2-arylamino pyrimidines and uses thereof

Abstract

The application relates to the fields of medicine and chemical industry, and relates to 2-arylamino pyrimidine compounds and applications thereof, 2-arylamino pyrimidine compounds and a preparation method thereof and applications of the 2-arylamino pyrimidine compounds in the preparation of medicines for treating colon cancer. The structure of the 2-arylamino pyrimidine compound or a pharmaceutically acceptable salt thereof is shown in general formula (I), wherein Ar is shown in the claims and the specification. The 2-arylamino pyrimidine compound or the pharmaceutically acceptable salt thereof or the composition thereof has the activity of inhibiting FAK tyrosine kinase, can be used for preparing a FAK tyrosine kinase inhibitor, and can be used for preparing an anti-tumor medicine.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceuticals and chemicals, specifically to 2-arylaminopyrimidine compounds and their applications, including methods for preparing 2-arylaminopyrimidine compounds and their use in the preparation of drugs for treating colon cancer. Background Technology

[0002] Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that, upon phosphorylation activation, triggers a series of downstream signaling pathways, playing a crucial role in the basic physiological functions of normal and tumor cells, such as growth, movement, and proliferation. Small molecule focal adhesion kinase inhibitors exert anti-tumor effects by inhibiting the kinase activation process, thereby suppressing tumor cell proliferation and invasion.

[0003] FAK is a cytoplasmic non-receptor tyrosine kinase and a scaffold protein located in focal adhesion (the physical connection between the extracellular matrix and the cell's actin cytoskeleton, which is fundamentally important in human physiology, regulating cell adhesion, mechanosensing, and controlling cell growth and differentiation signals). It is located at the confluence of integrins and receptor tyrosine kinase signaling pathways and can transmit signals from the extracellular matrix to the cytoskeleton.

[0004] FAK is activated through interactions with integrins, growth factor receptors, G protein-coupled receptors, and cytokine receptors, and plays a crucial role in the regulation of cell adhesion, motility, proliferation, and the survival of many cell types. Aberrant expression of this kinase has been found in numerous cancers, such as lung cancer, colon cancer, gastric cancer, and ovarian cancer.

[0005] Given the urgent need for the treatment of colorectal cancer, it is necessary in this field to develop anti-colorectal cancer drugs with unique mechanisms of action and novel structures in order to expand the range of drugs for the treatment of colorectal cancer. Summary of the Invention

[0006] One of the objectives of this invention is to provide the 2-arylaminopyrimidine compounds or pharmaceutically acceptable salts thereof, which have good anti-colon cancer activity.

[0007] Another object of the present invention is to provide a pharmaceutical composition comprising the 2-arylaminopyrimidine compound or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide the use of the 2-arylaminopyrimidine compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of medicaments for treating colon cancer.

[0009] This invention is achieved through the following technical solution:

[0010] A 2-arylaminopyrimidine compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012]

[0013] Wherein, Ar is a substituted phenyl group, and the substituent is a halogen, C1-C6 alkoxy, C1-C6 alkyl, or -CO-(CH2). n CH3、-HN-(CH2) n CO-R, -O(CH2) n -R, a six-membered heterocyclic group, wherein the heterocyclic group contains 1-3 N, O or S heteroatoms;

[0014] R is

[0015] The C1-C6 alkyl group was replace;

[0016] The six-membered heterocycle contains 1-2 N or O heteroatoms; the heterocyclic group can be C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or (CH2). m OH substitution;

[0017] m, n = 1-3.

[0018] Furthermore, Ar is a substituted phenyl group, and the substituent is a halogen, C1-C4 alkoxy, C1-C4 alkyl, or -HN-(CH2). n CO-R, -O(CH2) n -R, a substituted or unsubstituted six-membered heterocyclic group, wherein the heterocyclic group is;

[0019] Furthermore, Ar is selected from:

[0020]

[0021] Specifically, the present invention preferably uses the following 2-arylaminopyrimidine compounds or pharmaceutically acceptable salts thereof:

[0022]

[0023] The compounds of the present invention are bases, wherein the desired salt form can be prepared by suitable methods known in the art, including treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or treating the free base with an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside (e.g., glucuronic acid or galacturonic acid), α-hydroxy acid (e.g., citric acid or tartaric acid), amino acid (e.g., aspartic acid or glutamic acid), aromatic acid (e.g., benzoic acid or cinnamic acid), sulfonic acid (e.g., toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), etc. The pharmaceutically acceptable salts described in this invention include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptaates, propionates, oxalates, malonates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrate, glycolic acid salts, tartrates, amygdalinates and sulfonates, xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates and naphthalene-2-sulfonates.

