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CN118978523A - A triazole heterocyclic compound - Google Patents

A triazole heterocyclic compound Download PDF

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CN118978523A
CN118978523A CN202411061757.1A CN202411061757A CN118978523A CN 118978523 A CN118978523 A CN 118978523A CN 202411061757 A CN202411061757 A CN 202411061757A CN 118978523 A CN118978523 A CN 118978523A
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吴予川
谢永华
刘霄
陈曦
郝蕊
胡永韩
乐美杰
强静
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Shanghai Xinnuo Life Sustaining Pharmaceutical Co ltd
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract

本发明公开了一种如式(I)所示的Cbl‑b抑制剂化合物、其用途及含其的药物组合物，该类抑制剂是潜在的肿瘤免疫治疗剂和自身免疫疾病治疗剂，本发明还公开了该类化合物在治疗肿瘤、I型糖尿病，Graves病、系统性红斑狼疮和多发性硬化症中的应用。 The present invention discloses a Cbl-b inhibitor compound as shown in formula (I), its use and a pharmaceutical composition containing the same. The inhibitor is a potential tumor immunotherapeutic agent and an autoimmune disease therapeutic agent. The present invention also discloses the use of the compound in treating tumors, type I diabetes, Graves' disease, systemic lupus erythematosus and multiple sclerosis.

Description

Triazole heterocyclic compound
Technical Field
The invention relates to a Cbl-b inhibitor compound, application thereof and a pharmaceutical composition containing the same.
Background
Cbl-b (Casitas B-lymphoma) is an E3 ligase containing RING FINGER domain, is mainly expressed in peripheral immune cells, and has the function of regulating various immune cell functions.
In T cells Cbl-b is present in the cytoplasm and recruits to the cell membrane upon stimulation by TCR signaling, exerting a variety of negative regulatory effects on TCR signaling pathways, such as degradation of cd3ζ, reduction of LAT and Vav1 phosphorylation, inhibition of PLC- γ1 activation, etc. Meanwhile, the beta subunit p85 of the ubiquitinated PI3K can also act on the downstream of the CD28, so that the PI3K pathway dependent on the CD28 is inhibited, the T cell activation threshold is lowered, and the activation can be performed without a co-stimulation signal. The Cbl-b knocked-out T cells show remarkable proliferation activity increase, cytokine IL-2 and other expression increase, active marker expression increase, and depletion marker expression decrease, and are more tolerant to Treg, TGF-beta, PD-L1 and other negative regulation signals. Cbl-b knockdown CAR-T cells exhibited stronger tumor killing and better inhibited tumor growth when Cbl-b knockdown T cells were used in combination with immune checkpoint inhibitor CTLA-4 antibodies.
In B cells, molecules downstream of the BCR signaling pathway, such as Syk, PLC-. Gamma.2, p85/PI3K, vav, and Grb2, are all Cbl-B substrates, and their knockdown places B cells in a sustained activated state, such as increased Ca2+ flux and increased expression of activated marker CD 69. In addition, cbl-b plays a regulatory role in innate immune cells such as macrophages, dendritic cells, NK cells and monocytes.
Systemic knockout of Cbl-b in mice did not see significant effects on their growth and reproduction, and only exhibited spontaneous autoimmune disease symptoms such as increased anti-double-stranded DNA autoantibodies in serum, multiple organ inflammatory cell infiltration, and the like. And CBL-B knockout mice are also more sensitive to multiple autoimmune models. The spontaneous tumor incidence of Cbl-b knockout mice is significantly reduced due to the regulatory effect of Cbl-b on various immune cells. The growth of various transplantation tumor models including solid tumor and blood tumor is also obviously inhibited.
In addition, single Nucleotide Polymorphisms (SNPs) and mutations in Cbl-b are associated with a variety of human autoimmune diseases, such as those found in type I diabetes, graves' disease, systemic lupus erythematosus and multiple sclerosis.
In summary, cbl-b is an important regulator of immune cell activity, a potential therapeutic target for tumor immunotherapy and autoimmune diseases.
Disclosure of Invention
The present invention provides a compound of formula (I):
Wherein R 1 is independently C 1-3 alkyl, -CN, halogen or hydroxy, n is 1 or 2
Further, when R 1 is C 1-3 alkyl, R 1 may be optionally substituted with halogen or —cn.
The compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described above may be:
The invention also provides the use of a compound as shown above, or a pharmaceutically acceptable salt thereof, in the preparation of a Cbl-b inhibitor, such as a tumor, type I diabetes, graves disease, systemic lupus erythematosus, multiple sclerosis, and the like.
The invention also provides a pharmaceutical composition comprising a compound as shown above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The structures of the compounds described in the examples below were determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).
The Nuclear Magnetic Resonance (NMR) measuring instrument used a Bruker 400MHz NMR instrument, and the measuring solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3), hexadeuterated dimethyl sulfoxide (DMSO-d 6), and the internal standard substance was Tetramethylsilane (TMS).
Abbreviations in Nuclear Magnetic Resonance (NMR) data in the following examples represent the following meanings:
s: single peak, d: double peak, t: triplet, q: quadruplet, dd: double peak, m: multiple peaks, br: broad peak, J: coupling constant, hz: hertz, delta: chemical shift.
All chemical shift (delta) values are given in parts per million (ppm).
The Mass Spectrum (MS) measuring instrument uses an Agilent 6120B mass spectrometer, and the ion source is an electrospray ion source (ESI).
