of HDAC7 in NB4 cells at a concentration of 1. Mu.M, 5. Mu.M
1. The experimental method comprises the following steps:
cell culture and administration: NB4 cells were placed in 5% CO 2 Is cultured in a constant temperature incubator at 37 ℃ under the condition of RPMI-1640+10% Gibco serum. Anti-mycoplasma drugs were administered three times before resuscitation. The cell suspension was added to a 15mL centrifuge tube, centrifuged at 1500rpm for 4min, the supernatant was discarded, resuspended in 2mL of culture medium and counted. The cell suspension was seeded in 6-well plates, 50 ten thousand cells per well, and the test compound was added at the appropriate concentration. And collecting samples after 12-24 hours.
Sample preparation: at the end of the time of action, the cells are collected and washed once with PBS; adding 4% SDS (sodium dodecyl sulfate) of corresponding volume according to the cell quantity to lyse the cells, and performing ultrasonic treatment until the cells are not sticky; centrifuging at room temperature for 30min at 12,000 g; the supernatant was transferred to a new EP tube for protein quantification.
Taking 2mg/mL BSA standard substance for sesquidilution to obtain the concentration used by a standard curve, wherein the concentration is sequentially 2mg/mL,1mg/mL,0.5mg/mL,0.25mg/mL and 0.0625mg/mL; according to 200 mu L of A solution and 4 mu L B solution in the BCA quantitative kit for each sample, taking corresponding volumes of A solution and B solution (the volume ratio is 50:1) and uniformly mixing; adding 10 mu L of BSA with different concentrations and samples into a 96-well plate respectively, adding 200 mu L of mixed solution A and solution B, gently photographing, and placing at 37 ℃ for light-shielding reaction for 30min; after the reaction is finished, measuring an absorbance value at 562nm, calculating the concentration of the sample protein by using a standard curve, and adding a certain amount of 6×loading buffer into 20 μg protein according to the volume to make the final concentration be 1×loading buffer; heating and denaturing at 95 ℃ for 10min, cooling, centrifuging and mixing uniformly, performing Western Blot experiment, and freezing the rest sample at-80 ℃. The compounds were tested for degradation of HDAC7 in NB4 cells at a concentration of 1 μm, 5 μm and the results are shown in table 2.
2. Experimental results
The experimental results can be obtained: the compounds of the invention can degrade HDAC7 in NB4 cells, where series C and series D significantly degrade HDAC7.
TABLE 2 degradation screening test of the inventive Compounds in NB4 cells
Figure BDA0004109444430000461
"A" represents >75%; "B" represents 50% to 75%; "C" represents 15% to 50%; "D" represents <15%
Example 14
Proliferation inhibition of compounds of the invention on NB4 cells
1. Experimental method
Testing proliferation inhibition of different compounds on NB4 cells by CCK8 method with TMP269 as positive control, IC 50 Values were calculated using Graphpad Prism v9.3.0 software and the results are shown in table 3.
2. Experimental results
The experimental results can be obtained: the proliferation inhibitory activity of the compounds of the present invention in NB4 cells is significantly better than that of the positive molecule TMP269.
TABLE 3 inhibition of proliferation of compounds of the invention on NB4 cells
No. TMP269 C6 C7 C8 C10 D3
IC 50 (μM) D A C B C A
"A" represents 0 to 1. Mu.M; "B" represents 1 to 5. Mu.M; "C" represents 5-15. Mu.M; "D" represents > 15. Mu.M
Example 15
Proliferation inhibition of compounds of the invention on a variety of DLBCL cells
1. Experimental method
Using CCK8 method, TMP269 was used as positive pairIn the light of the above, different compounds were tested for proliferation inhibition, IC, on a variety of DLBCL cells 50 Values were calculated using Graphpad Prism v9.3.0 software and the results are shown in table 4.
2. Experimental results
The experimental results can be obtained: the compounds of the invention have proliferation inhibitory activity significantly superior to that of the positive molecule TMP269 in a variety of DLBCL cell lines.