[0024] The pharmaceutical compositions of the present invention typically contain one of the compounds of the present invention. However, in some embodiments, the pharmaceutical compositions of the present invention contain one or more of the compounds of the present invention. Additionally, the pharmaceutical compositions of the present invention may also be compositions of one or more of the compounds of the present invention with one or more other pharmaceutically active compounds.

[0025] This invention provides the use of the 2-arylaminopyrimidine compounds or pharmaceutically acceptable salts thereof in the preparation of FAK tyrosine kinase inhibitors.

[0026] The present invention provides the use of pharmaceutical compositions containing the 2-arylaminopyrimidine compound or a pharmaceutically acceptable salt thereof in the preparation of FAK tyrosine kinase inhibitors.

[0027] The 2-arylaminopyrimidine compounds of the present invention, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can inhibit tumor proliferation and can be used to prepare antitumor drugs.

[0028] The tumor is preferably colon cancer.

[0029] The compounds described in this invention, or pharmaceutically acceptable salts thereof, or combinations thereof, exert their anti-colon cancer effects by inhibiting FAK tyrosine kinase.

[0030] The compounds of this invention have the potential to be developed into novel and highly effective FAK inhibitors. Screening for antitumor activity shows that the compounds of this invention have a strong ability to inhibit the proliferation of colon cancer cells HCT116, SW620, SW837, and CW2, and have significant application value for the treatment of related tumor diseases, especially colon cancer. Detailed Implementation

[0031] The present invention will be further described and explained below with reference to specific embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0032] Experimental methods in this invention, where specific conditions are not specified, are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available, conventional reagents.

[0033] Example 1: Preparation of compound I-1-I-16

[0034] The technical solution adopted in this invention is as follows:

[0035]

[0036] Preparation of I-1 to I-16

[0037] 2,4,5-Trichloropyrimidine and TEA were added dropwise to compound 2 in THF at room temperature. After the addition was complete, the reaction was carried out at 40°C for 6 h, and the solvent was evaporated. Column chromatography yielded intermediate 3. Boc protection was removed by ethyl hydrochloride, and the intermediate reacted with isopropylsulfonyl chloride under alkaline conditions to generate 6. Different aromatic amines (Ar) reacted with 6 in ethanol at 70°C for 6 h under p-toluenesulfonic acid catalysis to generate I-1 to I-16. The target compound was synthesized according to the above method, and the NMR and HRMS data are as follows:

[0038] Compound I-1

[0039] The preparation process is as follows: Intermediate 6 (3.0 mmol), aromatic amine (3.0 mmol), and p-toluenesulfonic acid (4.5 mmol) were reacted in 15 mL of anhydrous ethanol at 70 °C for 6 h. Ethanol was removed under reduced pressure, and the mixture was extracted with saturated sodium bicarbonate / dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then separated by column chromatography (DCM:MeOH) to give compound I-1, with a yield of 45.1%. (The preparation methods for compounds I-2 to I-16 are as described above.)

[0040] 11H NMR (CDCl3, 600 MHz): 7.84 (1H, s), 7.43 (2H, d, J = 8.88 Hz), 7.00 (1H, s), 6.88 (2H, d, J = 8.88 Hz), 5.65 (1H, t, J = 5.88 Hz), 3.85 (4H, t, J = 4.62 Hz), 3.56 - 3.41 (4H, m), 3.22 (1H, t, J = 8.22 Hz), 3.16 - 3.11 (1H, m), 3.10 (4H, t, J = 4.68 Hz), 3.06 (1H, dd, J = 7.68, 4.86 Hz), 2.10 - 2.00 (1H, m), 1.85 - 1.80 (1H, m), 1.80 - 1.75 (1H, m), 1.58 - 1.53 (1H, m), 1.43 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0041] 13 13C NMR (CDCl3) δ 158.1, 157.8, 151.9, 147.2, 132.5, 121.1 (2C), 116.5 (2C), 104.5, 67.0 (2C), 53.4, 50.1 (2C), 49.3, 47.2, 42.7, 35.1, 27.7, 23.9, 16.8 (2C). HR MS (ESI + ) C 23 H 34 ClN6O3S + , cacld: 509.2096, found: 509.20612.

