Adamantane derivative as well as preparation method and application thereof

Abstract

The invention discloses an adamantane derivative as well as a preparation method and application thereof. The invention specifically discloses an adamantane derivative shown as a formula I or a pharmaceutically acceptable salt thereof. The compound disclosed by the invention has a relatively good inhibition effect on skin melanoma cells and liver cancer cells (HepG2), and has relatively good anti-tumor activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an adamantane derivative, a preparation method and application thereof. Background Art

[0002] Adamantane is a class of compounds with a highly symmetrical cage structure, named for its carbon skeleton, which is equivalent to a basic unit of the natural diamond lattice. Adamantane has poor water solubility and good fat solubility. Its unique structure and physicochemical properties have attracted great attention from scientists. In recent years, research on adamantane has emerged in an endless stream, covering a variety of fields such as pharmacy, organic chemistry, and polymer materials. Since the first discovery of the antiviral activity of 1-adamantaneamine in 1964, studies on the biological activity and mechanism of action of adamantane derivatives have been reported one after another. Studies have shown that most adamantane derivatives have pharmacological effects such as antiviral, antitumor, and antidepressant effects (LAMOUREUX G, ARTAVIAG. Use of the Adamantane Structure in Medicinal Chemistry. Current Medicinal Chemistry, 2010, 17(26):2967-2978.). Compared with the antiviral field, there are relatively few studies on the anti-tumor activity of adamantane derivatives (ROUCHAL M, RUDOLFOVA J, KRYSTOFV, VOJACKOVA V, CMELIK R, VICHAR. Adamantane-substituted purines and their beta-cyclodextrin complexes: synthesis and biological activity. International Journal of Molecular Sciences, 2021, 22(23): 12675). Summary of the Invention

[0003] In response to the shortcomings of current research on adamantane derivatives in anti-tumor and other aspects, the present invention provides a class of adamantane derivatives with anti-tumor activity, their preparation method and application. These compounds have a good inhibitory effect on skin melanoma cells and liver cancer cells (HepG2).

[0004] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0005]

[0006] Among them, R 1 -COOR 1a or H;

[0007] R 1a C 1-6 alkyl;

[0008] R 2 for

[0009] R 3 C 6-10 Aryl, 5-6 membered heteroaryl, one or more R a Substituted C 6-10 Aryl or one or more R b substituted 5-6 membered heteroaryl; said 5-6 membered heteroaryl and one or more R b The heteroatoms in the substituted 5-6 heteroaryl group are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0010] Each R a and R b are independently halogen, C 1-3 Alkyl, hydroxy, nitro or C 1-3 Alkoxy.

[0011] In one embodiment of the present invention, R 1a In the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl.

[0012] In one embodiment of the present invention, R 3 In the C 6-10 Aryl or one or more R a Substituted C 6-10 The aryl group in the aryl group is a phenyl group.

[0013] In one embodiment of the present invention, R 3 wherein the 5-6 membered heteroaryl group is replaced by one or more R b The heteroaryl group in the substituted 5- to 6-membered heteroaryl group is thienyl or thiazinyl.

[0014] In one embodiment of the present invention, R a and R b wherein the halogen is F, Cl, Br or I, preferably F.

[0015] In one embodiment of the present invention, R a and R b In the C 1-3 The alkyl group is methyl, ethyl or n-propyl.

[0016] In one embodiment of the present invention, R a and Rb In the C 1-3 Alkoxy is -OCH3, -OCH2CH3 or -O(CH2)2CH3, preferably -OCH3.

[0017] In one embodiment of the present invention, R 1 -COOR 1a .

[0018] In one embodiment of the present invention, each R a and R b are independently halogen or C 1-3 Alkoxy.

[0019] In one embodiment of the present invention, R 3 for wherein m is an integer from 0 to 5, and n is an integer from 0 to 3. m is preferably 1 or 2. n is preferably 0.

[0020] In one embodiment of the present invention, R 3 for

[0021] In one embodiment of the present invention, R 1 -COOR 1a ;

[0022] R 1a C 1-6 alkyl;

[0023] R 2 for

[0024] R 3 C 6-10 Aryl, 5-6 membered heteroaryl, one or more R a Substituted C 6-10 Aryl, or one or more R b substituted 5-6 membered heteroaryl; said 5-6 membered heteroaryl and one or more R b The heteroatoms in the substituted 5-6 heteroaryl group are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0025] Each R a and R b are independently halogen or C 1-3 Alkoxy.

[0026] In one embodiment of the present invention, R 1 for

[0027] In one embodiment of the present invention, R 2 for

[0028] In one embodiment of the present invention, R 3 for

[0029] In one embodiment of the present invention, each R a and R b are independently F or -OCH3.

[0030] In one embodiment of the present invention, the compound represented by Formula I is a compound represented by Formula Ia:

[0031]

[0032] Among them, R 1 、R 2 and R 3 As described in any of the above options.

[0033] In one embodiment of the present invention, the compound represented by formula I is any one of the following compounds:

[0034]

[0035]

[0036] The present invention also provides a method for preparing a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, which is Scheme 1 or Scheme 2:

[0037] Solution 1 includes the following steps:

[0038] In a solvent, in the presence of a condensing agent and a base, the compound represented by Formula II and the compound represented by Formula III-a undergo a condensation reaction as shown below to prepare a compound represented by Formula I.

[0039]

[0040] Among them, R 4 for R 2 for R 1 and R 3 As described in any of the above options;

[0041] Solution 2 includes the following steps:

[0042] In a solvent, the compound represented by formula II reacts with the compound represented by formula III-b as shown below to prepare the compound represented by formula I.

[0043]

[0044] Among them, R 4 for R 2 for

[0045] R 1 and R 3 As described in any of the above options.