Intermediate preparation examples
Synthesis of Int-A:
Step 1:
To a solution of methyl 4-bromo-3- (trifluoromethyl) benzoate (20.0 g,70.66 mmol) in sulfuric acid (300.0 mL) was added nitric acid (8.91 g,141.32mmol,6.36 mL). The resulting mixture was stirred at 80℃for 2 hours. TLC monitoring showed that the predominant new spot was generated (PE: ea=5:1, r f =0.1). The mixture was slowly poured into ice water, filtered, and the filter cake concentrated in vacuo to give the crude product Int-A1 (20.0 g,63.69mmol, 90% yield) as a white solid, which was used directly in the next reaction.
Step 2:
To a solution of Int-A1 (20 g,63.69 mmol) in methanol (250.0 mL) was slowly added dropwise sulfuric acid (62.5 g,636.90mmol,33.9 mL). The mixture was stirred at 80℃for 2 hours. TLC showed complete consumption of the reaction and detection of new spots (PE: ea=10:1, r f =0.8). The reaction mixture was poured into 200mL of ice water, filtered, and the filter cake was concentrated under reduced pressure to give the crude product Int-A2 (18.75 g,57.32mmol, yield 90%) as a white solid. 1H NMR(DMSO-d6 400 MHz) δ=8.77 (s, 1H), 8.39 (s, 1H), 3.94 (s, 3H).
Step 3:
Int-A2 (15.0 g,45.73 mmol) was dissolved in ethanol (200.0 mL), followed by iron powder (7.66 g,137.18 mmol), ammonium chloride (7.34 g,137.18 mmol) and water (20.0 mL). The reaction solution was stirred at 25℃for 3 hours. LCMS showed the reaction was consumed. The reaction was filtered, then diluted with 200mL of water and extracted with 300mL of ethyl acetate (150 mL x 2). The combined organic layers were washed with 200mL of saturated brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude Int-A3 (10.0 g,33.55mmol, 73% yield) as a grey solid, which was used directly in the next step, LCMS (ESI) m/z=298.0, 300.0[ m+h ] +.
Step 4:
To a solution of Int-A3 (10 g,33.55 mmol) in pyridine (150 mL) was added potassium ethylsulphonate (10.76 g,67.10 mmol). The reaction solution was stirred at 110℃for 12 hours. LCMS showed the reaction was consumed. The reaction was quenched with 200mL of ice water, then diluted with 100mL of ethyl acetate and extracted with 400mL (200 mL x 2) of ethyl acetate. The combined organic layers were washed with 200mL (100 mL x 2) of saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=10/1 to 1/1) to give Int-a (4.0 g,13.64mmol, 41% yield) as a brown solid, LCMS (ESI) m/z=294.2 [ m+h ] +.
Synthesis of Int-B:
Step 1:
Methyl iodide (14.53 g,102.29 mmol) was added to a solution of Int-A (10 g,34.097 mmol) and potassium carbonate (14.12 g,102.29 mmol) in ethyl acetate (100 mL). The reaction mixture was stirred at room temperature for 16 hours, after which time the solid was removed by filtration, washed twice with ethyl acetate, and the solvent was dried by spin-drying to give Int-B1 (2.0 g, yield 19%) as a yellow solid LCMS (ESI) m/z=307.9 [ m+h ] +.
Step 2:
Lithium aluminum hydride (0.74 g,19.52 mmol) was added to a solution of Int-B1 (3.0 g,9.76 mmol) in tetrahydrofuran (20 mL) at 0deg.C and reacted for 1 hour at 0deg.C. The reaction was quenched with ice water, then filtered through celite, the filter cake was washed several times with ethyl acetate, the filtrate was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried and spin-dried to give Int-B2 (2.3 g, yield 84%) as a yellow solid LCMS (ESI) m/z=280.0 [ m+h ] +.
Step 3:
Manganese dioxide (7.16 g,82.35 mmol) was added to a solution of Int-B2 (2.3 g,8.23 mmol) in dichloromethane (30 mL). The reaction was carried out at room temperature for 16 hours, and the spin-dried solvent was purified by column chromatography to give Int-B3 (1.5 g, yield 66%) as a yellow solid LCMS (ESI) m/z=278.0 [ m+h ] +.
Step 4:
Triethylamine (1.39 g,13.74 mmol) was added to a solution of Int-B3 (635 mg,2.29 mmol) and (S) -3-methylpiperidine hydrochloride (465.94 mg,3.44 mmol) in dichloroethane (20 mL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.97 g,4.58 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 hours. The solvent was then dried and purified by column chromatography to give Int-B (680 mg, 82% yield) as a yellow oil, LCMS (ESI) m/z=361.1 [ m+h ] +.
Synthesis of Int-C:
Step 1:
Int-A (10.0 g,34.1 mmol) was dissolved in acetic acid (100.0 mL) and then iron powder (19.04 g,341.0 mmol) was added. The reaction solution was stirred at 110℃for 16 hours. Then filtered through celite and the filtrate was washed with 100mL ethyl acetate. Then neutralized with 200mL of saturated sodium bicarbonate solution and extracted with 200mL (100 mL x 2) of ethyl acetate. The combined organic layers were washed with 200mL (100 mL x 2) of saturated brine. Dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=5/1 to 3/1) to give Int-C1 (6.5 g,24.88mmol, 73% yield) as a pale yellow solid, LCMS (ESI) m/z=262.2 [ m+h ] +.