[0042] Compound I - 2

[0043] 1 1H NMR (CDCl3, 600 MHz): 7.84 (1H, s), 7.43 (2H, d, J = 8.94 Hz), 6.98 (1H, s), 6.89 (2H, d, J = 8.94 Hz), 5.67 (1H, t, J = 5.88 Hz), 3.56 - 3.41 (4H, m), 3.19 - 3.11 (6H, m), 3.01 (1H, dd, J = 7.68, 4.86 Hz), 2.61 (4H, bro.s), 2.37 (3H, s), 2.08 - 2.00 (1H, m), 1.86 - 1.80 (1H, m), 1.80 - 1.73 (1H, m), 1.58 - 1.54 (1H, m), 1.40 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0044] 13 C NMR(CDCl3)δ158.3,158.0,153.1,146.9,132.7,121.0(2C),116.9(2C),104.4,55.1 (2C),53.4,49.7(2C),49.4,47.2,45.9,42.7,35.2,27.7,24.0,16.8(2C).HRMS(ESI + C 24 H 37 ClN7O2S + ,cacld:522.2412,found:522.23699.

[0045] Compound I-3

[0046] 1 H NMR(CDCl3,600MHz)7.86(1H,s),7.43(2H,d,J=8.64Hz),6.90(2H,d,J=8.64Hz),6.85(1H,s), 5.58(1H,t,J=5.88Hz),3.53-3.43(4H,m),3.23-3.13(6H,m),3.03(1H,dd,J=12.62,7.74Hz), 2.65(4H,bro.s),2.50(2H,q,J=7.12Hz),2.08-2.00(1H,m),1.86-1.76(2H,m),1.58-1.54(1H ,m),1.40-1.35(1H,m),1.30(3H,d,J=1.68Hz),1.29(3H,d,J=1.68Hz),1.15(3H,t,J=7.12Hz).

[0047] 13 C NMR(CDCl3)δ158.4,158.0,153.1,147.1,132.5,121.0(2C),116.9(2C),104.4,53. 4,52.8(2C),52.4,49.8(2C),49.4,47.2,42.7,35.2,27.7,24.0,16.8(2C),11.9.HR MS(ESI + C 25 H 39 ClN7O2S + ,cacld:536.2569,found:536.25305.

[0048] Compound I-4

[0049] 1 1H NMR (CDCl3, 600 MHz): δ 7.84 (1H, s), 7.40 (2H, d, J = 8.88 Hz), 7.00 (1H, s), 6.92 (2H, d, J = 8.88 Hz), 5.63 (1H, t, J = 5.88 Hz), 3.84 - 3.80 (1H, m), 3.53 - 3.44 (6H, m), 3.23 - 3.19 (1H, m), 3.14 (1H, quintet, J = 6.84 Hz), 3.03 (1H, dd, J = 12.62, 7.74 Hz), 2.88 - 2.84 (2H, m), 2.08 - 2.00 (3H, m), 1.86 - 1.76 (1H, m), 1.79 - 1.74 (1H, m), 1.74 - 1.67 (2H, m), 1.58 - 1.54 (1H, m), 1.40 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0050] 13 13C NMR (CDCl3): δ 158.3, 158.0, 153.0, 147.1, 132.4, 121.0 (2C), 117.4 (2C), 104.3, 67.8, 53.4, 49.4, 48.1 (2C), 47.1, 42.7, 35.2, 34.3 (2C), 27.7, 24.0, 16.8 (2C). HRMS (ESI + ) C 24 H 36 ClN6O3S + , calcd: 523.2253, found: 523.22155.

