Degradation agent for degrading DDR1 protein by targeting USP7 as well as preparation method and application of degradation agent

Abstract

The invention relates to a USP7-targeted DDR1 protein degradation agent as well as a preparation method and application thereof, in particular to a compound as shown in a formula I in the specification, and discloses a preparation method and application of the compound and a pharmaceutical composition containing the compound. The compound has excellent DDR1 degradation activity and anti-proliferative activity, and can be used for treating cancers and other diseases related to DDR1 activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a degrader that targets USP7 to degrade DDR1 protein, and discloses its preparation method and application. The compound has excellent DDR1 degradation activity and anti-proliferative activity, and can be used to treat cancer and other diseases related to DDR1 activity. Background Art

[0002] Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family. Its intracellular kinase activity interacts with the extracellular matrix to promote tumor cell proliferation, while its extracellular, non-enzymatically active domain creates a physical barrier to immune evasion. Although DDR1 inhibitors and antibodies have been developed, targeting DDR1 kinase activity alone cannot completely abrogate the biological effects mediated by its scaffolding function. Therefore, developing DDR1 degraders is a potentially more effective therapeutic strategy. By screening a proprietary small molecule ubiquitination library, we identified NSC632839, which significantly induces DDR1 protein degradation. Mechanistically, chemical proteomics and genetic studies suggest that NSC632839 acts by inhibiting USP7, which interacts with DDR1, stabilizes its structure, and deubiquitinates it, thereby preventing its proteasomal degradation. Importantly, we found that TP53 deletion or mutation in tumor cells and clinical samples significantly upregulates DDR1 expression and enhances its interaction with USP7. Treatment with NSC632839 restored TP53 expression, significantly reducing DDR1 levels. In primary patient samples, targeting USP7 with NSC632839 effectively eliminated tumor cells, providing a promising therapeutic strategy for addressing tumor recurrence driven by TP53 mutations. This study highlights the potential of USP7 inhibition to degrade DDR1 as a new approach for treating TP53 mutation-enriched tumors. Summary of the Invention

[0003] Purpose of the invention: The present invention aims to provide a degrading agent that targets the deubiquitinating enzyme USP7 to degrade DDR1 protein; another purpose of the present invention is to provide a method for preparing a degrading agent that targets the deubiquitinating enzyme USP7 to degrade DDR1 protein; another purpose of the present invention is to provide the use of a degrading agent that targets the deubiquitinating enzyme USP7 to degrade DDR1 protein in the preparation of a pharmaceutical composition for preventing or treating a disease that responds to the inhibition of DDR1 activity in a subject.

[0004] Technical solution: The compound of the present invention as shown in formula I or a pharmaceutically acceptable salt thereof,

[0005]

[0006] in:

[0007] X1 is selected from the following group: H, C1-C5 alkyl, hydroxyl, (CH2) n NH p (CH3) 3-p , C1-C5 alkoxy, C1-C5 alkylthio, halogen, C1-C5 haloalkyl, C6-C 10 Aromatic ring, C6-C 10 Cycloalkyl, C6-C 10 Halogenated aryl, a 5-12 membered heterocyclic group having one heteroatom selected from the group consisting of N, S and O, a 6-membered aromatic ring and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S and O, a C 10 -C 16 Condensed ring aromatic group; n = 0-5, p = 0-3;

[0008] R1 is selected from the group consisting of H, halogen, -OH, a 5-6 membered saturated heterocyclic group containing one N atom, and a 5-6 membered saturated heterocyclic group containing one N atom and one O atom;

[0009] R2 is selected from the group consisting of H, halogen, (CH2) n NH p (CH3) 3-p , C1-C6 alkyl.

[0010] Among them, n=0, 1, 2, 3, 4, 5, p=0, 1, 2, 3.

[0011] Preferably, X1 is selected from the group consisting of H, C1-C3 alkyl, hydroxyl, (CH2) n NH p (CH3) 3-p , C1-C3 alkoxy, C1-C3 alkylthio, halogen, C1-C3 haloalkyl, C6-C8 aromatic ring, C6-C8 cycloalkyl, C6-C8 haloaryl, a 5-12 membered heterocyclic group having one heteroatom selected from the group consisting of N, S and O, a 6-membered aromatic ring and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S and O, a C 10 -C 16 Condensed ring aromatic group.

[0012] Preferably, the halogen is F, Cl, Br, I.