Step 2:
To a solution of Int-C1 (2.0 g,7.66 mmol) in tetrahydrofuran (200.0 mL) was added lithium aluminum hydride (581.2 mg,15.31 mmol) at 0deg.C. After the reaction solution was reacted at 0℃for 1 hour, water (15 mL), 15% sodium hydroxide solution (15 mL) and water (45 mL) were added at 0℃to quench the reaction. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=10/1 to 3/1) to give Int-C2 (1.2 g,5.15mmol, 67% yield) as a yellow solid, LCMS (ESI) m/z=233.9 [ m+h ] +. Step 3:
Int-C2 (1.19 g,5.10 mmol) was dissolved in dichloromethane (20.0 mL) and sulfoxide chloride (7.3 g,61.2mmol,4.4 mL) was then added dropwise. The reaction was stirred at 25 ℃ for 1 hour, LCMS monitoring indicated the consumption of the reaction. The reaction solution was concentrated under reduced pressure and dried under vacuum to give crude Int-C (1.2, 4.77mmol, yield 93%) as a brown solid, which was used directly in the next step. LCMS (ESI) m/z=252.2 [ m+h ] +.
Synthesis of Int-D and Int-E:
Step 1:
To a solution of methyl 2- (3-bromophenyl) acetate (20.0 g,87.31 mmol) in DMF (300.0 mL) was added NaH (13.9 g,349.24mmol,60% purity) and stirred at 0deg.C for 1 hour. 1, 3-dibromo-2-methyl-propane (22.6 g,104.77 mmol) was then added to the reaction solution. After stirring the reaction solution for 2 hours at 20 ℃, the reaction was quenched by adding 400mL of aqueous ammonium chloride solution at 0 ℃, then diluted with 200mL of water and extracted three times with ethyl acetate (300 mL x 3). The combined organic phases were washed three times with saturated aqueous saline (300 ml x 3) and dried over sodium sulfate. Filtration and concentration under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 3/1) to give Int-D1 (20.5 g,72.40mmol, yield) as a colorless oil 83％),LCMS(ESI)m/z＝294.2[M+H]+.1H NMR(400MHz,CDCl3)δppm 7.51(dt,J＝4.98,1.79Hz,1H)7.39(tdd,J＝7.70,7.70,1.83,1.10Hz,1H)7.27(s,1H))7.22-7.16(m,1H)3.71-3.60(m,3H)2.91-2.36(m,3H)1.81-1.62(m,2H)1.48(s,3H).
Step 2:
Int-D1 (20.0 g,70.63 mmol) was dissolved in ethanol (100 mL) and hydrazine hydrate (41.6 g,706.31mmol,40.39mL,85% purity) was added. After stirring the reaction solution at 80 ℃ for 16 hours, the reaction was cooled to room temperature, the pH of the solution was adjusted to 3 to 4 with hydrochloric acid solution (1M), then the solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (basic condition) to give Int-D2 (14.5 g,51.21mmol, yield 73%) as a pale yellow oil, LCMS (ESI) M/z=281.1, 283.1[ m+h ] +.
Step 3:
To a solution of Int-D2 (6.0 g,21.19 mmol) in acetonitrile (60.0 mL) was added dropwise N, N-dimethylformamide dimethyl acetal (3.0 g,25.43mmol,3.4 mL) at room temperature. The reaction solution was stirred at 100℃for 1 hour, then acetic acid (1.27 g,21.19mmol,1.2 mL) was added, and a solution of methylamine in ethanol (5.26 g,50.85mmol,30% purity) was added dropwise. The reaction solution was stirred at 100℃for 1 hour. The reaction was concentrated by distillation under the reduced pressure to give residue which was purified by preparative HPLC (FA) to give Int-D (3.0 g,9.80mmol, 46% yield) as a white solid, LCMS (ESI) m/z=306.0, 308.0[ m+h ] +.
Step 4:
Int-D (500.0 mg,1.63 mmol) was dissolved in dioxane (20.0 mL), and bis-pinacolatyldiboron (497.6 mg,1.96 mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride (119.48 mg,0.16 mmol), potassium acetate (240.4 mg,2.45 mmol) was added, degassed and filled with nitrogen three times, and then reacted at 100℃for 1 hour under a nitrogen atmosphere. The reaction was filtered and concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (FA conditions) to give Int-E (500.0 mg,1.42mmol, yield 87%) as a brown oil, LCMS (ESI) m/z=354.5 [ m+h ] +.
Synthesis of Int-F:
Step 1:
Sodium hydride (7.57 g,315.45 mmol) was dissolved in tetrahydrofuran (500 mL) and a solution of trimethyl phosphorylacetate (31.60 g,173.50 mmol) in tetrahydrofuran (50 mL) was added dropwise at 0deg.C, reacted for 1 hour under nitrogen protection at 0deg.C, followed by a solution of 3-oxo-cyclobutanenitrile (15 g,157.73 mmol) in tetrahydrofuran (50 mL). After stirring the reaction solution at room temperature overnight, quenching with aqueous ammonium chloride and extraction with ethyl acetate, spin-drying the organic phase and purifying the organic phase by column (PE/ea=5:1) to give Int-F1 (6.2 g, yield) as a white solid 26％),LCMS(ESI)m/z＝152.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ5.76(p,J＝2.3Hz,1H),3.58–3.45(m,2H),3.40–3.28(m,1H),3.28–3.16(m,2H).
Step 2:
in a 250mL round bottom flask, int-F1 (6.2 g,41.015 mmol) was dissolved in 1, 4-dioxane (60 mL), potassium hydroxide (2.99 g,53.32 mmol) in water (30 mL), (3- ((t-butoxycarbonyl) amino) phenyl) boronic acid (14.58 g,61.52 mmol) and (1, 5-cyclooctadiene) rhodium (I) chloride dimer (1.01 g,2.05 mmol) were added, the reaction mixture was stirred overnight under nitrogen at room temperature, quenched with ammonium chloride solution and extracted with ethyl acetate, the organic phase was dried by column purification (PE/EA (5:1)) to give an off-white solid Int-F2 (4.9 g, yield 35%), S (ESI) m/z=345.0 [ M+H ] +.
