Preparation method of HPK1 inhibitor and intermediate thereof

Abstract

The invention provides a preparation method of an HPK1 inhibitor and an intermediate thereof, which comprises the following steps: step 4, reacting a compound 7 with a compound 8 or a salt thereof in the presence of phosphate and a palladium catalyst to obtain a compound 9; 5, carrying out hydrolysis reaction on the compound 9 in inorganic alkali to obtain a compound 10; 6, the compound 10 and a compound 6 are subjected to a condensation reaction under the condition of organic alkali, and a compound 11 is obtained; the phosphate in the step 4 is selected from potassium phosphate, cesium phosphate, sodium phosphate, potassium hydrogen phosphate or sodium hydrogen phosphate. The new route provided by the invention is simple to operate and mild in condition, the final product can be obtained at high yield, and the process stability is good; efficient preparation of key intermediates is achieved, a solid foundation is laid for industrial enlarged production of products, and wide market application prospects and important social and economic values are shown.

Description

Technical Field

[0001] This invention relates to methods for preparing HPK1 inhibitors and their intermediates, and belongs to the fields of pharmaceutical and chemical technology. Background Technology

[0002] DS21150768 is a potent orally administered active HPK1 inhibitor that demonstrates effective activity in enhancing T cell function, playing a vital role in the pharmaceutical field. However, its synthesis method is not currently reported. The combination of DS21150768 and anti-PD-L1 significantly inhibits tumor growth, indicating that their synergistic effect can overcome the immune resistance of poorly immunogenic tumors. This combination therapy highlights a promising strategy aimed at cancers that evade immune surveillance due to low tumor antigenicity, thereby broadening the potential application of immunotherapy in drug-resistant tumor types.

[0003] Therefore, designing and implementing a synthesis method that is suitable for industrial production, easy to operate, and has a high yield has become a key focus of research and development for those skilled in the art. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the first aspect of this invention provides a method for preparing compound 11, comprising the following steps:

[0005] Step 4: Compound 7 reacts with compound 8 or its salt in the presence of phosphate and palladium catalyst to give compound 9;

[0006] Step 5: Compound 9 undergoes a hydrolysis reaction in an inorganic base to obtain compound 10;

[0007] Step 6: Compound 10 and Compound 6 undergo a condensation reaction under organic base conditions to obtain Compound 11;

[0008]

[0009]

[0010] Step 4: The phosphate is selected from potassium phosphate, cesium phosphate, sodium phosphate, potassium hydrogen phosphate, or sodium hydrogen phosphate;

[0011] X1 is independently selected from F, Cl, and Br, and X0 is selected from Cl, Br, and I, with X0 having a higher activity than X1;

[0012] As a further improvement of the present invention, the activity of X0 is greater than that of X1. In the aminoalkylation (nucleophilic substitution reaction) of haloalkanes, the order of activity of leaving groups is I>Br>Cl>F; when X1 is F, X0 is selected from Cl, Br, I; when X1 is Cl, X0 is selected from Br, I; when X1 is Br, X0 is selected from I.

[0013] R1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl or tert-pentyl;

[0014] R2 is H or an amino protecting group, wherein R2 is not always H, and the amino protecting group is selected from tert-butoxycarbonyl, p-valeryl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

[0015] As a further improvement of the present invention, step 4 is carried out in a solvent, wherein the solvent is selected from one or more of toluene, xylene, dioxane, tert-butanol, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or water;

[0016] As a further improvement of the present invention, the solvent in step 4 is a combination of dioxane and water, wherein the volume ratio of dioxane to water is 1:(0.1 to 0.5), preferably 1:(0.1 to 0.3);

[0017] As a further improvement of the present invention, the volume of solvent used in step 4 (mL) is 5 to 15 times the mass of compound 7 (g), preferably 8 to 12 times.

[0018] As a further improvement of the present invention, the molar ratio of compound 7 to phosphate in step 4 is 1:(1-5), preferably 1:(2-4);

[0019] As a further improvement of the present invention, the palladium catalyst in step 4 is selected from Pd(PPh3)4, Pd(OAc)2, PdCl2(dppf), Pd2(dba3), Pd(dba2) or Pd(dppf)2Cl2;

[0020] As a further improvement of the present invention, the molar ratio of compound 7 to palladium catalyst in step 4 is 1:(0.01-0.07), preferably 1:(0.03-0.06;

[0021] As a further improvement of the present invention, the reaction temperature in step 4 is 50-100°C, preferably 70-90°C;

[0022] As a further improvement of the present invention, the reaction time in step 4 is 8 to 18 hours, preferably 10 to 17 hours;

[0023] As a further improvement of the present invention, the inorganic base in step 5 is selected from one or any combination of alkali metal carbonates, alkali metal hydroxides, or alkaline earth metal hydroxides; the inorganic base is selected from one or any combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, or barium hydroxide; preferably one or any combination of lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0024] As a further improvement of the present invention, the molar ratio of compound 9 to inorganic base in step 5 is 1:(1-5), preferably 1:(3-5);

[0025] As a further improvement of the present invention, step 5 is carried out in a solvent, wherein the solvent is selected from one or more of alcohol solvents, ether solvents or water; preferably, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, isobutanol, n-pentanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, and water.