[0013] Preferably, X1 is selected from the group consisting of H, methyl, butyl, hydroxy, amino, dimethylamino, C1-C5 alkoxy, C1-C5 alkylthio, halogen, haloalkyl, C6-C 10 Aromatic ring, C6-C 10Cycloalkyl, halogenated phenyl, 5-6 membered saturated heterocyclic group containing one N or O atom, a cyclic ring composed of benzene and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S, and O, a cyclic ring composed of pyrimidine and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S, and O, naphthyl, anthracenyl, phenanthrenyl, and pyrenyl.

[0014] Preferably, X1 is selected from the following group: H, methyl, propyl, isobutyl, trifluoromethyl, cyclohexane, hydroxy, amino, methoxy, methylthio, dimethylamino, phenyl, piperidinyl, tetrahydropyrrolyl, ethylthio, fluorophenyl, naphthyl, tetrahydrofuranyl, indolyl, benzofuranyl, benzothiophenyl, thienopyrimidinyl, benzothiazolyl.

[0015] Preferably, R1 is selected from the group consisting of H, halogen, -OH, piperidinyl, morpholinyl; and / or, R2 is selected from the group consisting of amino, -NHCH3, methyl.

[0016] In a preferred embodiment, the following preferred compounds are provided:

[0017]

[0018]

[0019]

[0020] On the other hand, the present invention provides a method for preparing the above-mentioned compound or a pharmaceutically acceptable salt thereof, characterized in that:

[0021]

[0022] The compound of formula I is obtained by reacting 4-piperidone hydrochloride with a 5-formaldehyde intermediate.

[0023] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the above-mentioned compounds, or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, the present invention provides a use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a DDR1 degrading agent.

[0025] In another aspect, the present invention provides a use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug, wherein the tumor is a DDR1-related tumor.

[0026] In another aspect, the present invention provides a use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for preventing or treating a disease in a subject that responds to inhibition or degradation of DDR1 activity.

[0027] The above-mentioned compound, or a pharmaceutically acceptable salt thereof, is used in combination with other tumor immunotherapeutic agents, wherein the other tumor immunosuppressants are selected from the following groups: small molecule compounds and antibodies (including but not limited to PD-1, PD-L1, CTLA-4, STING agonists, LAG3 antagonists, etc.), tumor-targeted drugs, and radiotherapy regimens.

[0028] The use of the above-mentioned compounds and pharmaceutically acceptable salts thereof in combination with CAR-T immunotherapy in cancer immunotherapy.

[0029] Furthermore, the disease is cancer.

[0030] In another aspect, the present invention provides a use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, in targeting the deubiquitinating enzyme USP7 to degrade DDR1 protein.

[0031] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0032] When administered in combination, the pharmaceutical composition may further comprise one or more other pharmaceutically acceptable compounds. One or more other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with the compound of the present invention.

[0033] The term "C 1-5 The term "alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 5 (specifically 1, 2, 3, 4 or 5). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl and the like.

[0034] The term "C1-C5 alkoxy" refers to an -O-C1-C5 alkyl group, wherein the C1-C5 alkyl group is as defined above, i.e., contains 1-5 carbon atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0035] The term "C1-C5 alkylthio" refers to -S-C1-C5 alkyl, wherein the C1-C5 alkyl group is as defined above, i.e., contains 1-5 carbon atoms. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, and the like.

[0036] The term "C6-C 10 "Cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged or spirocyclic ring. Preferably, C6-C 10 Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0037] The term "C6-C 10 "Aryl" means a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring system containing 6 to 10 carbon atoms, preferably a monocyclic C6-C 10 Aryl, the term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0038] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing 5-14 members, or preferably 5-10 members, or preferably 5-8 members, more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms being preferably 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0039] The term "halogen" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl, CHCl, CHCl, CF, CHF, CHF, CBr, CHBr, CHBr, CI, CHI, CHI, CHCF, CFCF, etc.

[0040] The term "fluoromethyl" refers to monofluoromethyl, difluoromethyl, trifluoromethyl and the like groups.

[0041] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially undersaturated (non-completely unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically a 3 to 7 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, but excluding -OO-, -OS- or -SS- moieties) independently selected from sulphur, oxygen and / or nitrogen. Non-limiting examples of heterocyclic radicals include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0042] The term "5-12 membered heterocyclic group" refers to a cyclic structure composed of 5 to 12 atoms, which contains at least one non-carbon heteroatom (such as N, O, S, etc.), and all atoms in the ring are connected by single bonds or double bonds to form a closed system.