[0046] The reaction conditions and operations of Scheme 1 and Scheme 2 are conventional reaction conditions and operations in the art.

[0047] In one embodiment of the present invention, in Scheme 1, the solvent is an organic solvent, preferably a halogenated hydrocarbon solvent, such as dichloromethane.

[0048] In one embodiment of the present invention, in Scheme 1, the molar volume ratio of the compound represented by Formula II to the solvent is 0.1 to 0.3 mol / L, preferably 0.2 mol / L.

[0049] In one embodiment of the present invention, in Scheme 1, the condensing agent is conventional in the art, such as O-benzotriazole-tetramethyluronium hexafluorophosphate.

[0050] In one embodiment of the present invention, in Scheme 1, the molar ratio of the condensing agent to the compound represented by Formula II is 1.5:1 to 3:1.

[0051] In one embodiment of the present invention, in Scheme 1, the base is conventional in the art, preferably triethylamine or DIPEA.

[0052] In one embodiment of the present invention, in Scheme 1, the molar ratio of the base to the compound of Formula II is 1:1 to 2:1.

[0053] In one embodiment of the present invention, in Scheme 1, the molar ratio of the compound represented by Formula II to the compound represented by Formula III-a is 1:1 to 1:2.

[0054] In one embodiment of the present invention, in Scheme 1, the reaction temperature of the condensation reaction is 0-50°C, preferably room temperature.

[0055] In one embodiment of the present invention, in Scheme 1, the reaction time of the condensation reaction is 24-48 hours.

[0056] In one embodiment of the present invention, in Scheme 2, the solvent is an organic solvent, preferably a halogenated hydrocarbon solvent, such as dichloromethane.

[0057] In one embodiment of the present invention, in Scheme 2, the molar volume ratio of the compound represented by Formula II to the solvent is 0.1 to 0.3 mol / L, preferably 0.2 mol / L.

[0058] In one embodiment of the present invention, in Scheme 2, the molar ratio of the compound represented by Formula II to the compound represented by Formula III-b is 1:1 to 1:2.

[0059] In one embodiment of the present invention, in Scheme 2, the reaction temperature is 0-50°C, preferably room temperature.

[0060] In one embodiment of the present invention, in Scheme 2, the reaction time is 24-48 hours.

[0061] The present invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0062] The present invention also provides a use of the compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a drug for treating tumors.

[0063] In one embodiment of the present invention, in the application, the tumor is skin melanoma or liver cancer.

[0064] Explanation of terms

[0065] The term "halogen" refers to F, Cl, Br, I.

[0066] The term "alkyl" refers to an alkyl group containing one or more carbon atoms, for example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl.

[0067] The term "alkoxy" refers to -O-alkyl, wherein alkyl is as described above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, pentoxy, and the like.

[0068] The term "aryl" refers to a radical having the specified number of ring carbon atoms (e.g., C 6-10 or C6-C 10). Examples of aryl groups include, but are not limited to, phenyl or naphthyl.

[0069] The term "heteroaryl" refers to an aromatic, monocyclic or bicyclic cyclic group having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (e.g., one, two, or more of N, O, and S). Heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, or indolyl.

[0070] The term "hydroxy" refers to -OH.

[0071] The term "cyano" refers to -CN.

[0072] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.

[0073] As used herein, the term "substituted" and its variant forms herein refer to the replacement of one or more (such as 1, 2, 3 or 4) atoms or groups of atoms (such as hydrogen atoms) on the designated atom by other equivalents, provided that the normal valence of the designated atom or group of atoms in the current situation is not exceeded and a stable compound can be formed. When the connecting bond in a substituent is shown as a chemical bond between two atoms connected to each other in a ring system, it means that the substituent can be connected to any ring atom in the ring system.

[0074] Solid lines may be used in this application Solid wedge or virtual wedge Depicting carbon-carbon bonds of compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists.

[0075] As used herein, the term "therapeutically effective amount" refers to an amount effective at the dosage and for the period of time required to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or condition being treated, the anatomy of the specific target organ being administered, the patient's size, or the severity of the disease or symptoms. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation.

[0076] In the present invention, "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0077] For the purposes of this invention, "pharmaceutical excipients" refer to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. These excipients are all substances contained in pharmaceutical preparations, other than the active ingredient. For details, see the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0078] In the present invention, unless otherwise specified, "room temperature" refers to 10-40°C, preferably 20-30°C, for example 25°C.

[0079] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0080] The reagents and raw materials used in the present invention are commercially available. DETAILED DESCRIPTION

[0081] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0082] The present invention is further described in detail below with reference to specific examples, but the present invention is not limited to the following examples. The examples are for better illustrating certain specific embodiments of the present invention and cannot be interpreted as limiting the scope of the invention in any way. The conditions not specified in the examples are conventional conditions. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products. Among them, (S)-(3-amino-1,1,1-trifluoro-2-phenylpropan-2-yl)carbamic acid tert-butyl ester and other trifluoromethylimine derivatives in the examples are prepared according to the preparation method (N-Protecting group tuning of theenantioselectivity in Strecker reactions of trifluoromethyl ketimines tosynthesize quaternary a-trifluoromethyl amino nitriles by ion pair catalysis, ChemComm, 2020, 56, pp: 1581-1584).