Step 3:
In a 250mL round bottom flask, int-F2 (4.9 g,14.23 mmol) was dissolved in tetrahydrofuran (50 mL), lithium hydroxide (0.75 g,17.78 mmol), water (25 mL) and methanol (12.5 mL) were added, stirred overnight at room temperature under nitrogen, the reaction mixture was adjusted to pH 3 with hydrochloric acid solution, then extracted with ethyl acetate, the organic phase was dried by spin-drying to give crude Int-F3 (4.89 g) as an off-white solid, LCMS (ESI) m/z=353.0 [ M+Na ] +.
Step 4:
In a 250mL round bottom flask, int-F3 (4.89 g,14.80 mmol), 4-methyl thiosemicarbazide (2.33 g,22.20 mmol) was dissolved in DMF (50 mL), DIEA (5.74 g,44.40 mmol) and HATU (7.32 g,19.24 mmol) were added, reacted at room temperature under nitrogen for four hours followed by NaOH (1M) (30 mL), reacted overnight at 50℃and the reaction mixture quenched with ammonium chloride solution and extracted with ethyl acetate and the organic phase was dried to give an yellow oil Int-F4 (5.3 g, yield 90%), LCMS (ESI) M/z=400.1 [ M+H ] +.
Step 5:
In a 250mL round bottom flask, int-F4 (5.3 g,13.27 mmol) was dissolved in dichloromethane (50 mL), acetic acid (11.15 g,185.72 mmol) was added, hydrogen peroxide (30%) (1.13 g,33.17 mmol) was added at 0deg.C, the reaction mixture was quenched with sodium bicarbonate solution at room temperature under nitrogen for two hours, then extracted with dichloromethane, the organic phase was dried by column purification (DCM/MeOH (10:1)) to give Int-F5 (5.0 g, 100%) as a yellow oil, LCMS (ESI) m/z=368.1 [ M+H ] +.
Step 6:
In a 250mL round bottom flask, int-F5 (5 g,13.61 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (50 mL) was added, and the reaction was carried out at room temperature under nitrogen for half an hour, and the spin-dried solvent was purified by passing through a reverse phase column (column: C18 silica gel column; mobile phase: acetonitrile aqueous solution (0.1% FA), 10% to 50% gradient elution; UV 254nm monitoring) to give Int-F6 (2.5 g, yield 69%) as a yellow solid, LCMS (ESI) m/z=268.2 [ M+H ] +.
Step 7:
In a 100mL round bottom flask, int-F6 (2.5 g,9.35 mmol), copper bromide (4.18 g,18.70 mmol) was dissolved in acetonitrile (30 mL), tert-butyl nitrite (1.45 g,14.03 mmol) was slowly added at 0deg.C, reacted for one hour under nitrogen at 0deg.C, the reaction solution was quenched with ammonia and extracted with dichloromethane, the organic phase was dried by spin-drying, and purified by reverse phase column (column: C18 silica gel column; mobile phase: acetonitrile aqueous solution (0.1% FA), gradient elution 10% to 50% over 10 min; UV 254nm monitoring) to give Int-F (900 mg, 29% yield) as a yellow solid, LCMS (ESI) m/z=331.0, 333.0[ M+H ] +.
Synthesis of Int-G:
Referring to the synthesis method of Int-E, the method is synthesized by taking Int-F as a raw material. LCMS (ESI) m/z=379.2 [ m+h ] +.
Synthesis of Int-H and Int-I:
Referring to the synthesis of Int-D and Int-E, respectively, 1-bis (bromomethyl) cyclopropane was synthesized as the corresponding starting material to give Int-H (LCMS (ESI) m/z=318.2, 320.2[ m+h ] + as a brown oil, respectively. And Int-I (LCMS (ESI) m/z=366.1 [ m+h ] +).
Synthesis of Int-J and Int-K:
Referring to the synthesis of Int-D and Int-E, respectively, int-J (LCMS (ESI) m/z=334.2, 336.2[ m+h ] +) and Int-K (LCMS (ESI) m/z=379.2 [ m+h ] +) were synthesized as colorless oils using 3-bis (bromomethyl) butylene oxide as the corresponding starting materials.
Synthesis of Int-L:
Step 1:
To a solution of m-bromophenylacetonitrile (18.0 g,91.82 mmol) in THF (300 mL) at 0deg.C was slowly added dropwise magnesium isopropylbromide (1M, 202.0 mL) followed by epichlorohydrin (15.3 g,165.27mmol,13.0 mL). The reaction was stirred at 25℃for 45 minutes, and then slowly added dropwise to magnesium isopropylbromide (1M, 183.6 mL) over 30 minutes, and the reaction was slowly heated to 60℃and stirred for 14 hours. TLC showed complete consumption of the reaction and detection of new spots (ethyl acetate/petroleum ether=2:1, r f =0.4). The reaction solution was slowly poured into ice water, ph=4 was adjusted with 1M HCl, water (400 mL) was added, ethyl acetate (600 mL) was added for extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=3/1 to 1/1) to give Int-L1 (12.2 g, yield 53%) as a pale yellow oil.
Step 2:
Compound Int-L1 (12.0 g,47.60 mmol) was dissolved in EtOH (120 mL), and then sodium hydroxide (7.6 g,190.40 mmol) was added to an aqueous solution (36 mL), and the reaction solution was slowly warmed to 90℃and stirred for 16 hours. LCMS checked the completion of the reaction, and the reaction was adjusted to ph=1-2 with 2M HCl, water (300 mL) was added, extracted with ethyl acetate (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was concentrated to remove the solvent to give crude Int-L2 (11.0 g, 85% yield) as a brown oil, which was used directly in the next step without further purification. LCMS (ESI) m/z= 267.9 ({ 79Br}M-H)-,236.9({81Br}M-H)-).