[0043] The term "5- to 12-membered heterocyclic group having one heteroatom selected from the group consisting of N, S and O" refers to a 5- to 12-membered heterocyclic group containing one N, S or O.

[0044] The term "a cyclic ring consisting of a 6-membered aromatic ring and a 5-membered aromatic heterocycle having one heteroatom selected from the group consisting of N, S, and O" refers to a cyclic ring consisting of a 6-membered aromatic heterocycle or a 6-membered non-aromatic heterocycle (benzene ring) and a 5-membered aromatic heterocycle containing one heteroatom (such as N, O, S, etc.).

[0045] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen groups. Examples include, but are not limited to, -CF3, etc.

[0046] The term "haloaryl" refers to an aryl group substituted with one or more halogen groups, examples of which include, but are not limited to wait.

[0047] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0048] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: it has excellent DDR1 degradation activity and anti-cell proliferation activity, and can be used to prepare a pharmaceutical composition for treating cancer and other DDR1 activity-related diseases. DETAILED DESCRIPTION

[0049] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0050]

[0051] in:

[0052] X1 is selected from the following group: H, C1-C5 alkyl, hydroxyl, (CH2) n NH p (CH3) 3-p , C1-C5 alkoxy, C1-C5 alkylthio, halogen, C1-C5 haloalkyl, C6-C 10 Aromatic ring, C6-C 10 Cycloalkyl, C6-C 10 Halogenated aryl, a 5-12 membered heterocyclic group having one heteroatom selected from the group consisting of N, S and O, a 6-membered aromatic ring and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S and O, a C 10 -C 16 Condensed ring aromatic group; n = 0-5, p = 0-3;

[0053] R1 is selected from the group consisting of H, halogen, -OH, a 5-6 membered saturated heterocyclic group containing one N atom, and a 5-6 membered saturated heterocyclic group containing one N atom and one O atom;

[0054] R2 is selected from the group consisting of H, halogen, (CH2) n NH p (CH3) 3-p , C1-C6 alkyl.

[0055] The compound of formula I of the present invention can be prepared by the following exemplary method:

[0056]

[0057] The compound of formula I is obtained by reacting 4-piperidone hydrochloride with 5-formaldehyde containing different substituents.

[0058] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0059] Key intermediate 1.2-((1H-indol-4-yl)amino)pyrimidine-5-carboxaldehyde

[0060]

[0061] 4-Aminoindole (1 mmol), 5-bromo-2-chloropyrimidine (1.05 mmol), and 4 M dioxane hydrochloride solution (1.5 mmol) were added to ethanol and reacted under reflux for 8 h. After the reaction, the mixture was dried under reduced pressure without purification.

[0062] A mixture of the above compound (0.0112 mol), dichlorobis(triphenylphosphine)palladium (0.00228 mol), sodium formate (0.0336 mol), and magnesium sulfate (1 g) in DMF (50 ml) was stirred at 100°C in the presence of carbon monoxide for 20 hours. The mixture was filtered through celite and then poured into water. The precipitate was filtered, washed with water and Et2O, and dried to obtain the key intermediate 1. MS (ESI): M / Z = 239.2 [M+H] + .

[0063]

[0064]

[0065] Example 1. (3E,5E)-3,5-bis(pyrimidin-5-ylmethylene)piperidin-4-one

[0066]

[0067] Pyrimidine-5-carboxaldehyde (1.24 g, 11.5 mmol) and 4-piperidone hydrochloride monohydrate (860 mg, 5.6 mmol) were added to 15 mL of glacial acetic acid and stirred for 5 minutes. Dry hydrogen chloride gas was passed through the mixture for approximately 50 minutes until a clear solution was obtained. The reaction mixture was stirred at room temperature for 18 hours. The precipitate formed by the reaction was collected by filtration and stirred with a mixture of saturated aqueous potassium carbonate and EA at room temperature for 1 hour. The free base was collected by filtration, washed with ice water, and dried under vacuum to obtain the title compound. MS (ESI): M / Z = 380 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.04(t,J=1.7Hz,1H),8.79–8.74(m,2H),7.85(t,J=0.9Hz,1H),4.05(p,J=4.1Hz,1H),3.87(dd,J=4.2,0.9Hz,2H).