[0083] Example 1 Preparation of Compound I-1

[0084]

[0085] At room temperature and under nitrogen protection, (S)-tert-butyl (3-amino-1,1,1-trifluoro-2-phenylpropan-2-yl)carbamate (304 mg, 1.0 mmol, 1 eq) was dissolved in 5 ml of dichloromethane, and then O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU; 569 mg, 1.5 mmol, 1.5 eq) and N,N-diisopropylethylamine (DIPEA; 258 mg, 2.0 mmol, 2.0 eq) were added and stirred for 5 minutes, followed by the addition of 1-adamantanecarboxylic acid (180 mg, 1.0 mmol, 1.0 eq) and stirring for 48 hours. After TLC indicated the reaction endpoint, 5 ml of water was added to the system and extracted with dichloromethane (5 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (0.09 MPa, 38°C). Column chromatography was performed using a developing ratio of petroleum ether to ethyl acetate (5:1). The eluate was concentrated under reduced pressure (0.09 MPa, 38°C) to obtain 307.9 mg of a white solid (i.e., Compound I-1). The yield was 66%. The product identification data are as follows: 1H NMR (400MHz, CDCl3) δ7.37-7.35(m,5H),7.04(s,1H),5.65(s,1H),4.50(s,1H ),3.80(dd,J=14.3,2.7Hz,1H),1.96(s,3H),1.69-1.60(m,12H),1.45(s,9H); 13 C NMR (101MHz, CDCl3) δ178.21,154.79,133.38,128.70,128.32,127.06,125.12(d,J =286.4Hz),81.21,65.86(d,J=25.5Hz),42.85,40.57,38.88,36.46,28.16,28.05; 19 F NMR(376MHz, CDCl3)δ-75.66; HRMS(ESI):calcd for[C 25 H 34 F3N2O3]requires467.25160; found 467.25122; [α] D 25 =-21.6 (c = 0.5, CHCl3).

[0086] Example 2 Preparation of Compound I-2

[0087]

[0088] The preparation method was the same as that of I-1, yielding 291 mg of a white solid. The yield was 60%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.36-7.32(m,2H),7.02-7.06(m,3H),5.73(s,1H),4.50(s, 1H),3.71(dd,J=14.3,2.3Hz,1H),1.95(s,3H),1.71–1.59(m,12H),1.43(s,9H); 13 C NMR (101MHz, CDCl3) δ178.28, 162.80 (d, J=248.6Hz), 154.78, 129.13 (d, J=8.7Hz), 128.29, 124.95 (q, J= 286.1Hz), 115.27 (d, J = 21.7Hz), 81.40, 65.54 (q, J = 25.9Hz), 42.90, 40.57, 38.88, 36.42, 28.13, 28.01; 19F NMR(376MHz, CDCl3)δ-76.04,-113.24; HRMS(ESI):calcd for[C 25 H 33 F4N2O3]requires 485.24218; found 485.24222; [α] D 25 =-27.2 (c = 0.5, CHCl3).

[0089] Example 3 Preparation of Compound I-3

[0090]

[0091] The preparation method was the same as that of I-1, yielding 312 mg of a white solid. The yield was 62%. The product identification data are as follows: 1 H NMR (500MHz, CDCl3) δ6.93-6.92 (d, J = 7.2Hz, 3H), 6.81-6.77 (m, 1H), 5.92 (s, 1H), 4.3 7(s,1H),3.72(dd,J=14.5,3.9Hz,1H),1.97(s,3H),1.70-1.61(m,12H),1.43(s,9H); 13 C NMR(101MHz, CDCl3)δ178.54,162.80(dd,J=248.6,12.7Hz),154.53,137.73,124.72(q,J=286.9Hz),110.54 (d,J=27.3Hz),104.28(t,J=25.2Hz),81.64,65.81(q,J=26.1Hz),43.03,40.59,38.87,36.39,28.09,28.00; 19 F NMR(376MHz, CDCl3)δ-74.64,-108.74; HRMS(ESI):calcd for[C 25 H 32 F5N2O3]requires 503.2328; found 485.503.2321; [α] D 25 =-14.0 (c = 0.5, CHCl3).

[0092] Example 4 Preparation of Compound I-4

[0093]

[0094] The preparation method was the same as that of I-1, yielding 305 mg of a white solid. The yield was 63%. The product identification data are as follows:1 H NMR (400MHz, CDCl3) δ7.37-7.31(m,1H),7.18(d,J=7.9Hz,1H),7.09-7.03(m,2H),6.89(s,1H),5.73(s,1H) ,4.45(s,1H),3.77(dd,J=14.4,3.2Hz,1H),2.79(s,1H),1.97(s,3H),1.67(m,12H),1.41(d,J=30.1Hz,9H); 13 C NMR (101MHz, CDCl3) δ178.41, 162.65 (d, J = 245.9Hz), 154.69, 129.88 (d, J = 8.1Hz), 128.33, 124.91 (d, J = 286.7Hz), 122. 82,115.73(d,J=21.0Hz),114.52(d,J=24.6Hz),81.50,65.74(d,J=26.2Hz),42.95,40.60,38.88,36.43,28.14,28.03; 19 F NMR(376MHz, CDCl3)δ-75.21,-112.25; HRMS(ESI):calcd for[C 25 H 33 F4N2O3]requires 485.24218; found 485.24238; [α] D 25 =-27.8 (c = 0.5, CHCl3).

[0095] Example 5 Preparation of Compound I-5

[0096]

[0097] The preparation method was the same as that of I-1, yielding 313 mg of a white solid. The yield was 63%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.26-7.22(m,1H),7.02-6.89(m,3H),6.85(d,J=8.2Hz,1H),5.63 (s,1H),4.43(s,1H),3.77-3.74(m,4H),1.93(s,3H),1.66-1.57(m,12H),1.42(s,9H); 13C NMR (101MHz, CDCl3) δ178.21, 159.53, 154.75, 135.02, 129.28, 125.09 (d, J = 286.8Hz), 119.21, 114.36,113.01,81.19,65.91(d,J=25.4Hz),55.19,42.77,40.56,38.87,36.46,28.17,28.05; 19 F NMR(376MHz, CDCl3)δ-75.40; HRMS(ESI):calcd for[C 26 H 36 F3N2O4]requires 497.2622; found497.2618; [α] D 25 =-16.5 (c = 0.5, CHCl3).