[0026] As a further improvement of the present invention, the solvent in step 5 is selected from a combination of methanol, tetrahydrofuran and water, wherein the volume ratio of methanol, tetrahydrofuran and water is 1:1:(0.3-1); preferably 1:1:(0.5-0.8).

[0027] As a further improvement of the present invention, the volume of solvent used in step 5 (mL) is 3 to 25 times the mass of compound 9 (g); preferably 5 to 20 times.

[0028] As a further improvement of the present invention, the preferred reaction solvent in step 5 is selected mainly from the viewpoints of reactivity, selectivity and ease of acquisition. The inventors only used alcohol solvents, which resulted in a large amount of raw materials not reacting, which was not conducive to the reaction. However, when methanol was used in combination with ether solvents and water, it was unexpectedly found that the reaction effect was good and the yield could reach 90% or more.

[0029] As a further improvement of the present invention, the reaction temperature in step 5 is 40-60°C, preferably 45-55°C;

[0030] As a further improvement of the present invention, the reaction time of step 5 is 8 to 18 hours, preferably 10 to 17 hours;

[0031] As a further improvement of the present invention, step 6 is carried out in an organic solvent, wherein the solvent is selected from one or more of ether solvents, haloalkane solvents, sulfone solvents or amide solvents, preferably haloalkane solvents; the haloalkane solvent is selected from dichloromethane, dichloroethane or chloroform, preferably dichloromethane; the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran or dioxane, preferably dioxane; the sulfone solvent is dimethyl sulfoxide; the amide solvent is selected from N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide, preferably N,N-dimethylformamide;

[0032] As a further improvement of the present invention, most preferably, the solvent in step 6 is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide or dimethyl sulfoxide;

[0033] As a further improvement of the present invention, the organic base in step 6 is selected from N,N-diisopropylethylamine, diethylamine, triethylamine, pyridine, triethylenediamine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, 2,6-dimethylpyridine, imidazole or N-methylimidazole; preferably N,N-diisopropylethylamine;

[0034] As a further improvement of the present invention, the molar ratio of compound 10 to organic base in step 6 is 1:(1-4), preferably 1:(2-3);

[0035] As a further improvement of the present invention, the condensing agent in step 6 is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), O-(benzotriazole-1-yl) The following are options: 1-N,N,N',N'-tetramethylureonium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethylureonium hexafluorophosphate (HOTU), or propylphosphonic anhydride (T3P); preferably at least one of EDCI, HOBT, DCC, HBTU, HATU, and CDI.

[0036] As a further improvement of the present invention, the molar ratio of compound 10 to condensing agent in step 6 is 1:(1-3), preferably 1:(1-2);

[0037] As a further improvement of the present invention, the molar ratio of compound 10 to compound 6 in step 6 is 1:(1~1.5);

[0038] As a further improvement of the present invention, the temperature of the reaction in step 6 is 15-30°C;

[0039] As a further improvement of the present invention, the reaction time in step 6 is 8 to 18 hours, preferably 10 to 17 hours;

[0040] As a further improvement of the present invention, the method for preparing compound 11 further includes a method for preparing compound 6, the method for preparing compound 6 comprising the following steps:

[0041] Step 1: Under alkaline conditions, compound 1 reacts with an amino protecting agent to give compound 2;

[0042] Step 2: Compound 2 undergoes a Suzuki-Miyaura coupling reaction with compound 3 under alkaline and palladium catalytic conditions to give compound 4;

[0043] Step 3: Compound 4 undergoes a Suzuki-Miyaura coupling reaction with compound 5 under alkaline and palladium catalytic conditions to give compound 6;

[0044]

[0045] X2 is selected from Br and I, and X3 is selected from Cl and Br, with X2 having a higher activity than X3;

[0046] As a further improvement of the present invention, the activity of X2 is greater than that of X3. In the aminoalkylation (nucleophilic substitution reaction) of haloalkanes, the order of activity of leaving groups is I>Br>Cl; when X3 is Cl, X2 is selected from Br and I; when X3 is Br, X2 is selected from I.

[0047] R2 is H or an amino protecting group, wherein R2 is not simultaneously H, and the amino protecting group is selected from tert-butoxycarbonyl, p-valeryl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

[0048] The R3 groups are each independently selected from the following groups:

[0049]

[0050] As a further improvement of the present invention, the amino protection reaction described in step 1 is a conventional amino protection method well known to those skilled in the art, and a suitable amino protecting reagent can be selected according to the protecting group and reactivity; the amino protecting reagent is di-tert-butyl dicarbonate.