TABLE 4 inhibition of proliferation of the compounds of the invention on Multi-bead lymphoma cells
Figure BDA0004109444430000471
Figure BDA0004109444430000481
"+". ++ + "representative of 0-1.5. Mu.M; "+". ++'s representative of 1.5-3. Mu.M; "++" represents 3-13. Mu.M; "+" represents > 13. Mu.M
Example 16
Preliminary pharmacokinetic profile of Compounds of the invention in ICR mice
1. Experimental method
ICR mice were given an oral gavage at a dose of 30mg/kg, and 150. Mu.L to 200. Mu.L of blood was collected by orbital blood collection at eight time points of 0, 0.25, 0.5, 1,2,4, 8 and 24 hours. The blood sample was centrifuged at 5000 rpm at 4℃for 15min and the supernatant was aspirated to the EP tube for storage. mu.L of the supernatant of the sample to be tested was aspirated into the EP tube, 200. Mu.L of chromatographic acetonitrile was added, and the mixture was centrifuged at 13500 rpm at 4℃for 10min, and the supernatant was aspirated into the sample bottle. The compound concentration was determined using a high performance liquid mass spectrometer model number Waters Xevo TQ, loratadine as an internal standard compound. Calculation C max 、T max 、T 1/2 And AUC, plotted with Graphpad 9.3.0. The results are shown in Table 5.
2. Experimental results
TABLE 5 preliminary pharmacokinetic parameters of Compounds C6, C7
Figure BDA0004109444430000482
The experimental results can be obtained: in ICR mice, compound C6 and compound C7 have certain oral absorption activity under the condition of oral lavage of 30 mg/kg.

Claims (9)

1.A compound having a structure represented by the general formula (I):
Figure FDA0004109444420000011
or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof;
wherein:
linker is a linking group selected from one or more of the following groups: straight-chain or branched alkyl, alkoxy, alkylamino, halogenated heterocycle, alkenyl, alkynyl, alkenylene, alkynylene, alkynyloxy, alkynylamino, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, and cycloalkyl, heterofused cycloalkyl, aromatic ring, halogenated aromatic ring, heteroaromatic ring, -CO (CH) 2 ) n -、-CO(CH 2 ) n O-、-(CH 2 ) n NH 2 -、-(CH 2 ) n NR 1 -、-CO(CH 2 ) n NH-、-CO(CH 2 ) n NR 1 -、-(CH 2 ) n CONH(CH 2 ) n -、-(CH 2 ) n CONH(CH 2 ) n NH-、-(CH 2 ) n CONH(CH 2 ) n NR 1 -、-CO(CH 2 ) n NHCO(CH 2 ) n -、-CO(CH 2 ) n NHCO(CH 2 ) n NH-、-CO(CH 2 ) n NHCO(CH 2 ) n NR 1 -、-CO(CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n -、-CO(CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NH-、
-CO(CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NR 1 -、-CH 2 (CH 2 OCH 2 ) n CH 2 -、-CH 2 (CH 2 OCH 2 ) n CH 2 NH-、-CH 2 (CH 2 OCH 2 ) n CH 2 NR 1 -、-CH 2 (CH 2 OCH 2 ) n CH 2 O-、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NH-、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NR 1 -、
-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NH-、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CH 2 NHCO(CH 2 ) n NR 1 -、-CH 2 CONHCH 2 (CH 2 OCH 2 ) n CO-、-CH 2 (CH 2 OCH 2 ) n CH 2 CO-, or any combination thereof;
n represents a natural number of 1 to 20;
R 1 is H or C 1-10 An alkyl group;
e3 ligand is an E3 ligase ligand of CRBN or VHL.
2. A compound according to claim 1, characterized in that:
linker is a connecting group, wherein the ring system combination is any combination of 1-4 ring systems, the ring system size is four-membered ring to six-membered ring, and the ring system types comprise bridge ring, spiro ring and parallel ring; including but not limited to the following structures:
Figure FDA0004109444420000021
3. a compound according to claim 1, characterized in that:
e3 ligand is an E3 ligase ligand selected from one of the following ligands:
Figure FDA0004109444420000031
4. the compound according to claim 1, characterized in that: a compound selected from the group consisting of stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, as shown below:
Figure FDA0004109444420000032
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Figure FDA0004109444420000041
/>
Figure FDA0004109444420000051
/>
Figure FDA0004109444420000061
/>
Figure FDA0004109444420000071
/>
Figure FDA0004109444420000081
5. a pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4.
6. A pharmaceutical formulation comprising one or more of the compounds, compositions of any one of claims 1 to 5.
7. Use of a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease that benefits from HDAC7 protein degradation.
8. The use according to claim 7, wherein the disease is selected from the group consisting of: acute myeloid lymphoblastic leukemia, diffuse large B-cell lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma, non-small cell lung cancer, esophageal cancer, gastric cancer, colon cancer, breast cancer, renal cancer, liver cancer.
9. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of AML and DLBCL.
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