[0098] Example 6 Preparation of Compound I-6

[0099]

[0100] The preparation method was the same as that of I-1, yielding 312 mg of a white solid. The yield was 66%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.28(s,1H),7.07(d,J=3.0Hz,1H),6.99(t,J=4.3Hz,1H),6.83(s,1H),5.71(s,1 H),4.33(dd,J=14.8,7.2Hz,1H),3.94(dd,J=14.2,4.6Hz,1H),1.97(s,3H),1.69(m,13H),1.45(s,9H); 13 C NMR (101MHz, CDCl3) δ178.16,154.31,138.31,127.38,126.69,125.71,124.66(q,J =286.8Hz),81.31,64.46(q,J=27.1Hz),42.77,40.59,38.91,36.46,28.12,28.06; 19 F NMR(376MHz, CDCl3)δ-76.50; HRMS(ESI):calcd for[C 23 H 32 F3N2O3S]requires473.20802;found 473.20829;[α] D 25 =-24.0 (c = 0.5, CHCl3).

[0101] Example 7 Preparation of Compound II-1

[0102]

[0103] The preparation method was the same as that of I-1, yielding 303 mg of a white solid. The yield was 65%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.43-7.32(m,5H),7.07(s,1H),5.71(s,1H),4.57(s,1H),3.85(dd,J =14.2,2.6Hz,1H),2.36(s,1H),2.23(s,1H),2.10(s,1H),1.91-1.55(m,12H),1.44(s,9H); 13 C NMR (101MHz, CDCl3) δ174.62,154.84,133.45,128.70,128.44,127.04,125.12(d,J=286.5Hz),81.24,65 .92(d,J=25.8Hz),49.91,42.91,38.22,38.19,37.31,33.53,33.10,32.80,29.53,28.13,27.40,27.25; 19 F NMR(376MHz, CDCl3)δ-75.39; HRMS(ESI):calcd for[C 25 H 34 F3N2O3]requires 467.25160; found 467.25130; [α] D 25 =-12.2 (c = 0.5, CHCl3).

[0104] Example 8 Preparation of Compound II-2

[0105]

[0106] The preparation method was the same as that of I-1, yielding 291 mg of a white solid. The yield was 60%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.40-7.36(m,2H),7.08-7.01(m,3H),5.78(s,1H),4.56(s,1H),3.77(dd ,J=14.4,3.1Hz,1H),2.34(s,1H),2.21(s,1H),2.09(s,1H),1.96-1.50(m,12H),1.43(s,9H);13 C NMR (101MHz, CDCl3) δ174.64, 162.83 (d, J = 248.6Hz), 154.74, 129.09 (d, J = 8.3Hz), 128.39, 124.99 (q, J = 286.7Hz), 115.36 (d,J=21.7Hz),81.36,65.67(q,J=25.7Hz),49.95,43.00,38.22,38.19,37.28,33.13,32.84,29.54,28.09,27.40,27.24; 19 FNMR(376MHz, CDCl3)δ-75.58,-113.36; HRMS(ESI):calcd for[C 25 H 33 F4N2O3]requires485.24218;found 485.24222;[α] D 25 =-25.0 (c = 0.5, CHCl3).

[0107] Example 9 Preparation of Compound II-3

[0108]

[0109] The preparation method was the same as that of I-1, yielding 317 mg of a white solid. The yield was 63%. The product identification data are as follows: 1 H NMR(500MHz, CDCl3)δ6.96-6.95(m,3H),6.79-6.75(m,1H),6.05(s,1H),4.35(s,1H),3.78(dd ,J=14.5,4.3Hz,1H),2.38(s,1H),2.21(s,1H),2.11(s,1H),1.55-1.85(m,12H),1.41(s,9H); 13 C NMR(101MHz, CDCl3)δ175.13,162.87(dd,J=248.8,12.7Hz),154.46,138.08,124.77(q,J=287.3Hz),110.46(d,J=27.0Hz),10 4.18(t,J=25.2Hz),81.47,65.91(q,J=25.7Hz),49.93,43.34,38.20,38.17,37.23,33.06,32.89,29.66,28.03,27.38,27.28; 19F NMR(376MHz, CDCl3)δ-73.92,-108.68; HRMS(ESI):calcd for[C 25 H 32 F5N2O3]requires503.2328;found 503.2321;[α] D 25 =-9.6 (c = 1.0, CHCl3).

[0110] Example 10 Preparation of Compound II-4

[0111]

[0112] The preparation method was the same as that of I-1, yielding 305 mg of a white solid. The yield was 63%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.37-7.31(m,1H),7.22(d,J=7.9Hz,1H),7.14(d,J=10.4Hz,1H),7.06-6.94(m,2H),5.79(s,1H ),4.51(s,1H),3.83(dd,J=14.4,3.0Hz,1H),2.38(s,1H),2.23(s,1H),2.11(s,1H),1.85-1.68(m,12H),1.44(s,9H); 13 C NMR (101MHz, CDCl3) δ174.84, 162.73 (d, J = 246.2Hz), 154.68, 129.98 (d, J = 8.2Hz), 128.43, 124.93 (d, J = 286.7Hz), 122.79, 115.70 (d, J = 2 1.1Hz), 114.50 (d, J = 23.7Hz), 81.48, 65.82 (d, J = 25.8Hz), 49.98, 38.23, 38.20, 37.28, 33.52, 33.10, 32.86, 29.60, 28.10, 27.41, 27.28; 19 F NMR(376MHz, CDCl3)δ-74.87,-112.13; HRMS(ESI):calcd for[C 25 H 33 F4N2O3]requires485.24218; found485.24224; [α] D 25 =-14.4 (c = 0.5, CHCl3).