[0051] Compound I - 5

[0052] 11H NMR (CDCl3, 600 MHz): δ 7.85 (1H, s), 7.65 (1H, dd, J = 14.88, 2.46 Hz), 7.21 (1H, s), 6.92 (1H, dd, J = 8.70, 1.68 Hz), 6.88 (1H, t, J = 8.70 Hz), 5.70 (1H, t, J = 5.88 Hz), 3.59 - 3.55 (1H, m), 3.47 - 3.44 (2H, m), 3.40 - 3.36 (1H, m), 3.28 - 3.25 (1H, m), 3.18 - 3.12 (2H, m), 3.07 (4H, broad s), 2.63 (4H, broad s), 2.36 (3H, s), 2.08 - 2.04 (1H, m), 1.86 - 1.76 (1H, m), 1.79 - 1.74 (1H, m), 1.58 - 1.54 (1H, m), 1.40 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0053] 13 13C NMR (CDCl3) δ 158.0, 157.8, 155.6 (J = 2,44.3 Hz), 153.0, 135.5 (J = 11.0 Hz), 134.5 (J = 9.4 Hz), 119.2 (J = 4.3 Hz), 114.7 (J = 2.9 Hz), 107.9 (J = 26.2 Hz), 104.9, 55.2 (2C), 53.5, 50.8 (2C), 49.2, 47.2, 46.0, 42.6, 35.0, 27.6, 23.8, 16.8 (2C). HR MS (ESI + ) C 24 H 36 ClFN7O2S + , calcd: 540.2318, found: 540.22793.

[0054] Compound I - 6

[0055] 11H NMR (CDCl3, 600 MHz): 7.87 (1H, s), 7.64 (1H, d, J = 14.80 Hz), 7.13 (1H, s), 7.02 (1H, d, J = 9.04 Hz), 6.88 (1H, t, J = 90.4 Hz), 5.77 (1H, t, J = 5.88 Hz), 3.62 - 3.44 (4H, m), 3.40 - 3.59 (4H, m), 3.51 - 3.40 (4H, m), 3.32 - 3.30 (1H, m), 3.17 (1H, quintet, J = 6.84 Hz), 3.04 - 3.02 (1H, m), 2.96 - 2.91 (4H, m), 2.12 (3H, s), 2.03 - 2.00 (1H, m), 1.90 - 1.84 (1H, m), 1.79 - 1.74 (1H, m), 1.61 - 1.54 (1H, m), 1.49 - 1.40 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0056] 13 13C NMR (CDCl3) δ 169.0, 158.0, 157.8, 155.6 (J = 244.8 Hz), 153.0, 135.9 (J = 11.0 Hz), 134.0 (J = 9.4 Hz), 119.5 (J = 4.3 Hz), 114.6 (J = 2.9 Hz), 107.8 (J = 26.2 Hz), 105.1, 55.2 (2C), 53.5, 51.7 (2C), 49.2, 47.2, 46.6 (2C), 41.7, 34.9, 27.6, 23.7, 21.4, 16.8 (2C).

[0057] HR MS (ESI + ) C 25 H 36 ClFN7O3S + , calcd: 568.2267, found: 568.22199.

[0058] Compound I - 7

[0059] 11H NMR (CDCl3, 600 MHz): 7.84 (1H, s), 7.65 (1H, dd, J = 14.76, 2.40 Hz), 7.31 (1H, s), 6.90 (1H, dd, J = 8.70, 1.68 Hz), 6.88 (1H, t, J = 8.70 Hz), 5.85 (1H, t, J = 5.88 Hz), 3.85 - 3.80 (1H, m), 3.61 - 3.57 (1H, m), 3.49 - 3.43 (2H, m), 3.38 - 3.35 (1H, m), 3.32 - 3.27 (3H, m), 3.17 - 3.13 (2H, m), 2.80 (2H, t, J = 10.68 Hz), 2.08 - 2.04 (1H, m), 2.04 - 2.01 (2H, m), 1.87 - 1.83 (1H, m), 1.79 - 1.74 (2H, m), 1.58 - 1.54 (1H, m), 1.40 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0060] 13 13C NMR (CDCl3) δ 158.1, 157.6, 155.6 (J = 244.5 Hz), 153.0, 135.2 (J = 2.0 Hz), 135.1 (J = 11.2 Hz), 119.5 (J = 4.3 Hz), 114.7 (J = 2.9 Hz), 107.9 (J = 26.3 Hz), 104.9, 67.6, 53.5, 49.2, 49.0 (2C), 47.2, 42.6, 34.9, 34.7 (2C), 27.5, 23.7, 16.8 (2C). HR MS (ESI + ) C 24 H 35 ClFN6O3S + , calcd: 541.2158, found: 541.21163.