[0051] As a further improvement of the present invention, the method of the amino protection reaction in step 1 is as follows: in an organic solvent, compound 1 reacts with an amino protection reagent in the presence of a base and a catalyst to obtain compound 2;

[0052] As a further improvement of the present invention, the molar ratio of compound 1 to amino protecting agent in step 1 is 1:(2-3);

[0053] As a further improvement of the present invention, step 1 is carried out in an organic solvent, wherein the organic solvent is selected from one or any combination of ether solvents, haloalkane solvents, or nitrile solvents, preferably nitrile solvents; the nitrile solvent is acetonitrile; the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran, or dioxane, preferably dioxane; the haloalkane solvent is selected from dichloromethane, dichloroethane, or chloroform, preferably dichloromethane;

[0054] As a further improvement of the present invention, the organic solvent in step 1 is more preferably one or more of dichloromethane, tetrahydrofuran, dioxane, or acetonitrile;

[0055] As a further improvement of the present invention, the volume of the organic solvent used in step 1 (mL) is 5 to 30 times the mass of compound 1 (g), preferably 10 to 20 times.

[0056] As a further improvement of the present invention, the alkali mentioned in step 1 is an inorganic alkali or an organic alkali;

[0057] As a further improvement of the present invention, the inorganic base mentioned in step 1 is selected from potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or lithium carbonate, preferably sodium bicarbonate or cesium carbonate.

[0058] As a further improvement of the present invention, the organic base mentioned in step 1 is selected from N,N-diisopropylethylamine, diethylamine, triethylamine, pyridine or 2,6-dimethylpyridine, preferably triethylamine or diethylamine;

[0059] As a further improvement of the present invention, the molar ratio of compound 1 to organic base in step 1 is 1:(1-4), preferably 1:(2-3.5);

[0060] As a further improvement of the present invention, a catalyst may be selectively added in step 1, wherein the catalyst is selected from 4-dimethylaminopyridine (DMAP) and 4-pyrrolidinylpyridine (PPY), preferably DMAP;

[0061] As a further improvement of the present invention, the molar ratio of compound 1 to catalyst in step 1 is 1:(0.05~0.15);

[0062] As a further improvement of the present invention, the temperature of the reaction in step 1 is 15-30°C;

[0063] As a further improvement of the present invention, the reaction time in step 1 is 8 to 18 hours, preferably 10 to 17 hours;

[0064] As a further improvement of the present invention, step 2 is carried out in a solvent, wherein the solvent is a combination of an ether solvent and water, wherein the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran or dioxane; the volume ratio of the ether solvent to water is 1:(0.1-0.4), preferably 1:(0.2-0.3);

[0065] As a further improvement of the present invention, the base in step 2 is an organic base or an inorganic base. The inorganic base is selected from potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or lithium carbonate. The organic base is selected from triethylamine, pyridine, diisopropylethylamine, or N,N-dimethylaniline, preferably potassium phosphate, sodium phosphate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate, and more preferably potassium phosphate or sodium phosphate.

[0066] As a further improvement of the present invention, the molar ratio of compound 3 to base in step 2 is 1:(1-4), preferably 1:(2.5-3.5);

[0067] As a further improvement of the present invention, the palladium catalyst in step 2 is selected from Pd(PPh3)4, Pd(OAc)2, PdCl2(dppf), Pd2(dba3), Pd(dba2) or Pd(dppf)2Cl2;

[0068] As a further improvement of the present invention, the molar ratio of compound 3 to palladium catalyst in step 2 is 1:(0.01-0.07), preferably 1:(0.03-0.06;

[0069] As a further improvement of the present invention, the molar ratio of compound 3 to compound 2 in step 2 is 1:(1~1.5);

[0070] As a further improvement of the present invention, the reaction temperature in step 2 is 50-100°C, preferably 70-90°C;

[0071] As a further improvement of the present invention, the reaction time in step 2 is 8 to 18 hours, preferably 10 to 17 hours;

[0072] As a further improvement of the present invention, the solvent in step 3 is selected from a combination of ether solvent and water, wherein the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran or dioxane; the volume ratio of the ether solvent to water is 1:(0.1-0.4), preferably 1:(0.2-0.3);

[0073] As a further improvement of the present invention, the base in step 3 is an organic base or an inorganic base, wherein the inorganic base is potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or lithium carbonate, and the organic base is triethylamine, pyridine, diisopropylethylamine, or N,N-dimethylaniline; preferably sodium carbonate, potassium carbonate, potassium bicarbonate, or sodium bicarbonate, more preferably potassium carbonate or sodium carbonate;

[0074] As a further improvement of the present invention, the molar ratio of compound 4 to base in step 3 is 1:(1-4), preferably 1:(2.5-3.5);

[0075] As a further improvement of the present invention, the palladium catalyst in step 3 is selected from Pd(PPh3)4, Pd(OAc)2, PdCl2(dppf), Pd2(dba3), Pd(dba2) or Pd(dppf)2Cl2;

[0076] As a further improvement of the present invention, the molar ratio of compound 4 to catalyst in step 3 is 1:(0.01-0.07), preferably 1:(0.03-0.06;

[0077] As a further improvement of the present invention, the molar ratio of compound 4 to compound 5 in step 3 is 1:(1~1.5);