[0113] Example 11 Preparation of Compound II-5

[0114]

[0115] The preparation method was the same as that of I-1, yielding 308 mg of a white solid. The yield was 62%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.24-7.22(m,1H),7.01-6.93(m,3H),6.83(dd,J=8.1,1.8Hz,1H),5.67(s,1H),4.50(s,1H), 3.81(dd,J=14.6,3.3Hz,1H),3.75(s,3H),2.32(s,1H),2.19(s,1H),2.07(s,1H),1.81-1.47(m,12H),1.41(s,9H); 13 C NMR (101MHz, CDCl3) δ174.52,159.63,154.72,135.22,129.39,125.12(d,J=286.8Hz),119.19,114.13,113.19,81.1 4,66.01(d,J=25.8Hz),55.20,49.99,42.85,38.27,38.23,37.33,33.07,32.85,29.61,29.58,28.14,27.45,27.33; 19 FNMR(376MHz, CDCl3)δ-74.97; HRMS(ESI):calcd for[C 26 H 36 F3N2O4]requires 497.2622; found 497.2614; [α] D 25 =-16.5 (c = 0.5, CHCl3).

[0116] Example 12 Preparation of Compound II-6

[0117]

[0118] The preparation method was the same as that of I-1, yielding 288 mg of a white solid. The yield was 61%. The product identification data are as follows: 1H NMR (400MHz, CDCl3) δ7.28(d,J=5.1Hz,1H),7.12(d,J=3.1Hz,1H),7.00(t,J=4.4Hz,1H),6.87(s,1H),5.76(s,1H),4.39 (dd,J=13.8,7.5Hz,1H),4.00(dd,J=14.3,4.8Hz,1H),2.38(s,1H),2.24(s,1H),2.14(s,1H),1.74(m,12H),1.44(s,9H); 13 C NMR (101MHz, CDCl3) δ174.58,154.27,138.39,127.49,126.77,125.72,124.67(q,J=287.0Hz),81.28,64 .50(q,J=27.1Hz),49.99,42.91,38.27,38.25,37.33,33.11,32.93,29.70,29.62,28.10,27.44,27.33; 19 FNMR(376MHz, CDCl3)δ-76.24; HRMS(ESI):calcd for[C 23 H 32 F3N2O3S]requires473.20802;found 473.20787;[α] D 25 =-15.0 (c = 1.0, CHCl3).

[0119] Example 13 Preparation of Compound III-1

[0120]

[0121] The preparation method was the same as that of I-1, yielding 336 mg of a white solid. The yield was 70%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.44-7.33(m,5H),6.62(s,1H),5.76(s,1H),4.40(s,1H),3 .83(dd,J=14.4,3.8Hz,1H),1.90-1.86(m,5H),1.71-1.50(m,12H),1.44(s,9H); 13C NMR (101MHz, CDCl3) δ171.61,154.63,133.65,128.71,128.42,126.95,125.17(d,J=28 6.9Hz), 81.08, 65.88 (d, J = 25.8Hz), 51.69, 43.41, 42.35, 36.67, 32.70, 28.61, 28.14; 19 F NMR(376MHz, CDCl3)δ-74.25; HRMS(ESI):calcd for[C 26 H 36 F3N2O3]requires 481.26725; found481.26725; [α] D 25 =-13.7 (c = 0.5, CHCl3).

[0122] Example 14 Preparation of Compound III-2

[0123]

[0124] The preparation method was the same as that of I-1, yielding 324 mg of a white solid. Yield: 65%. Product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.37-7.41(m,2H),7.05(t,J=8.6Hz,2H),6.71(s,1H),5.87(s,1H),4.37( s,1H),3.75(dd,J=14.5,3.6Hz,1H),1.90(s,3H),1.85(s,2H),1.68-1.48(m,12H),1.42(s,9H); 13 C NMR (101MHz, CDCl3) δ171.76, 162.80 (d, J = 248.5Hz), 154.59, 128.99 (d, J = 8.1Hz), 128.41, 125.03 (q, J = 287 .0Hz), 115.39 (d, J = 21.7Hz), 81.25, 65.62 (q, J = 26.0Hz), 51.61, 43.48, 42.36, 36.64, 32.70, 28.58, 28.11; 19 F NMR(376MHz, CDCl3)δ-74.46,-113.28; HRMS(ESI):calcd for[C 26 H 35 F4N2O3]requires 499.25783; found499.25761; [α] D25 =-16.5 (c = 0.5, CHCl3).

[0125] Example 15 Preparation of Compound III-3

[0126]

[0127] The preparation method was the same as that of I-1, yielding 341 mg of a white solid. The yield was 66%. The product identification data are as follows: 1 H NMR (500MHz, CDCl3) δ6.96 (d, J = 7.0Hz, 2H), 6.79-6.75 (m, 2H), 6.22 (s, 1H), 4.12 (s, 1 H),3.75(dd,J=14.5,4.7Hz,1H),1.91-1.88(m,5H),1.67-1.51(m,12H),1.41(s,9H); 13 C NMR (101MHz, CDCl3) δ172.40,162.87(dd,J=248.7,12.7Hz),154.30,138.24,124.82(q,J=287.7Hz),110.35(d, J=27.0Hz),104.18(t,J=25.1Hz),81.32,65.94(q,J=26.2Hz),51.38,44.04,42.41,36.61,32.77,28.57,28.05; 19 F NMR(376MHz, CDCl3)δ-72.45,-108.65; HRMS(ESI):calcd for[C 26 H 34 F5N2O3]requires 517.2484; found 517.2481; [α] D 25 =-1.0 (c = 1.0, CHCl3).