[0061] Compound I - 8

[0062] 11H NMR (CDCl3, 600 MHz) δ 7.87 (1H, s), 7.65 (1H, d, J = 14.76 Hz), 7.05 (1H, s), 6.97 (1H, d, J = 8.84 Hz), 6.92 (1H, t, J = 8.84 Hz), 5.72 (1H, t, J = 5.88 Hz), 3.56 (2H, d, J = 6.08 Hz), 3.50 - 3.32 (6H, m), 3.31 - 3.26 (1H, m), 3.18 - 3.13 (2H, m), 2.65 (2H, t, J = 11.08 Hz), 2.08 - 2.04 (1H, m), 1.87 - 1.77 (4H, m), 1.64 - 1.56 (1H, m), 1.50 - 1.46 (4H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0063] 13 13C NMR (CDCl3) δ 一158.0, 157.8, 155.7 (J = 243.9 Hz), 152.9, 135.5 (J = 9.6 Hz), 135.0 (J = 10.9 Hz), 119.2 (J = 4.3 Hz), 114.7 (J = 2.8 Hz), 107.9 (J = 26.3 Hz), 104.9, 67.9, 53.5, 51.5 (2C), 49.2, 47.2, 42.6, 38.4, 35.0, 29.1 (2C), 27.6, 23.8, 16.8 (2C). HR MS (ESI + ) C 25 H 37 ClFN6O3S + , calcd: 555.2315, found: 555.22754.

[0064] Compound I - 9

[0065] 11H NMR(CDCl3, 600 MHz): 7.85 (1H, s), 7.66 (1H, dd, J = 14.76, 2.40 Hz), 7.23 (1H, s), 6.99 (1H, dd, J = 8.84, 2.00 Hz), 6.92 (1H, t, J = 8.84 Hz), 5.72 (1H, t, J = 5.88 Hz), 3.65 (2H, d, J = 5.40 Hz), 3.59 - 3.55 (1H, m), 3.47 - 3.43 (2H, m), 3.40 - 3.36 (1H, m), 3.31 - 3.26 (1H, m), 3.17 - 3.12 (2H, m), 3.07 (4H, broad s), 2.71 (4H, broad s), 2.62 (2H, t, J = 5.34 Hz), 2.08 - 2.04 (1H, m), 1.79 - 1.76 (1H, m), 1.72 - 1.69 (1H, m), 1.58 - 1.52 (1H, m), 1.48 - 1.44 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0066] 13 13C NMR(CDCl3) δ 158.0, 157.8, 155.6 (J = 244.3 Hz), 152.9, 135.5 (J = 11.0 Hz), 134.5 (J = 9.4 Hz), 119.2 (J = 4.3 Hz), 114.7 (J = 2.9 Hz), 107.9 (J = 26.2 Hz), 104.9, 59.5, 57.6, 53.5, 53.1 (2C), 50.8 (2C), 49.2, 47.2, 42.6, 35.0, 27.6, 23.8, 16.8 (2C). HR MS(ESI + ) C 25 H 38 ClFN7O3S + , calculated: 570.2424, found: 570.23796.

[0067] Compound I - 10

[0068] 11H NMR (CDCl3, 600 MHz) δ 8.18 (1H, d, J = 8.46 Hz), 7.86 (1H, s), 7.34 (1H, s), 6.52 (1H, dd, J = 8.46, 2.40 Hz), 6.51 (1H, d, J = 2.40 Hz), 5.63 (1H, broad s), 3.86 (3H, s), 3.86 (4H, t, J = 4.68 Hz), 3.56 - 3.41 (4H, m), 3.22 (1H, t, J = 8.22 Hz), 3.17 - 3.10 (1H, m), 3.10 (4H, t, J = 4.68 Hz), 3.06 (1H, dd, J = 7.68, 4.86 Hz), 2.12 - 2.02 (1H, m), 1.89 - 1.82 (1H, m), 1.81 - 1.75 (1H, m), 1.58 - 1.53 (1H, m), 1.43 - 1.39 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0069] 13 13C NMR (CDCl3) δ 158.1, 158.0, 153.0, 149.0, 146.9, 123.0, 119.6, 107.8, 104.3, 100.3, 66.9 (2C), 55.7, 53.4, 50.5 (2C), 49.3, 47.1, 42.8, 35.2, 27.8, 24.0, 16.8 (2C). HRMS (ESI + ) C 24 H 36 ClN6O4S + , calcd: 539.2202, found: 539.21643.