[0078] As a further improvement of the present invention, the reaction temperature in step 3 is 50-100°C, preferably 70-90°C;

[0079] As a further improvement of the present invention, the reaction time in step 3 is 8 to 18 hours, preferably 10 to 17 hours;

[0080] A second aspect of the present invention provides a method for preparing compound 9, the method comprising the following steps:

[0081] Step 4: Compound 7 reacts with compound 8 or its salt in the presence of phosphate and palladium catalyst to give compound 9;

[0082]

[0083] The phosphate mentioned in step 4 is selected from potassium phosphate, cesium phosphate, sodium phosphate, potassium hydrogen phosphate, or sodium hydrogen phosphate;

[0084] The X0, X1, or R1 substituents are defined as described in the first aspect of the invention;

[0085] The conditions and operations for preparing compound 9 of the present invention are as described in any of the steps in step 4 of the first aspect of the present invention.

[0086] A third aspect of the present invention provides a method for preparing compound 10, comprising the following steps:

[0087] Step 5: Compound 9 undergoes a hydrolysis reaction in an inorganic base to obtain compound 10;

[0088]

[0089] The X1 or R1 substituent is defined as described in the first aspect of the invention;

[0090] The conditions and operations for preparing compound 10 of the present invention are as described in any of the steps of step 5 of the first aspect of the present invention;

[0091] A fourth aspect of the present invention provides intermediate compounds of formulas 2, 4, 6, 9, 10, and 11, the structures of which are as follows:

[0092]

[0093] in,

[0094] X1 is independently selected from F, Cl, and Br, and X0 is selected from Cl, Br, and I, with X0 having a higher activity than X1;

[0095] X2 is selected from Br and I, and X3 is selected from Cl and Br, with X2 having a greater activity than X3;

[0096] R1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl or tert-pentyl;

[0097] R2 is H or an amino protecting group, wherein R2 is not always H, and the amino protecting group is selected from tert-butoxycarbonyl, p-valeryl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

[0098] The fifth aspect of the present invention provides a method for preparing an HPK1 inhibitor, including the preparation methods of the first, second, and third aspects above, and preparing an HPK1 inhibitor by removing an amino protecting group from compound 11 described in the fourth aspect of the present invention, or preparing compound 11 by removing an amino protecting group from intermediate compounds 2, 4, 6, 9, and 10, wherein compound 11 is prepared by removing an amino protecting group from compound 11.

[0099] As a further improvement of the present invention, a method for preparing compound 12 of DS21150768 is provided;

[0100]

[0101] Wherein, X1 is F; R2 is H or an amino protecting group, wherein R2 is not simultaneously H, and the amino protecting group is selected from tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

[0102] As a further improvement of the present invention, the method for removing the amino protecting group is a conventional deprotection method well known to those skilled in the art, and a suitable removal method can be selected according to the protecting group and reactivity; when the amino protecting group is tert-butoxycarbonyl, the removal method can be carried out using an acidic system, preferably, the acid is selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.

[0103] Beneficial technical effects of the present invention:

[0104] 1. Through creative labor, this invention has successfully designed and synthesized a series of novel key intermediates for HPK1 inhibitors (compounds 2, 4, 6, 9, 10, and 11). The novel intermediate compounds of this invention contribute to the innovative methods for producing subsequent inhibitor products from them. Furthermore, the preparation methods of the novel intermediate compounds of this invention are simple to operate, have high yields, produce high-quality products, and are easy to implement for large-scale industrial production, laying an important foundation for the large-scale preparation of HPK1 inhibitors.

[0105] 2. This invention is the first to develop a controllable synthesis method for HPK1 inhibitors. Through innovative design of reaction systems and process parameters, a complete preparation route for HPK1 inhibitors has been successfully constructed, filling the technological gap in the field of synthetic chemistry for this type of compound and providing key raw material guarantees for pharmaceutical intermediates, functional materials and other fields.

[0106] 3. Further research revealed that the reaction system exhibits extremely stringent selectivity for the base, particularly concerning the substrate with its unique structure in step 4 of this invention. Surprisingly, phosphate bases demonstrated significant advantages over conventional bases (such as carbonates and hydroxides): not only did they dramatically increase the product yield from 39% to 80% (an increase of over 40%), but more importantly, they effectively suppressed side reactions (such as dehalogenation), achieving unexpected technical results.

[0107] 4. A breakthrough was achieved in step 5 of this invention through systematic screening of reaction conditions. Precisely controlling the reaction temperature within the range of 40-60℃ significantly improves reaction efficiency (reducing reaction time by more than 50%) compared to conventional room temperature reaction conditions. More importantly, by establishing a temperature-sensitive reaction system, a raw material conversion rate of >99% and a product yield consistently above 90% were achieved, completely solving the technical problem of incomplete raw material reaction.