[0128] Example 16 Preparation of Compound III-4

[0129]

[0130] The preparation method was the same as that of I-1, yielding 324 mg of a white solid. Yield: 65%. Product identification data are as follows: 1H NMR (400MHz, CDCl3) δ7.35(q,J=8.0Hz,1H),7.22(d,J=7.9Hz,1H),7.14(d,J=10.4Hz,1H),7.05(m,1H),5.90(s ,1H),3.81(dd,J=14.4,3.8Hz,1H),1.89(m,5H),1.66(d,J=12.5Hz,5H),1.59(s,2H),1.50(s,5H),1.43(s,9H); 13 C NMR (101MHz, CDCl3) δ171.99, 162.72 (d, J=246.1Hz), 154.55, 129.98 (d, J= 8.1Hz),128.44,127.13,124.95(q,J=287.1Hz),122.68,115.74(d,J=20.9H z),114.46(d,J=24.2Hz),81.39,65.75(q,J=25.5Hz),51.61,48.54,43.58 ,42.37,42.31,36.71,36.64,32.74,28.61,28.59,28.10; HRMS(ESI):calcd for[C 26 H 35 F4N2O3]requires 499.25783; found 499.25693; 19 F NMR(376MHz, CDCl3)δ-73.80,-112.09; [α] D 25 =-6.2 (c = 0.5, CHCl3).

[0131] Example 17 Preparation of Compound III-5

[0132]

[0133] The preparation method was the same as that of I-1, yielding 352 mg of a white solid. The yield was 69%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.21 (d, J = 8.6Hz, 1H), 6.95-6.91 (m, 2H), 6.82-6.80 (m, 1H), 6.58 (s, 1H), 5.71 (s, 1 H),4.32(dd,J=12.5,6.2Hz,1H),3.77-3.72(m,4H),1.83-1.79(m,5H),1.61-1.42(m,12H),1.38(s,9H); 13C NMR (101MHz, CDCl3) δ171.62,159.61,154.61,135.21,129.38,125.12(q,J=286.9Hz),119.13,114 .20,113.13,81.08,65.93(q,J=25.4Hz),55.19,51.72,43.28,42.34,36.65,32.70,28.61,28.15; 19 F NMR(376MHz, CDCl3)δ-74.12; HRMS(ESI):calcd for[C 27 H 38 F3N2O4]requires 511.2778; found 511.2772; [α] D 25 =-8.6 (c = 0.5, CHCl3).

[0134] Example 18 Preparation of Compound III-6

[0135]

[0136] The preparation method was the same as that of I-1, yielding 321 mg of a white solid. The yield was 66%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.29(d,J=5.1Hz,1H),7.13(d,J=3.0Hz,1H),7.01(t,J=4.3Hz,1H),6.47(s,1H),5.81(s,1H),4.2 8(dd,J=14.1,7.6Hz,1H),3.96(dd,J=14.3,4.9Hz,1H),1.90(d,J=10.7Hz,5H),1.62(m,7H),1.51(s,5H),1.45(s,9H); 13 C NMR (101MHz, CDCl3) δ171.59,154.15,138.34,127.43,126.77,125.73,124.67 (q, J=28 7.0Hz), 81.22, 64.44 (q, J = 27.1Hz), 51.71, 43.33, 42.35, 36.67, 32.68, 28.61, 28.12; 19 F NMR(376MHz, CDCl3)δ-75.58; HRMS(ESI):calcd for[C 24 H 34 F3N2O3S]requires 487.22367; found 487.22341; [α]D 25 =-9.7 (c = 0.5, CHCl3).

[0137] Example 19 Preparation of Compound IV-1

[0138]

[0139] Under nitrogen at room temperature, tert-butyl (S)-(3-amino-1,1,1-trifluoro-2-phenylpropan-2-yl)carbamate (304 mg, 1.0 mmol, 1 eq) was dissolved in 5 ml of dichloromethane. 1-Isocyanadamantane (161 mg, 1.0 mmol, 1.0 eq) was added and stirred for 24 hours. TLC indicated the reaction endpoint. After completion, 5 ml of water was added and the mixture was extracted with dichloromethane (5 ml x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure (0.09 MPa, 38°C). Column chromatography was performed using a developing ratio of petroleum ether to ethyl acetate (10:1). The eluate was concentrated under reduced pressure (0.09 MPa, 38°C) to obtain 400 mg of a white solid (i.e., Compound IV-1). The yield was 83%. Product identification data are as follows: 1 HNMR(400MHz, CDCl3)δ7.43-7.30(m,5H),6.17(s,1H),5.34(s,1H),4.34(s,1H),4.1 3(s,1H),3.72(d,J=12.0Hz,1H),2.03(s,3H),1.88(s,6H),1.64(s,6H),1.41(s,9H); 13 C NMR(101MHz,CDCl3)δ157.39,154.65,128.29,126.73,125.49(q,J=286.7H z),80.56,66.28(q,J=25.1Hz),50.93,45.31,42.19,36.33,29.53,28.14; 19 F NMR(376MHz, CDCl3)δ-72.48; HRMS(ESI):calcd for[C 25 H 35 F3N3O3]requires 482.26250; found 482.26178; [α] D 25 =-6.9 (c = 0.5, CHCl3).

[0140] Example 20 Preparation of Compound IV-2

[0141]

[0142] The preparation method was the same as that of IV-1, yielding 380 mg of a white solid. The yield was 76%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.39-7.36(m,2H),7.02(t,J=8.5Hz,2H),6.44(s,1H),5.49(s,1H),4.58(s,1 H),3.99(s,1H),3.60(dd,J=14.5,4.1Hz,1H),2.02(s,3H),1.86(s,6H),1.63(s,6H),1.38(s,9H); 13 C NMR(101MHz, CDCl3) δ162.50(d,J=248.1Hz),157.55,154.57,128.62(d,J=7.0Hz),128.28,125.40(q,J= 288.5Hz), 115.18 (d, J = 21.5Hz), 80.68, 65.98 (q, J = 25.6Hz), 50.91, 45.52, 42.16, 36.30, 29.50, 28.11; 19 F NMR(376MHz, CDCl3)δ-72.31,-114.02; HRMS(ESI):calcd for[C 25 H 34 F4N3O3]requires 500.25308; found 500.25312.[α] D 25 =-11.2 (c = 0.5, CHCl3).