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] Biological activity test example 1: DDR1 degradation activity test

[0081] In HCT116 cells, molecular cloning technology was used to add an 11-amino acid HiBiT peptide tag to the DDR1 protein. After adding Lytic reagent to lyse the cells, the complementary polypeptide LgBiT in the reagent combined with HiBiT to form a complete Nanoluciferase, which emitted bright fluorescence after reacting with the substrate. The luminescence intensity was proportional to the amount of HiBiT-labeled DDR1 in the cell lysate, successfully constructing the HCT116 DDR1-HiBiT cell screening system. HCT116 DDR1-HiBiT cells were plated in 96-well white plates with 3,000 cells per well. After 24 hours, the above compounds were added to the cells at a concentration of 10 μM. After incubation in the cell culture incubator for 24 hours, the cells were screened using Nano- HiBiT Lytic Reagent (Promega) was used for the assay. The amount of HiBiT reagent is usually equal to the total amount to be added to the well plus the additional amount required for dispensing. Dilute LgBiT protein 1:100 and Nano- HiBiT reagent substrate 1:50 to an appropriate volume of room temperature Nano- Add 20 μL of detection solution to each well and shake for about 3 minutes to fully lyse the cells. Place the cells in a microplate reader to measure the chemiluminescence signal.

[0082] The average values of the positive and negative wells were calculated as the positive control value (Signalpos, usually DMSO) and the negative control value (Signalneg, usually parent cells). The degradation rate of the working well signal value (Signaltest) was calculated according to the formula Degradation Rate (%) = (1-Signaltest-Signalneg / Signalpos-Signalneg) × 100%. The calculated inhibition rate was used to draw a concentration-inhibition rate curve using nonlinear fitting in GraphPad Prism software, and DC was calculated. 50 value.

[0083] Biological activity test example 2: cell antiproliferative activity test

[0084] NSCLC cell lines (A549, NCI-H1703, NCI-H358) and DLBCL cell lines (U-2932, Pfeiffer) with high DDR1 expression were used to test the anti-proliferative effects of the compounds. A certain number of cells were cultured in 96-well white plates, and the compounds were diluted in a gradient and added to the cells. After incubation for 48 hours, the cells were treated with CelTiter- 3D CellViability Kit detects cell viability. The principle of this kit is that living cells contain ATP, while dead cells do not. The proprietary lysis buffer in the 3D kit lyses cells, releasing ATP and activating the luciferase reaction. A microplate reader is used to detect the chemiluminescent signal, which is generated by the reaction of ATP with the luciferase / luciferin substrate. The luminescence intensity is proportional to cell activity. The specific steps are: 1) Remove the cell culture plate and equilibrate at room temperature for ~30 minutes (to allow for a uniform temperature and ensure a stable reaction); 2) Add reagents: Add 20μL of CelTiter-4 to each well of the 96-well plate. Add 3D detection solution to the cell culture medium; 3) Lyse cells: Gently shake for 3-5 minutes to mix; 4) Read the luminescence signal: Use a microplate reader to read the luminescence signal value.

[0085] The inhibition rate was calculated according to the formula Inhibition Rate (%) = (1-Signaltest-Signalneg / Signalpos-Signalneg) × 100%. The calculated cell proliferation inhibition rate was used to draw a concentration-inhibition rate curve using nonlinear fitting in GraphPad Prism software, and the IC 50 value.

[0086] Biological activity test example 3: Test of compound inhibition rate on USP7 enzyme activity

[0087] The Ub-AMC / Rho method was used to detect the inhibitory effect of compounds on USP7 enzyme activity.

[0088] Principle: Ub-AMC / Rho is a fluorescent substrate: a fluorescent group, AMC (7-amino-4-methylcoumarin) or Rhodamine, is attached to the C-terminus of ubiquitin (Ub). Before cleavage, AMC or Rhodamine is masked by ubiquitin and lacks strong fluorescence. When a deubiquitinating enzyme (DUB) cleaves the bond between Ub and AMC or Rhodamine, the free AMC or Rhodamine is released, generating intense fluorescence. The increase in fluorescence signal is proportional to DUB activity, enabling real-time, quantitative detection of DUB enzymatic activity.