Step 3:
To a solution of compound Int-L2 (11.0 g,40.57 mmol) in DMF (100 mL) was added HATU (18.5 g,48.69 mmol) and N, N-diisopropylethylamine (10.5 g,81.15 mmol), and finally N-methylhydrazothioformamide (5.1 g,48.69 mmol) and the reaction stirred at 20℃for half an hour. LCMS detects completion of the reaction, the reaction solution was added with water (400 mL), extracted with ethyl acetate (600 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the solvent removed from the residue by concentration, and the residue purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% ammonia), fifteen minutes of 20% to 70% elution; detector, UV 254 nm.) to afford Int-L3 (4.0 g, yield 28%) as a pale yellow solid. LCMS (ESI) m/z= 355.9 ({ 79Br}M-H)－,357.9({81Br}M-H)－).
Step 4:
Compound Int-L3 (3.8 g,10.61 mmol) was added to an aqueous solution (20 mL) of sodium hydroxide (4.2 g,106.07 mmol), and the reaction was stirred at 25deg.C for 16 hours. LCMS detects completion of the reaction, the reaction was adjusted to ph=1-2 with 1M HCl, water (150 mL) was added, ethyl acetate (300 mL) was added to extract, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the solvent was removed by concentration, and the residue was purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% formic acid), 35% to 65% elution for twelve minutes; detector, UV 254 nm.) to afford Int-L4 (3.0 g, 83% yield) as a pale yellow solid. LCMS (ESI) m/z=340.0 ({ 79Br}M+H)+,342.0({81Br}M+H)+).
Step 5:
To a dichloromethane solution (50.0 mL) of the compound Int-L4 (3.0 g,8.81 mmol) were added acetic acid (10.0 mL) and hydrogen peroxide (6.8 g,59.96mmol,30% purity), and the reaction solution was stirred at 25℃for 1 hour. LCMS detected completion of the reaction, and the reaction mixture was concentrated under reduced pressure to give crude Int-L5 (2.5 g, 81% yield) as a pale yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m/z= 307.9 ({ 79Br}M+H)+,309.9({81Br}M+H)+).
Step 6:
To a dioxane solution (2 mL) of compound Int-L5 (100.0 mg,324.49 umol) was added 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (23.7 mg,32.45 umol), potassium acetate (79.6 mg,811.23 umol) and bis-pinacolato borate (90.6 mg,356.94 umol), the mixture was replaced three times with nitrogen, and the reaction mixture was stirred at 100℃for 1 hour. LCMS detects completion of the reaction, the reaction solution is filtered and the filter cake is washed with ethyl acetate. After concentrating the filtrate under reduced pressure, crude Int-L (105.0 mg, yield 91%) was obtained as a dark brown solid, which was used directly in the next step without further purification. LCMS (ESI) m/z=356.1 [ m+h ] +.
Synthesis route of Int-M
Step 1:
To a solution of 3-bromophenylacetonitrile (15 g,76.51 mmol) in DMF (200 mL) was added NaH (9.18 g,229.54mmol,60% purity) in portions at zero degrees Celsius. After the addition, stirring was carried out at 0℃for 1 hour, and then 1, 3-dibromo-2, 2-dimethoxypropane (24.05 g,91.82 mmol) was added at 0 ℃. The resulting mixture was stirred at 60 degrees celsius for 11 hours. TLC showed complete consumption of the reaction and detection of new spots (ethyl acetate/petroleum ether=20:1, r f =0.45). The reaction mixture was quenched at zero degrees celsius with saturated ammonium chloride solution (500 mL), extracted with ethyl acetate (500 mL), the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by normal phase chromatography (mobile phase, petroleum ether/ethyl acetate, 20% to 50% elution for ten minutes; detector, UV 254 nm.) to give Int-M1 (5 g, yield) as a yellow oil 22％).1H NMR(400MHz,CD3OD)δppm 7.65(t,J＝1.77Hz,1H),7.50(m,2H),7.32-7.39(m,1H),3.28(s,3H),3.18(s,3H),3.05-3.11(m,2H),2.71-2.78(m,2H)
Step 2:
Compound Int-M1 (5 g,16.88 mmol), naOH (1.35 g,33.77 mmol), etOH (50 mL) and water (15 mL) were mixed at room temperature and stirred at 90℃for 15 hours. LCMS detects completion of the reaction, pour the reaction into water (200 mL) and extract with ethyl acetate (200 mL). The aqueous phase was adjusted to a pH of about 5 with 1M dilute hydrochloric acid. Ethyl acetate (200 mL) was then added to the mixture to extract, and the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Int-M2 (5.2 g, yield 97%) as a crude yellow solid. Directly used in the next step without further purification. LCMS (ESI) m/z=312.9 ({ 79Br}M-H)-,314.9({81Br}M-H)-).
Step 3:
HATU (7.53 g,19.80 mmol) and DIPEA (4.26 g,33.00 mmol) were added to a solution of Int-M2 (5.2 g,16.50 mmol) in DMF (50 mL) at room temperature followed by 4-methylaminothiourea (2.08 g,19.80 mmol). Stirred at 20 degrees celsius for 16 hours. LCMS detected completion of the reaction, and the reaction mixture was added to an aqueous solution (300 mL), extracted with ethyl acetate (300 mL), and the organic phase was washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude oil Int-M3 (6.6 g, yield 99%). Directly used in the next step without further purification. LCMS (ESI) m/z=370.2 ({ 79Br}M-MeO)+,372.2({81Br}M-MeO)+).