[0143] Example 21 Preparation of Compound IV-3

[0144]

[0145] The preparation method was the same as that of IV-1, yielding 404 mg of a white solid. Yield: 78%. Product identification data are as follows: 1 H NMR(500MHz, CDCl3)δ6.95-6.87(t,J=19.7Hz,3H),6.77-6.73(m,1H),5.58(s,1H),4.82(s, 1H),3.84(s,1H),3.55(d,J=8.1Hz,1H),2.01(s,3H),1.85(s,6H),1.62(s,6H),1.40(s,9H); 13C NMR(101MHz, CDCl3)δ162.80(dd,J=248.1,12.7Hz),157.91,154.43,139.01,125.15(q,J=287.3Hz),109.94 (d,J=26.0Hz),103.67(t,J=23.6Hz),80.81,66.31(q,J=26.9Hz),50.98,45.86,42.06,36.29,29.48,28.05; 19 F NMR(376MHz, CDCl3)δ-70.41,-109.00; HRMS(ESI):calcd for[C 25 H 33 F5N3O3]requires 518.2437; found 518.2430; [α] D 25 =-2.9 (c = 0.5, CHCl3).

[0146] Example 22 Preparation of Compound IV-4

[0147]

[0148] The preparation method was the same as that of IV-1, yielding 395 mg of a white solid. The yield was 79%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.37-7.32(m,1H),7.22(d,J=7.7Hz,1H),7.15(d,J=10.7Hz,1H),7.04(t,J=8.0Hz,1H),6. 16(s,1H),5.39(s,1H),4.16(s,2H),3.73(d,J=14.3Hz,1H),2.05(s,3H),1.88(s,6H),1.65(s,6H),1.42(s,9H); 13 CNMR(101MHz, CDCl3)δ163.94,154.57,129.89(d,J=8.2Hz),125.15(q,J=287.3Hz),122.57,115.42(d,J=19 .9Hz), 114.35 (d, J = 24.4Hz), 109.99, 81.02, 66.00 (q, J = 26.8Hz), 51.16, 42.14, 36.27, 29.65, 29.51, 28.14; 19 F NMR(376MHz, CDCl3)δ-72.95,-112.34; HRMS(ESI):calcd for[C 25 H34 F4N3O3]requires500.25308;found 500.25302;[α] D 25 =-1.5 (c = 0.5, CHCl3).

[0149] Example 23 Preparation of Compound IV-5

[0150]

[0151] The preparation method was the same as that of IV-1, yielding 399 mg of a white solid. The yield was 78%. The product identification data are as follows: 1 H NMR (400MHz, CDCl3) δ7.24(dd,J=9.5,6.5Hz,1H),6.96(m,2H),6.83(d,J=7.1Hz,1H),6.21(s,1H),5.32(s,1H),4.38 (s,1H),4.05(s,1H),3.75(s,3H),3.67(dd,J=14.4,3.1Hz,1H),2.00(s,3H),1.85(s,6H),1.61(s,6H),1.38(s,9H); 13 C NMR (101MHz, CDCl3) δ159.56,157.29,154.60,136.20,129.28,125.41(d,J=287.6Hz),118.97, 113.97,112.80,80.60,66.30(d,J=25.5Hz),55.19,50.97,45.18,42.19,36.32,29.52,28.16; 19 F NMR(376MHz,CDCl3)δ-72.45.HRMS(ESI):calcd for[C 26 H 37 F3N3O4]requires 512.2731; found 512.2725.[α] D 25 =-2.4 (c = 0.5, CHCl3).

[0152] Example 24 Preparation of Compound IV-6

[0153]

[0154] The preparation method was the same as that of IV-1, yielding 390 mg of a white solid. The yield was 80%. The product identification data are as follows: 1H NMR (400MHz, CDCl3) δ7.27 (s, 1H), 7.07 (d, J = 3.1Hz, 1H), 6.98 (m, 1H), 6.37 (s, 1H), 5.31 (s, 1H) ,4.54(s,1H),3.88(td,J=14.4,5.7Hz,2H),2.03(s,3H),1.89(s,6H),1.64(s,6H),1.40(s,9H); 13 C NMR (101MHz, CDCl3) δ157.37,154.23,138.99,127.11,126.14,125.43,124.94(q,J =287.7Hz),80.69,64.66(q,J=27.0Hz),50.96,45.37,42.19,36.34,29.52,28.16; 19 F NMR(376MHz,CDCl3)δ-73.97.HRMS(ESI):calcd for[C 23 H 33 F3N3O3S]requires488.22909; found488.22921.[α] D 25 =-1.9 (c = 0.5, CHCl3).