[0070] Compound I - 11

[0071] 11H NMR (CDCl3, 600 MHz) δ 8.16 (1H, d, J = 8.46 Hz), 7.86 (1H, s), 7.26 (1H, s), 6.52 (1H, dd, J = 8.46, 2.40 Hz), 6.51 (1H, d, J = 2.40 Hz), 5.59 (1H, t, J = 5.88 Hz), 3.85 (3H, s), 3.85 - 3.81 (1H, m), 3.55 - 3.40 (6H, m), 3.21 (1H, t, J = 8.22 Hz), 3.17 - 3.10 (1H, m), 3.06 (1H, dd, J = 7.68, 4.86 Hz), 2.87 (2H, d, J = 9.66 Hz), 2.12 - 1.98 (3H, m), 1.89 - 1.82 (1H, m), 1.81 - 1.75 (1H, m), 1.74 - 1.70 (2H, m), 1.58 - 1.53 (1H, m), 1.43 - 1.39 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0072] 13 13C NMR (CDCl3) δ 158.1, 158.0, 153.1, 148.9, 146.9, 122.8, 119.4, 108.7, 104.2, 101.3, 67.7, 55.7, 53.4, 49.3, 48.6 (2C), 47.2, 42.7, 35.2, 34.4 (2C), 27.7, 24.0, 16.8 (, 2C). HR MS (ESI + [[ID=[]]) C 25 H 38 ClN6O4S + , calcd: 553.2358, found: 553.23153.

[0073] Compound I - 12

[0074] 11H NMR (CDCl3, 600 MHz): 7.88 (1H, s), 7.51 (2H, d, J = 8.34 Hz), 7.23 (1H, 2H, d, J = 8.34 Hz), 7.03 (1H, s), 5.66 (1H, t, J = 5.88 Hz), 3.70 (4H, broad s), 3.57 - 3.52 (1H, m), 3.49 - 3.43 (5H, m), 3.26 - 3.23 (1H, m), 3.14 (1H, quintet, J = 6.84 Hz), 3.12 - 3.07 (1H, m), 2.45 (4H, broad s), 2.07 - 2.03 (1H, m), 1.86 - 1.82 (1H, m), 1.80 - 1.75 (1H, m), 1.58 - 1.53 (1H, m), 1.43 - 1.39 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0075] 13 13C NMR (CDCl3) δ 158.0, 158.0, 153.0, 139.1, 129.9 (2C), 118.9 (3C), 105.3, 66.8 (2C), 62.9, 53.4 (3C), 49.3, 47.2, 42.7, 35.1, 27.7, 23.9, 16.8 (2C). HR MS (ESI + ) C 24 H 36 ClN6O3S + , calculated: 523.2253, found: 523.22151.

[0076] Compound I - 13

[0077] 11H NMR (CDCl3, 600 MHz): 7.88 (1H, s), 7.54 (2H, d, J = 8.34 Hz), 7.30 (2H, d, J = 8.34 Hz), 7.10 (1H, s), 5.65 (1H, t, J = 5.88 Hz), 3.81 (1H, broad s), 3.65 (2H, s), 3.54 - 3.40 (4H, m), 3.23 (1H, t, J = 8.88 Hz), 3.17 - 3.13 (1H, m), 3.07 (1H, dd, J = 7.68, 4.86 Hz), 2.88 (2H, broad s), 2.43 (2H, broad s), 2.08 - 2.00 (3H, m), 1.87 - 1.83 (1H, m), 1.80 - 1.74 (1H, m), 1.73 - 1.63 (2H, m), 1.58 - 1.52 (1H, m), 1.44 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0078] 13 13C NMR (CDCl3) δ 158.0, 157.9, 153.0, 130.5 (2C), 118.9 (3C), 105.3, 66.2, 61.8, 53.4, 49.7 (2C), 49.3, 47.2, 42.7, 35.1, 32.8 (2C), 27.7, 23.9, 16.8 (2C). HR MS (ESI + ) C 25 H 38 ClN6O3S + , calculated: 537.2409, found: 537.23730.