[0089] Specific steps: Prepare enzyme activity assay buffer containing 40 mM Tris (Tris), pH 7.5; 20 mM magnesium chloride (MgCl2); 0.1 mg / ml bovine serum albumin (BSA); and 50 μM dithiothreitol (DTT). Dissolve the compound in pure DMSO to a 10 mM stock concentration. Serially dilute the compound in DMSO, starting at 100 μM, in triplicate for a total of six concentrations. Dilute the compound 1:20 in enzyme activity assay buffer and add 1 μL of the diluted compound to the working wells, with triplicate wells for each concentration. Add 1 μL of the 1:20 diluted DMSO solution to both the negative and positive control wells. Prepare a 2.5× substrate / ATP working solution containing enzyme activity assay buffer and 0.5 μg / μL substrate peptide probe (Ub-AMC / Rho). Add 2 μL of the 2.5× substrate working solution to each working well. Prepare 2.5× enzyme reaction working solution containing 2.5ng / μL USP7 recombinant protein enzyme activity test buffer, add 2μ1 of 2.5× enzyme reaction working solution to each working well, and only add 2μL of enzyme activity test buffer to the negative control well. Stick the sealing film and centrifuge it, place it at room temperature for 1h, add 5μL of detection reagent to each well after the reaction is completed, react at room temperature for 40min, and measure the final luminescent signal. Calculate the average values of the positive wells and negative wells respectively as the positive control value (Signalpos) and the negative control value (Signalneg). The inhibition rate of the working well signal value (Signaltest) is calculated according to the formula Inhibition Rate (%) = (1-Signaltest-Signalneg / Signalpos-Signalneg) × 100%. The calculated inhibition rate is used to draw a concentration-inhibition rate curve by nonlinear fitting in GraphPad Prism software, and the IC is calculated. 50 The experimental results are shown in the following table:

[0090] Table 1 DDR1 degradation activity and cell anti-proliferation activity test results

[0091]

[0092]

[0093] Among them, in DDR1 DC 50 In the test, A means 1μM≤DC 50 ≤3μM; B means 3μM<DC 50 ≤5μM; C represents DC 50 Values > 5 μM. IC of USP7 50 In the test, A means 10nM≤IC 50 ≤500nM; B means 500nM<IC 50≤1μM; C means 1μM<IC 50 ≤10μM. In the cell anti-proliferation activity test, A means 100nM≤IC 50 ≤1μM; B means 1μM<IC 50 ≤5μM; C means 5μM<IC 50 ≤10μM.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, in: X1 is selected from the following group: H, C1-C5 alkyl, hydroxyl, (CH2) n NH p (CH3) 3-p , C1-C5 alkoxy, C1-C5 alkylthio, halogen, C1-C5 haloalkyl, C6-C 10 Aromatic ring, C6-C 10 Cycloalkyl, C6-C 10 Halogenated aryl, a 5-12 membered heterocyclic group having one heteroatom selected from the group consisting of N, S and O, a 6-membered aromatic ring and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S and O, a C 10 -C 16 Condensed ring aromatic group; n = 0-5, p = 0-3; R1 is selected from the group consisting of H, halogen, -OH, a 5-6 membered saturated heterocyclic group containing one N atom, and a 5-6 membered saturated heterocyclic group containing one N atom and one O atom; R2 is selected from the group consisting of H, halogen, (CH2) n NH p (CH3) 3-p , C1-C6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that X1 is selected from the following groups: H, methyl, butyl, hydroxy, amino, dimethylamino, C1-C5 alkoxy, C1-C5 alkylthio, halogen, haloalkyl, C6-C 10 Aromatic ring, C6-C 10 Cycloalkyl, halogenated phenyl, 5-6 membered saturated heterocyclic group containing one N or O atom, a cyclic ring composed of benzene and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S, and O, a cyclic ring composed of pyrimidine and a 5-membered aromatic heterocyclic ring having one heteroatom selected from the group consisting of N, S, and O, naphthyl, anthracenyl, phenanthrenyl, and pyrenyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that X1 is selected from the following group: H, methyl, propyl, isobutyl, trifluoromethyl, cyclohexane, hydroxy, amino, methoxy, methylthio, dimethylamino, phenyl, piperidinyl, tetrahydropyrrolyl, ethylthio, fluorophenyl, naphthyl, tetrahydrofuranyl, indolyl, benzofuranyl, benzothiophenyl, thienopyrimidinyl, benzothiazolyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from the group consisting of H, halogen, -OH, piperidinyl, and morpholinyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R2 is selected from the group consisting of amino, -NHCH3, and methyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that Has any of the following structures:

7. A method for preparing the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I is obtained by reacting 4-piperidone hydrochloride with a 5-formaldehyde intermediate.

8. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to any one of claims 1 to 6 or pharmaceutically acceptable salts thereof.

9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a DDR1 degradation agent.

10. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug, wherein the tumor is a DDR1-related tumor.

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