[0155] Example 25 Activity Determination of Compounds

[0156] The models and batches of relevant experimental reagents and consumables are as follows

[0157]

[0158] Mouse melanoma B16F10 cells and human liver cancer cells HepG2 were evenly plated in a 96-well plate at a density of 6,000 cells / well using DMEM high-glucose medium (containing 10% fetal bovine serum FBS) and cultured at 37°C, 5% CO2 for 24 hours. Carefully aspirate the cell culture medium, and evenly dissolve the compounds of different concentrations in the cell culture medium (DMSO was used as the compound solvent, and the same volume used was used as the experimental blank control). The compounds were added to 96 wells at 100 μl / well and cultured for 48 hours at 37°C, 5% CO2. Aspirate the cell culture medium, and add 100 μl cell culture medium (without FBS) containing 10% CCK-8 reagent to each well. Continue incubating at 37°C for 2 hours, and then measure the OD value at 490 nm and the reference wavelength of 630 nm). The data obtained were used to calculate the activity and IC 50 Calculation. The vitality calculation formula is as follows:

[0159] Cell viability*(%)=[A(drug added)-A(blank)] / [A(0 drug added)-A(blank)]×100

[0160] Where A(drug added) is the absorbance of the wells containing cells, CCK-8 solution, and drug solution; A(blank) is the absorbance of the wells containing culture medium and CCK-8 solution but no cells; A(0 drug added) is the absorbance of the wells containing cells, CCK-8 solution, and no drug solution (if solvent is present, the solvent is used as the control). Cell viability: cell proliferation activity or cytotoxic activity. IC 50 The calculations were performed using GraphPad Prism 5 software: Nonlinear regression (curve fit) mode log (agonist) vs. response--Variable slope.

[0161] Table 1 Cytotoxicity and IC of compounds 50

[0162]

[0163]

[0164] "-" indicates not tested. In the table, B16F10 cells are mouse skin melanoma cells, and HepG2 cells are human hepatocellular carcinoma cells. % cytotoxicity indicates cell viability at a compound concentration of 50 μM. All treatments were performed for 48 hours.

[0165] Table 1 shows the cytotoxicity data of the compounds of the present invention against mouse skin melanoma cells and human liver cancer cells, as well as the IC values of some compounds. 50 The data show that the compounds of the present invention have good anti-tumor activity.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, in, R 1 -COOR 1a or H; R 1a C 1-6 alkyl; R 2 for R 3 C 6-10 Aryl, 5-6 membered heteroaryl, one or more R a Substituted C 6-10 Aryl or one or more R b substituted 5-6 membered heteroaryl; said 5-6 membered heteroaryl and one or more R b The heteroatoms in the substituted 5-6 heteroaryl group are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R a and R b are independently halogen, C 1-3 Alkyl, hydroxy, nitro or C 1-3 Alkoxy.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound of formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1)R 1a In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl; (2)R 3 In the C 6-10 Aryl or one or more R a Substituted C 6-10 The aryl group in the aryl group is phenyl; (3)R 3 wherein the 5-6 membered heteroaryl group is replaced by one or more R b The heteroaryl group in the substituted 5-6 membered heteroaryl group is thienyl or thiazinyl; (4)R a and R b wherein the halogen is F, Cl, Br or I, preferably F; (5)R a and R b In the C 1-3 Alkyl is methyl, ethyl or n-propyl; (6)R a and R b In the C 1-3 Alkoxy is -OCH3, -OCH2CH3 or -O(CH2)2CH3, preferably -OCH3.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound of formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1)R 1 -COOR 1a ; (2) Each R a and R b are independently halogen or C 1-3 alkoxy; (3)R 3 for Wherein, m is an integer of 0-5, n is an integer of 0-3; preferably 4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound of formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1)R 1 for (2)R 2 for (3)R 3 for (4) Each R a and R b are independently F or -OCH3.

5. The compound according to any one of claims 1 to 4, characterized in that The compound shown in Formula I is a compound shown in Formula Ia: Among them, R 1 、R 2 and R 3 As defined in any one of claims 1 to 4.

6. The compound according to claim 1, wherein The compound shown in formula I is any of the following compounds:

7. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: It is either Option 1 or Option 2: Solution 1 includes the following steps: In a solvent, in the presence of a condensing agent and a base, the compound represented by Formula II and the compound represented by Formula III-a undergo a condensation reaction as shown below to prepare a compound represented by Formula I. Among them, R 4 for R 2 for R 1 and R 3 As claimed in any one of claims 1 to 4; Solution 2 includes the following steps: In a solvent, the compound represented by formula II reacts with the compound represented by formula III-b as shown below to prepare the compound represented by formula I. Among them, R 4 for R 2 for R 1 and R 3 As claimed in any one of claims 1 to 4.

8. The preparation method according to claim 7, wherein The preparation method satisfies one or more of the following conditions: (1) In Scheme 1, the solvent is an organic solvent, preferably a halogenated hydrocarbon solvent, such as dichloromethane; (2) In Scheme 1, the molar volume ratio of the compound represented by Formula II to the solvent is 0.1 to 0.3 mol / L, preferably 0.2 mol / L; (3) In Scheme 1, the condensing agent is O-benzotriazole-tetramethyluronium hexafluorophosphate; (4) In Scheme 1, the molar ratio of the condensing agent to the compound represented by Formula II is 1.5:1 to 3:1; (5) In Scheme 1, the base is triethylamine or DIPEA; (6) In Scheme 1, the molar ratio of the base to the compound represented by Formula II is 1:1 to 2:1; (7) In Scheme 1, the molar ratio of the compound represented by Formula II to the compound represented by Formula III-a is 1:1 to 1:2; (8) In Scheme 1, the reaction temperature of the condensation reaction is 0-50°C, preferably room temperature; (9) In Scheme 1, the reaction time of the condensation reaction is 24-48 hours; (10) In Scheme 2, the solvent is an organic solvent, preferably a halogenated hydrocarbon solvent, such as dichloromethane; (11) In Scheme 2, the molar volume ratio of the compound represented by Formula II to the solvent is 0.1 to 0.3 mol / L, preferably 0.2 mol / L; (12) In Scheme 2, the molar ratio of the compound represented by Formula II to the compound represented by Formula III-b is 1:1 to 1:2; (13) In Scheme 2, the reaction temperature is 0-50°C, preferably room temperature; (14) In Scheme 2, the reaction time is 24-48 hours.

9. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and a pharmaceutically acceptable excipient.

10. Use of a compound of formula I according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating a tumor; preferably, the tumor is skin melanoma or liver cancer.

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