[0079] Compound I - 14

[0080] 11H NMR (CDCl3, 600 MHz): 7.88 (1H, s), 7.54 (2H, d, J = 8.34 Hz), 7.35 (2H, d, J = 8.34 Hz), 7.15 (1H, s), 5.68 (1H, t, J = 5.88 Hz), 3.76 (2H, s), 3.51 - 3.46 (5H, m), 3.42 - 3.40 (1H, m), 3.23 (1H, t, J = 8.88 Hz), 3.20 - 3.12 (2H, m), 3.10 - 3.02 (1H, m), 2.31 - 2.29 (2H, m), 2.08 - 2.00 (1H, m), 1.87 - 1.83 (1H, m), 1.80 - 1.74 (3H, m), 1.58 - 1.52 (4H, m), 1.44 - 1.36 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0081] 13 13C NMR (CDCl3) δ 158.0, 157.8, 153.0, 140.0, 131.1 (2C), 118.9 (3C), 105.3, 66.8, 61.5, 53.4, 52.4 (2C), 49.7, 47.2, 42.8, 37.4, 35.1, 27.7, 27.0 (2C), 23.9, 16.8 (2C). HR MS (ESI + ) C 26 H 40 ClN6O3S + , calcd: 551.2566, found: 551.25292.

[0082] Compound I - 15

[0083] 11H NMR (CDCl3, 600 MHz): 9.13 (1H, s), 7.86 (1H, s), 7.54 (2H, d, J = 9.18 Hz), 7.51 (2H, d, J = 9.18 Hz), 7.17 (1H, s), 5.66 (1H, t, J = 5.88 Hz), 3.77 - 3.74 (1H, m), 3.54 - 3.40 (4H, m), 3.21 (1H, t, J = 8.32 Hz), 3.16 - 3.11 (1H, m), 3.10 (2H, broad s), 3.05 (1H, dd, J = 7.68, 4.86 Hz), 2.88 - 2.81 (2H, m), 2.40 (2H, t, J = 10.62 Hz), 2.08 - 2.02 (1H, m), 1.96 - 1.93 (2H, m), 1.87 - 1.83 (1H, m), 1.80 - 1.74 (1H, m), 1.68 - 1.63 (2H, m), 1.58 - 1.52 (1H, m), 1.44 - 1.35 (1H, m), 1.30 (3H, d, J = 1.68 Hz), 1.29 (3H, d, J = 1.68 Hz).

[0084] 13 13C NMR (CDCl3) δ 168.1, 158.0, 157.9, 152.9, 136.2, 132.3, 120.1 (2C), 119.8 (2C), 104.9, 66.9, 61.9, 53.4, 51.5 (2C), 49.3, 47.2, 42.8, 35.2, 34.5 (2C), 27.7, 23.9, 16.8 (2C). HR MS (ESI + ) C 26 H 39 ClN7O4S + , calculated: 580.2467, found: 580.24225.

[0085] Compound I - 16

[0086] 1H NMR(CDCl3,600MHz)7.86(1H,s),7.42(2H,d,J=8.72Hz),6.90(1H,s),6.85(2H,d,J=8.72Hz),5.61(1H, t,J=5.88Hz),4.01(2H,t,J=6.00Hz),3.85(1H,bro.s),3.53-3.43(4H,m),3.22-3.11(2H,m),3.05(1H,d d,J=7.68,4.86Hz),2.96(2H,t,J=7.35Hz),2.74(2H,t,J=7.35Hz),2.52(2H,bro.s),2.09-2.02(5H,m), 1.85-1.71(4H,m),1.60-1.54(1H,m),1.44-1.35(1H,m),1.32(3H,d,J=1.68Hz),1.30(3H,d,J=1.68Hz).