[0108] 5. The route proposed in this invention is simple to operate, operates under mild conditions, can obtain the final product in high yield, and has good process stability; moreover, it realizes the efficient preparation of key intermediates, laying a solid foundation for the industrial-scale production of the product, and showing broad market application prospects and important socio-economic value. Attached Figure Description

[0109] Figure 1 The image shows the H-NMR spectrum of compound 11-1 from Example 6.

[0110] Figure 2 The image shows the H-NMR spectrum of compound 12-1 in Example 7. Detailed Implementation

[0111] The preparation method of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0112] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0113] Example 1

[0114]

[0115] Compound 1-1 (20 g, 66.91 mmol), TEA (20.31 g, 200.71 mmol), DMAP (0.82 g, 6.71 mmol), and acetonitrile (200 mL) were added to a 500 mL single-necked flask and stirred until homogeneous. Boc2O (37.97 g, 173.98 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, dried to dryness, and purified by silica gel column chromatography to give pure compound 2-1 (29.4 g, 88% yield, pink solid).

[0116] 1 H NMR (400MHz, Chloroform-d) δ8.52 (d, J = 2.2 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 1.43 (s, 18H).

[0117] Example 2

[0118]

[0119] Compound 2-1 (10 g, 20.03 mmol), compound 3-1 (3.51 g, 16.02 mmol), K3PO4 (12.76 g, 60.11 mmol), and Dioxane / H2O (160 mL / 40 mL) were added to a 500 mL single-necked flask under Ar protection. Pd(PPh3)4 (1.16 g, 1 mmol) was added, and the mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was washed with water, extracted with dichloromethane, dried to dryness, and purified by silica gel column chromatography to give pure compound 4-1 (6.37 g, 86% yield, brown solid).

[0120] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=2.4Hz,1H),8.02(d,J=2.4Hz,1H),7.10(d,J=8.5Hz,2H),6.66–6.56(m,2H),5.41(s,2H),1.23(s,18H).

[0121] Example 3

[0122]

[0123] Compound 4-1 (1.4 g, 3.01 mmol), compound 5-1 (0.84 g, 3.60 mmol), K2CO3 (1.25 g, 9.04 mmol), and Dioxane / H2O (16 mL / 4 mL) were added to a 100 mL single-necked flask under Ar protection. Pd(PPh3)4 (174 mg, 0.15 mmol) was added, and the mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was washed with water, extracted with dichloromethane, dried to dryness, and purified by silica gel column chromatography to give pure compound 6-1 (1.1 g, 74% yield, yellow solid).

[0124] 1 H NMR (400MHz, Chloroform-d) δ8.68(d,J=2.4Hz,1H),7.90(d,J=2.4Hz,1H),7.26–7.23(m,4H),6.77–6.72(m,2H),3.80(s,2H),2.63(s,6H),1.33(s,18H).

[0125] Example 4

[0126]

[0127] Compound 7-1 (2.4 g, 6.43 mmol), compound 8-1 (975 mg, 6.43 mmol), K3PO4 (4.09 g, 19.27 mmol), and Dioxane / H2O (20 mL / 4 mL) were added to a 100 mL single-necked flask under Ar protection. Pd(PPh3)4 (0.37 g, 0.32 mmol) was added, and the mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried to dryness, and purified by silica gel column chromatography to give pure compound 9-1 (1.85 g, 80% yield, off-white solid).

[0128] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),7.32–7.27(m,3H),7.15–7.06(m,2H), 5.84(d,J=7.8Hz,1H),3.87(s,3H),3.62(d,J=5.5Hz,2H),2.11(d,J=2.5Hz,6H).

[0129] Example 5

[0130]

[0131] Compound 9-1 (0.8 g, 2.22 mmol), LiOH (0.16 g, 6.68 mmol), MeOH (5 mL), THF (5 mL), and water (3 mL) were added to a 100 mL single-necked flask and reacted at 50 °C for 16 h. After the reaction was completed, the pH was adjusted to 1-2 with 2 M HCl, washed with water, extracted with ethyl acetate, and the organic phase was dried under evaporation to obtain pure compound 10-1 (0.69 g, 90% yield, off-white solid).

[0132] 1 H NMR(400MHz,Chloroform-d)δ15.27(s,1H),10.29(s,1H),7.36–7.28(m,3H),7.23 –7.17(m,2H),6.05(d,J=7.9Hz,1H),3.66(d,J=5.8Hz,2H),2.11(d,J=2.5Hz,6H).

[0133] Example 6

[0134]

[0135] Compound 10-1 (0.5 g, 1.44 mol), compound 6-1 (0.85 g, 1.73 mmol), HATU (0.66 g, 1.73 mmol), and DCM (20 mL) were added to a 100 mL single-necked flask under Ar protection. DIPEA (0.56 g, 4.33 mmol) was added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, the mixture was washed with water, extracted with dichloromethane, dried the organic phase, and subjected to silica gel column chromatography to obtain pure compound 11-1 (1.1 g, 93% yield, off-white solid).