Step 4:
To an aqueous solution (100 mL) of Int-M3 (6.6 g,16.41 mmol) was added NaOH (4.9 g,122.23 mmol) and the mixture was stirred at 20℃for 16 hours. LCMS detected completion of the reaction, the reaction mixture was added to water (300 mL), extracted with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude Int-M4 (6.2 g, yield 98%). Directly used in the next step without further purification. LCMS (ESI) m/z= 384.2 ({ 79Br}M+H)+,386.2({81Br}M+H)+).
Step 5:
HOAc (12 mL) and H 2O2 (19.07 g,168.19mmol,16.16mL,30% purity) were added to a solution of Int-M4 (6.2 g,17.17 mmol) in DCM (60 mL) and stirred at 20deg.C for 1 hour. LCMS detects completion of the reaction, quench the reaction slowly into saturated sodium sulfite solution (300 mL), extract with ethyl acetate (300 mL), wash the organic phase with saturated brine (300 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then separate and purify by C18 reverse phase chromatography column chromatography (mobile phase, acetonitrile/H 2 O (0.1% fa), 30% to 70% rinse for ten minutes; detector, UV 254 nm.) to give Int-M5 (3.1 g, 51% yield) as a colorless oil. LCMS (ESI) m/z= 352.3 ({ 79Br}M+H)+,354.3({81Br}M+H)+).
Step 6:
To a solution of Int-M5 (2.8 g,7.95 mmol) in MeOH (40 mL) at room temperature was added hydrochloric acid (4M, 10 mL) and stirred at 80℃for 12 hours. LCMS detected completion of the reaction, the reaction solution was added to 1300mL of water, extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by C18 reverse phase column chromatography (mobile phase, acetonitrile/H 2 O (0.1% FA), 30% to 70% elution for ten minutes; detector, UV 254 nm.) to give Int-M (2.3 g, 97% yield) as a yellow solid. LCMS (ESI) m/z=306.2 ({ 79Br}M+H)+,308.2({81Br}M+H)+).
Synthetic route for Int-N:
Step 1:
t-BuOK (109.9 mg,0.98 mmol) was added to a solution of Int-M (150.0 mg,0.49mmol and diethyl cyanomethylphosphonate (104.2 mg,0.59 mmol) in THF (10 mL) at zero degrees Celsius and stirred at 20 degrees Celsius for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution to extract, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Int-N1 (160 mg, yield 99%) as a crude yellow oil, which was used in the next step without further purification LCMS (ESI) M/z=329.2 [ m+h ] +.
Step 2:
To a solution of compound Int-N1 (140 mg,425.28 mmole) in methanol (10 mL) was added NaBH 4 (1.8 g,47.31 mmole) in portions at zero degrees Celsius. The mixture was stirred at 20 degrees celsius for 12 hours. LCMS detects completion of the reaction, the reaction was added to water (50 mL), ethyl acetate (50 mL) was added to extract, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% FA), 30% to 70% elution for ten minutes; detector, UV 254 nm.) to give Int-N2 (45 mg, 31% yield) as a colorless oil. LCMS (ESI) m/z=331.2 [ m+h ] +.
Step 3:
To a solution of the compound Int-N2 (35 mg,105.7 umol) in 1,4-dioxane (3 mL) was added B2Pin2(32.20mg,126.81umol),KOAc(20.74mg,211.35umol),Pd(dppf)Cl2(7.73mg,10.57umol), and the reaction solution was purged three times with nitrogen and stirred under an atmosphere of N 2 at 100 degrees celsius for 1 hour. LCMS detected completion of the reaction, and the reaction was filtered with suction and concentrated under reduced pressure to give crude Int-N as a brown oil (39 mg, 97% yield). Directly used in the next step without further purification. LCMS (ESI) m/z=379.3 [ m+h ] +.
Synthetic route of Int-O
Step 1:
To a solution of compound Int-N (500.0 mg,1.62 mmol) in dichloromethane (15 mL) was added triethylamine (328.35 mg,3.24 mmol) and methanesulfonic anhydride (423.94 mg,2.43 mmol), and the reaction was stirred at 20℃for 2 hours. LCMS detected completion of the reaction, water (150 mL) was added to the reaction solution, followed by extraction with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was freed of solvent by concentration, and the residue was purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O,35% to 70% rinse for thirteen minutes; detector, UV 254 nm.) to give Int-O1 (500.0 mg, 80% yield) as a pale yellow solid. LCMS (ESI +)m/z＝385.9({79Br}M+H)+,387.9({81Br}M+H)+).
Step 2:
To a solution of compound Int-O1 (500.0 mg,1.29 mmol) in dimethyl sulfoxide (10 mL) was added potassium cyanide (252.9 mg,3.88 mmol) and potassium carbonate (357.8 mg,2.59 mmol), and the mixture was replaced with nitrogen three times and stirred at 120℃for 16 hours. LCMS detects completion of the reaction, the reaction was quenched by addition of aqueous sodium hypochlorite (150 mL), extracted with additional water (100 mL) and ethyl acetate (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the solvent removed from the residue by concentration, and the residue purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% formic acid), 40% to 65% for eighteen minutes eluting with water; detector, UV 254 nm.) to afford Int-O21 (15.0 mg, yield 4%) as a pale yellow solid and Int-O22 (25.0 mg, yield 6%) as a pale yellow solid. LCMS (ESI +)m/z＝317.0({79Br}M+H)+,319.0({81Br}M+H)+).