[0087] 13 C NMR(CDCl3)δ158.3,158.0,154.4,153.1,133.2,121.4(2C),114.7(2C),104.6,66.2(2C) ,55.1,53.4,50.3(2C),49.4,47.1,42.7,35.2,33.0(2C),27.7,26.1,24.0,16.8(2C).HR MS(ESI + C 27 H 42 ClN6O4S + ,cacld:581.2671,found:581.26265.

[0088] Example 2: FAK kinase inhibitory activity of the target molecule

[0089] ADP-Glo ​​for kinase activity evaluation TM The kit was purchased from Promega. Experimental procedures were performed according to the manufacturer's instructions. For all samples, the concentration range was 0.1–100 nM. Experiments were conducted on 384-well plates, with the following main steps: 1) Different concentrations of the target compound (1–100 nM), 50 ng / mL FAK kinase, 0.5 μg / μL of the compound, and 125 μM ATP were added to 384-well plates and gently shaken to mix. See Table 1 for specific procedures; 2) Incubate at room temperature for 60 min; 3) Add 5 μL of ADP-Glo TM 4) Incubate at room temperature for 40 min; 5) Add 10 μL of kinase detection reagent; 6) Incubate at room temperature for 30 min; 7) Fluorescence signals were detected using an LB942 microplate reader (integration time 0.5–1 s). Results were analyzed using GraphPadPrism 5.0 (Table 1).

[0090] Example 3: Cell proliferation inhibitory activity of the target molecule

[0091] (1) Cell types and selection: HCT116 cells, SW620 cells, SW837 cells, and CW2 cells of colon cancer.

[0092] (2) Cell seeding: Collect cells in the logarithmic growth phase and adjust the cell suspension concentration to 4 × 10⁴ cells per well. 3 100 μL of cells were seeded into each well of a 96-well plate, with 3 replicates per group (margin wells were filled with sterile PBS).

[0093] (3) Cell culture: After cell seeding, the control group was cultured with 10% FBS RPMI-1640, while the experimental group was given different concentration gradients of the target substance (0.078-10 μmol / L) and cultured for 72 h at 37℃ in a 5% CO2 incubator.

[0094] (4) Color development: 10 μL of CK-8 solution (5 mg / ml) was added to both groups of cells after 72 h of culture, and the culture was terminated after 4 h.

[0095] (5) Colorimetric analysis: The absorbance value (OD value) of each well was measured on the enzyme-linked immunosorbent assay (ELISA) instrument. The wavelength was 450 nm. The instrument was zeroed using a cell-free RPMI-1640 culture medium blank well.

[0096] (6) Record the results: Cell growth inhibition rate = (absorbance value of control group - absorbance value of experimental group) / absorbance value of control group × 100%, cell proliferation rate = (absorbance value of experimental group / absorbance value of control group) × 100%.

[0097] (7) Plotting cell growth curves: Plotting the inhibitor concentration using the GraphPad Prism plotting software within GraphPad software, and estimating the IC50. 50 The results are shown in Table 1.

[0098] Table 1. Results of the study on the inhibitory activity of different target substances on FAK and cell proliferation (ICP-C) 50 )

[0099]

[0100]

[0101] The bioactivity results from Examples 2-3 demonstrate that the target molecules synthesized in this invention exhibit strong inhibitory effects on FAK kinase, reaching nanomolar levels. Cell proliferation inhibition results show that most compounds are highly effective in inhibiting HCT116, SW620, SW837, and CW2 colon cancer cells, indicating potential pharmaceutical value. This suggests that such molecules have the potential to be developed into novel, highly effective FAK tyrosine kinase inhibitors.

[0102] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. 2-Aromatic aminopyrimidine compounds of general formula (I) or pharmaceutically acceptable salts thereof: wherein, Ar is selected from: 。 2. The 2-arylamino pyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pharmaceutically acceptable salts are selected from sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, oxalates, malonates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrate, glycolic acid salts, tartrates, amygdalinates, xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, or naphthalene-2-sulfonates.

3. A method for preparing the 2-arylaminopyrimidine compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: wherein Ar is as described in claim 1.

4. A pharmaceutical composition comprising a 2-arylaminopyrimidine compound as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. The use of the 2-arylaminopyrimidine compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, in the preparation of a FAK tyrosine kinase inhibitor.

6. The use of the 2-arylaminopyrimidine compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 4 in the preparation of an antitumor drug, wherein the tumor is colon cancer.

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