[0136] 1 H NMR (400MHz, DMSO-d6) δ12.95(s,1H),10.84(t,J=6.0Hz,1H),8.86(d,J=2.4Hz,1H),8. 24(d,J=2.4Hz,1H),7.78–7.71(m,2H),7.69(d,J=7.8Hz,1H),7.67–7.59(m,1H),7.56( dd,J=7.0,3.3Hz,1H),7.48(ddd,J=9.8,7.8,5.8Hz,4H),7.36(t,J=8.8Hz,2H),6.29(d ,J=8.0Hz,1H),3.78(d,J=5.9Hz,2H),2.69(s,6H),2.06(d,J=2.6Hz,6H),1.24(s,18H).

[0137] Example 7

[0138]

[0139] Compound 11-1 (1.1 g, 1.34 mmol), dichloromethane (10 mL), and HCl / dioxane (4 mL, 4 M) were added to a 100 mL single-necked flask, stirred until homogeneous, and reacted at room temperature for 6 h. After the reaction was complete, the mixture was evaporated to dryness, freed with 5% NaOH, extracted with DCM, washed with water, dried the organic phase, and evaporated to dryness. The mixture was then subjected to silica gel column chromatography to obtain pure compound 12-1 (0.75 g, 90% yield, pale yellow solid).

[0140] 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),10.88(t,J=5.7Hz,1H),8.42(d,J=2.4Hz,1H),7.78–7.64(m,4H),7.56–7.44(m, 4H),7.44–7.29(m,4H),6.29(d,J=8.0Hz,1H),5.98(s,2H),3.78(d,J=6.0Hz,2H),2.44(s,6H),2.07(d,J=2.7Hz,6H).

[0141] Comparative Example 1

[0142] Compound 7-1 (2.4 g, 6.43 mmol), compound 8-1 (975 mg, 6.43 mmol), K2CO3 (2.67 g, 19.32 mmol), and Dioxane / H2O (20 ml / 4 ml) were added to a 100 ml single-necked flask under Ar protection. Pd(PPh3)4 (0.37 g, 0.32 mmol) was added, and the mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was washed with water, extracted with EA, dried the organic phase, and subjected to silica gel column chromatography to obtain pure compound 9-1 (0.9 g, 39% yield, off-white solid).

[0143] Comparative Example 2

[0144]

[0145] Compound 7-2 (0.8 g, 2.84 mmol), compound 8-1 (0.43 g, 2.84 mmol), K2CO3 (1.18 g, 8.54 mmol), and DMF (20 mL) were added to a 100 mL single-necked flask and reacted at 80 °C for 16 h. After the reaction was complete, the mixture was washed with water, extracted with EA, dried the organic phase, and subjected to silica gel column chromatography to obtain pure compound 9-1 (0.46 g, 45% yield, off-white solid).

[0146] Comparative Example 3

[0147] Compound 9-1 (0.8 g, 2.22 mmol), LiOH (0.16 g, 6.68 mmol), MeOH (5 mL), THF (5 mL), and water (3 mL) were added to a 100 mL single-necked flask and reacted at room temperature for 16 h. TLC showed that the reaction was incomplete. After extending the reaction to 32 h, TLC still showed that 10% of the starting material was incompletely reacted. The temperature was raised to 50 °C, and the reaction was completed after 3 h.

[0148] Comparative Example 4

[0149] Compound 9-1 (0.8 g, 2.22 mmol), KOH (0.62 g, 11.1 mmol), and MeOH (20 mL) were added to a 100 mL single-necked flask and reacted at room temperature for 16 h. TLC showed that a large amount of the starting material did not react. After extending the reaction to 32 h, 90% of the starting material was still unreacted by TLC. After heating to 50 °C and reacting overnight, 50% of the starting material remained unreacted.

[0150] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing compound 11, comprising the following steps: Step 4: Compound 7 reacts with compound 8 or its salt in the presence of phosphate and palladium catalyst to give compound 9; Step 5: Compound 9 undergoes a hydrolysis reaction in an inorganic base to obtain compound 10; Step 6: Compound 10 and Compound 6 undergo a condensation reaction under organic base conditions to obtain Compound 11; Step 4: The phosphate is selected from potassium phosphate, cesium phosphate, sodium phosphate, potassium hydrogen phosphate, or sodium hydrogen phosphate; X1 is independently selected from F, Cl, and Br, respectively, and X0 is selected from Cl, Br, and I, with X0 having greater activity than X1; R1 is a C1-C6 alkyl group, preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl or tert-pentyl; R2 is an H or an amino protecting group, wherein R2 is not always H, and the amino protecting group is selected from tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

2. The preparation method according to claim 1, characterized in that, Step (4) satisfies one or more of the following conditions: 1) Step 4 is carried out in a solvent, which is selected from one or more of toluene, xylene, dioxane, tert-butanol, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or water; preferably a combination of dioxane and water, with a volume ratio of dioxane to water of 1:(0.1 to 0.5), more preferably 1:(0.1 to 0.3); 2) The volume of solvent used in step 4 (mL) is 5 to 15 times the mass of compound 7 (g), preferably 8 to 12 times; 3) The molar ratio of compound 7 to phosphate in step 4 is 1:(1-5), preferably 1:(2-4); 4) The palladium catalyst mentioned in step 4 is selected from Pd(PPh3)4, Pd(OAc)2, PdCl2(dppf), Pd2(dba)3, Pd(dba)2 or Pd(dppf)2Cl2; 5) The molar ratio of compound 7 in step 4 to the palladium catalyst is 1:(0.01-0.07), preferably 1:(0.03-0.06). 6) The reaction temperature in step 4 is 50–100°C, preferably 70–90°C; 7) The reaction time in step 4 is 8 to 18 hours, preferably 10 to 17 hours.