Step 3:
To a dioxane solution (1 mL) of compound Int-O21 (15.0 mg,47.29 umol) was added 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (3.5 mg,4.73 umol), potassium acetate (13.9 mg,141.87 umol) and bis-pinacolato borate (14.4 mg,56.75 umol), the mixture was replaced with nitrogen three times, and the reaction mixture was stirred at 100℃for 1 hour. LCMS detects completion of the reaction, the reaction solution is filtered and the filter cake is washed with ethyl acetate. After concentrating the filtrate under reduced pressure, crude Int-O (15.0 mg, yield 87%) was obtained as a dark brown solid, which was used directly in the next step without further purification. LCMS (ESI +)m/z＝365.1[M+H]+).
Synthesis of Int-P
Step 1:
To a solution of compound Int-M (1.0 g,3.27 mmol) in THF (6 mL) at zero degrees, a solution of methylmagnesium bromide in THF (1.6M, 10.21 mL) was added dropwise and the reaction stirred at 20 degrees celsius for 16 hours. LCMS detected completion of the reaction, and the reaction was added to a saturated aqueous NH 4 Cl solution (50 mL) at zero degrees, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the solvent removed by concentration, and the residue purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% FA), 17% to 37% elution for ten minutes; detector, UV 254 nm.) to give Int-P1 (65.0 mg, 8% yield) as a white solid. LCMS (ESI +)m/z＝322.0({79Br}M+H)+,324.0({81Br}M+H)+).
Step 2:
Pd (dppf) Cl 2 (13.6 mg,18.62 mol), KOAc (45.7 mg,465.55 mol) and B 2Pin2 (52.0 mg,204.84 mol) were added to a solution of compound Int-P1 (60.0 mg,186.22 mol) in dioxane (1 mL), and the reaction was stirred at 100℃for 1 hour. LCMS detected completion of the reaction, and the reaction was concentrated under reduced pressure to give Int-P as a black solid (60.0 mg, yield 87%) which was used directly in the next step without further purification. LCMS (ESI) m/z=370.0 [ m+h ] +.
Int-Q synthesis route
Step 1:
To a solution of compound Int-M2 (4.0 g,12.69 mmol) in MeOH (50 mL) at room temperature was added H 2SO4 (9.2 g,91.93 mmol) and stirred at 80℃for 16H. LCMS detected completion of the reaction, the reaction solution was suction filtered, concentrated under reduced pressure, and then purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% FA), 30% to 70% rinse for ten minutes; detector, UV 254 nm) to afford Int-Q1 as a pale yellow solid (1.65 g, yield 45%). LCMS (ESI) m/z=283.0 [ m+h ] +.
Step 2:
BAST (1.41 g,6.36 mmol) was added dropwise to a solution of Int-Q1 (1.5 g,5.30 mmol) in DCM (20 mL) at zero degrees Celsius. After the addition, stirring was carried out at this temperature for 1 hour. The resulting mixture was stirred at 20℃for 16 hours. LCMS checked the completion of the reaction, and the reaction was filtered off with suction, the filter cake was washed with ethyl acetate and water, the filtrate was extracted, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to remove the solvent by concentration to give Int-Q2 as a crude yellow oil (1.6 g, 98% yield). Directly used in the next step without further purification .1H NMR(400MHz,DMSO-d6)δppm 7.50-7.55(m,2H),7.33-7.39(m,2H),3.62(s,3H),3.37-3.47(m,2H),3.15-3.25(m,2H)
Step 3:
NaOH (419.48 mg,10.49 mmol) was added to an aqueous solution (15 mL) of Int-Q2 (1.6 g,5.24 mmol) and stirred at 20deg.C for 12 hours. LCMS checked the completion of the reaction, and the reaction was filtered off with suction, the filter cake was washed with ethyl acetate and water, the filtrate was extracted, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to remove the solvent by concentration to give Int-Q3 as a crude yellow oil (1.43 g, 93% yield). Directly used in the next step without further purification. LCMS (ESI) m/z=288.9 [ m+h ] +.
Step 4:
HATU (2.24 g,5.90mmol,1.2 eq) and DIPEA (1.27 g,9.83 mmol) were added to a solution of Int-Q3 (1.43 g,4.91 mmol), 4-methyl thiosemicarbazide (619.94 mg,5.90 mmol) in DMF (15 mL) and stirred at 20℃for 16 h. LCMS checked the completion of the reaction, and the reaction solution was filtered with suction, the filter cake was washed with ethyl acetate and water, the filtrate was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was concentrated to remove the solvent to give Int-Q4 as a crude brown solid (1.85 g, 99% yield). Directly used in the next step without further purification. LCMS (ESI) m/z=376.0 [ m+h ] +.
Step 5:
to an aqueous solution (20 mL) of Int-Q4 (1.8 g,4.76 mmol) was added NaOH (1.9 g,47.59 mmol) and the mixture was stirred at 20℃for 16 hours. LCMS checked the completion of the reaction, and the reaction was washed with ethyl acetate and water, the filter cake was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was concentrated to remove the solvent to give Int-Q5 as a crude yellow oil (1.71 g, 100% yield). Directly used in the next step without further purification. LCMS (ESI) m/z=360.2 [ m+h ] +.
Step 6:
to a solution of Int-Q5 (1.7 g,4.72 mmol) in DCM (20 mL) was added HOAc (4 mL),
H 2O2 (2 mL) was stirred at 20℃for 1 hour. LCMS detected completion of the reaction, quenched the reaction by addition of saturated sodium sulfite solution, washing the cake with ethyl acetate and water, extracting the filtrate, drying over anhydrous sodium sulfate, concentrating under reduced pressure, removing the solvent from the residue by concentration, and purifying by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% FA), 30% to 70% elution for ten minutes; detector, UV 254 nm.) to afford Int-Q as a colorless oil (585 mg, 37% yield). LCMS (ESI) m/z=328.2
[M+H]+。
EXAMPLE 1 Synthesis of Compound Cpd 13
Step 1:
To a solution of compound Int-C (1 g,3.98 mmol) in acetonitrile (20 mL) was added 1-methylcyclobutyl-1-amine (724.8 mg,5.96 mmol), K 2CO3 (5.5 g,39.74 mmol) and NaI (893.4 mg,5.96 mmol) at room temperature, and the reaction was stirred at 20 degrees celsius for 12 hours. LCMS detects completion of the reaction, the reaction solution is filtered and the filter cake is washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate, 80% to 20% elution for twenty minutes) to give Cpd 13-1 (754 mg, yield 63%) as a yellow oil. LCMS (ESI) m/z=301.3 [ m+h ] +.
Step 2:
To a solution of compound Cpd 13-1 (754 mg,2.52 mmol) in DMF (20 mL) at room temperature was added CbzOsu (938.6 mg,3.76 mmol) and K 2CO3 (1.04 g,7.54 mmol), and the reaction was stirred at 20 ℃ for 2 hours. LCMS checked the completion of the reaction, and the reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate, 80% to 40% eluting for twenty minutes) to give Cpd 13-2 as a yellow solid (1 g, 91% yield). LCMS (ESI) m/z=435.3 [ m+h ] +.
Step 3:
To a solution of compound Cpd 13-2 (1 g,2.3 mmol) in DMF (20 mL) was added CCl 4 (20 mL) at room temperature, then t BuONa (442.3 mg,4.60 mmol) was added to the above system at 0 degrees celsius and the reaction stirred at 20 degrees celsius for 2 hours. LCMS checked the completion of the reaction, and the reaction mixture was added with water (200 mL), extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate, 80% to 40% eluting for twenty minutes) to give Cpd 13-3 as a yellow oil (571 mg, yield 52%). LCMS (ESI)
m/z＝469.2[M+H]+。
Step 4:
To a solution of compound Cpd 13-3 (360 mg,0.76 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added Int-E-P1 (298 mg,0.84 mmol), K 2CO3 (318 mg,2.30 mmol) and Pd (dppf) Cl 2 (56.1 mg,0.076 mmol), and the reaction was purged three times with N 2 and stirred at 100℃for 1 hour under an atmosphere of N 2. LCMS detects completion of the reaction, the reaction solution is filtered off with suction and the filter cake is washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by C18 reverse phase chromatography (mobile phase, acetonitrile/H 2 O (0.1% FA), elution 5% to 80% for twenty minutes; detector, UV 254 nm.) to give Cpd 13-4 as a yellow oil (243 mg, yield 47%). LCMS (ESI) m/z=660.4 [ m+h ] +.
Step 5:
To a solution of compound Cpd 13-4 (243 mg,0.37 mmol) in MeOH (5 mL) was added Pd/C (200 mg) and the reaction was stirred under an H 2 atmosphere at 20℃for 16H. LCMS detects completion of the reaction, the reaction solution is filtered and the filter cake is washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by chromatography on a C18 reverse phase chromatography column (mobile phase, acetonitrile/H 2 O (0.05% aqueous ammonia), 30% to 90% elution for fifteen minutes; detector, UV 254 nm.) to give Cpd 13 as a white solid (138.6 mg, yield) 70％)LCMS(ESI)m/z＝526.4[M+H]+.1H NMR(400MHz,CD3OD)δppm 8.33(s,1H),8.29(s,1H),8.19(s,1H),8.05(br d,J＝6.72Hz,1H),7.88(s,1H),7.57-7.65(m,2H),3.93(s,2H),3.32(br s,3H),2.94-3.08(m,2H),2.57-2.81(m,3H),2.07-2.26(m,2H),1.74-1.98(m,4H),1.42(s,3H),1.18(d,J＝5.99Hz,3H).
The compounds corresponding to examples 2-8 below were obtained by a synthesis similar to that of example 1, substituting the corresponding starting materials.
Effect example biological experimental method
Test compounds were dissolved in 100% DMSO and the stock concentration was 10mM. The initial concentration was tested at 10 μm, diluted in a three-fold gradient, ten data points, each point repeated twice.
The binding constant of the compound to Cbl-b was determined by detecting its competition with a fluorescent probe (BODIPY label). The experiment was performed in 384 well plates using the TR-FRET platform. Each well contained 0.5nM biotin-labeled Cbl-b or 2.5nM Cbl, 50nM fluorescent probe, 1 Xstrepitavidin-Tb (Cisbio) and 0.5% DMSO. The reaction buffer was 20mM Hepes,PH7.5,150mM NaCl,0.01% TritionX-100,0.01% BSA and 0.5M TCEP. The compound was incubated with either Cbl-b or Cbl at 25℃for 10min, and probe and strepavidin-Tb were added. After incubation for 1 hour at 25℃the TR-FRET signal is read at 490/520 nm. From this reading, the percent inhibition of the compound on probe binding was calculated, IC 50 of the compound was calculated using a four parameter fit, see in particular table 1:
TABLE 1
Wherein A represents IC 50 is less than or equal to 100nM; b represents 100nM < IC 50 < 1000nM; c represents 1000nM < IC 50.ltoreq.3000 nM, "-" represents as yet untested.

Claims (5)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Wherein R 1 is independently C 1-3 alkyl, -CN, halogen or hydroxy, n is 1 or 2;
when R 1 is C 1-3 alkyl, R 1 may optionally be substituted by halogen or-CN.
2. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, which is:
3. A pharmaceutical composition comprising a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for the preparation of a Cbl-b inhibitor.
5. The use according to claim 4, comprising tumors, type I diabetes, graves' disease, systemic lupus erythematosus and multiple sclerosis.
CN202411061757.1A 2024-08-02 2024-08-02 A triazole heterocyclic compound Pending CN118978523A (en)

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