3. The preparation method according to claim 1, characterized in that, Step (5) satisfies one or more of the following conditions: 1) The inorganic base mentioned in step 5 is selected from one or any combination of alkali metal carbonates, alkali metal hydroxides or alkaline earth metal hydroxides. Preferably, the inorganic base is selected from one or any combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide; more preferably, one or any combination of lithium hydroxide, sodium hydroxide or potassium hydroxide. 2) The molar ratio of compound 9 to inorganic base in step 5 is 1:(1-5), preferably 1:(3-5); 3) Step 5 is carried out in a solvent, which is selected from one or more of alcohol solvents, ether solvents, or water; preferably methanol, ethanol, n-propanol, isopropanol, isobutanol, n-pentanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, etc. One or more of the following in water; 4) In step 5, the solvent is selected from a combination of methanol, tetrahydrofuran, and water, with a volume ratio of 1:

1. (0.3~1); preferred ratio is 1:1:(0.5~0.8); 5) The volume of solvent used in step 5 (mL) is 3 to 25 times the mass of compound 9 (g); preferably 5 to 20 times. 6) The reaction temperature in step 5 is 40–60°C, preferably 45–55°C; 7) The reaction time for step 5 is 8 to 18 hours, preferably 10 to 17 hours.

4. The method according to any one of claims 1 to 3, characterized in that, Step (6) satisfies one or more of the following conditions: 1) Step 6 is carried out in an organic solvent, the solvent being selected from one or more of ether solvents, haloalkane solvents, sulfone solvents or amide solvents, preferably haloalkane solvents; haloalkane solvents are selected from dichloromethane, dichloroethane or chloroform, preferably dichloromethane; ether solvents are selected from tetrahydrofuran, methyltetrahydrofuran or dioxane, preferably dioxane; sulfone solvents are dimethyl sulfoxide; amide solvents are selected from N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide, preferably N,N-dimethylformamide; most preferably, the solvent in step (6) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide or dimethyl sulfoxide; 2) The organic base in step 6 is selected from N,N-diisopropylethylamine, diethylamine, triethylamine, pyridine, triethylenediamine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, 2,6-dimethylpyridine, imidazole or N-methylimidazolium; preferably N,N-diisopropylethylamine; 3) The molar ratio of compound 10 to organic base in step 6 is 1:(1-4), preferably 1:(2-3); 4) The condensing agent mentioned in step 6 is selected from EDC, DCC, DIC, HATU, CDI, EDCI, HOBT, TBTU, HBTU, HATU, HOTU, or T3P; preferably at least one of EDCI, HOBT, DCC, HBTU, HATU, or CDI; 5) The molar ratio of compound 10 to condensing agent in step 6 is 1:(1-3), preferably 1:(1-2); 6) The molar ratio of compound 10 to compound 6 in step 6 is 1:(1~1.5); 7) The reaction temperature in step 6 is 15–30°C; 8) The reaction time in step 6 is 8 to 18 hours, preferably 10 to 17 hours.

5. A method for preparing compound 6 as described in claim 1, comprising the following steps: Step 1: Under alkaline conditions, compound 1 reacts with an amino protecting agent to give compound 2; Step 2: Compound 2 undergoes a Suzuki-Miyaura coupling reaction with compound 3 under alkaline and palladium catalytic conditions to give compound 4; Step 3: Compound 4 undergoes a Suzuki-Miyaura coupling reaction with compound 5 under alkaline and palladium catalytic conditions to give compound 6; X2 is selected from Br and I, and X3 is selected from Cl and Br, with X2 having a greater activity than X3; R2 is an H or an amino protecting group, wherein R2 is not always H, and the amino protecting group is selected from tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl. R3 is selected independently from the following groups:

6. The production method according to claim 5, wherein Step (1) satisfies one or more of the following conditions: 1) The amino protecting agent is di-tert-butyl dicarbonate; 2) The molar ratio of compound 1 in step 1 to the amino protecting agent is 1:(2-3); 3) Step 1 is carried out in an organic solvent, which is selected from one or any combination of ether solvents, haloalkane solvents or nitrile solvents, preferably nitrile solvents; the nitrile solvent is acetonitrile; the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran or dioxane, preferably dioxane; the haloalkane solvent is selected from dichloromethane, dichloroethane or chloroform, more preferably dichloromethane; most preferably dichloromethane, tetrahydrofuran, dioxane or acetonitrile or one or more. 4) The volume of organic solvent used in step 1 (mL) is 5 to 30 times the mass of compound 1 (g), preferably 10 to 20 times; 5) The base in step 1 is an inorganic or organic base; the inorganic base is selected from potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or lithium carbonate, preferably sodium bicarbonate or cesium carbonate; the organic base is selected from N,N-diisopropylethylamine, diethylamine, triethylamine, pyridine, or 2,6-dimethylpyridine; preferably triethylamine or diethylamine; 6) The molar ratio of compound 1 to organic base in step 1 is 1:(1-4), preferably 1:(2-3.5); 7) In step 1, a catalyst may be selectively added, wherein the catalyst is selected from DMAP and PPY, preferably DMAP; 8) The molar ratio of compound 1 in step 1 to the catalyst is 1:(0.05~0.15); 9) The reaction temperature in step 1 is 15–30°C; 10) The reaction time in step 1 is 8 to 18 hours, preferably 10 to 17 hours.

7. The production method according to claim 5 or 6, characterized by, Step (2) satisfies one or more of the following conditions: 1) Step 2 is carried out in a solvent, which is a combination of an ether solvent and water. The ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran, or dioxane; the volume ratio of the ether solvent to water is 1:(0.1-0.4), preferably 1: (0.2～0.3)； 2) The base mentioned in step 2 is an organic base or an inorganic base. The inorganic base is selected from potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or lithium carbonate. The organic base is selected from triethylamine, pyridine, diisopropylethylamine, or N,N-dimethylaniline. It is preferably potassium phosphate, sodium phosphate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate, and more preferably potassium phosphate or sodium phosphate. 3) The molar ratio of compound 3 to the base in step 2 is 1:(1-4), preferably 1:(2.5-3.5); 4) The palladium catalyst mentioned in step 2 is selected from Pd(PPh3)4, Pd(OAc)2, PdCl2(dppf), Pd2(dba3), Pd(dba)2 or Pd(dppf)2Cl2; 5) The molar ratio of compound 3 in step 2 to the palladium catalyst is 1:(0.01-0.07), preferably 1:(0.03-0.06; 6) The molar ratio of compound 3 to compound 2 in step 2 is 1:(1~1.5); 7) The reaction temperature in step 2 is 50–100°C, preferably 70–90°C; 8) The reaction time in step 2 is 8 to 18 hours, preferably 10 to 17 hours.

8. The production method according to claim 5 or 6, characterized by, Step (3) satisfies one or more of the following conditions: 1) The solvent in step 3 is selected from a combination of ether solvent and water, wherein the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran or dioxane; the volume ratio of the ether solvent to water is 1:(0.1-0.4), preferably 1:(0.2-0.3); 2) The base mentioned in step 3 is an organic base or an inorganic base. The inorganic base is potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or lithium carbonate. The organic base is triethylamine, pyridine, diisopropylethylamine, or N,N-dimethylaniline. Preferably, it is sodium carbonate, potassium carbonate, potassium bicarbonate, or sodium bicarbonate, and more preferably, it is potassium carbonate or sodium carbonate. 3) The molar ratio of compound 4 to the base in step 3 is 1:(1-4), preferably 1:(2.5-3.5); 4) The palladium catalyst mentioned in step 3 is selected from Pd(PPh3)4, Pd(OAc)2, PdCl2(dppf), Pd2(dba3), Pd(dba)2 or Pd(dppf)2Cl2; 5) The molar ratio of compound 4 to catalyst in step 3 is 1:(0.01-0.07), preferably 1:(0.03-0.06; 6) The molar ratio of compound 4 to compound 5 in step 3 is 1:(1~1.5); 7) The reaction temperature in step 3 is 50–100°C, preferably 70–90°C; 8) The reaction time in step 3 is 8 to 18 hours, preferably 10 to 17 hours.

9. An intermediate compound of formulas 2, 4, 6, 9, 10, and 11, having the following structure: in, X1 is independently selected from F, Cl, and Br, respectively, and X0 is selected from Cl, Br, and I, with X0 having greater activity than X1; R1 is a C1-C6 alkyl group, which is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl or pteropentyl; R2 is an H or an amino protecting group, wherein R2 is not always H, and the amino protecting group is selected from tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

10. A method for preparing an HPK1 inhibitor, comprising preparing compound 11 by the method described in claim 1, removing an amino protecting group from compound 11 to prepare an HPK1 inhibitor, or preparing compound 11 using intermediate compounds 2, 4, 6, 9, and 10, and removing an amino protecting group from compound 11 to prepare an HPK1 inhibitor. Preferably, the HPK1 inhibitor is compound 12 (DS21150768), and the preparation method of compound 12 is as follows: wherein X1 is F; R2 is H or an amino protecting group, wherein R2 is not always H, and the amino protecting group is selected from tert-butoxycarbonyl, pivaloyl, acetyl, propionyl, benzyl, allyl, p-methoxybenzyl or benzyloxycarbonyl.

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