English

• 1.   Introduction

  Cancer is the most common and serious disease that threatens human health and is the second leading disease after cardiovascular. According to the World Health Organization (WHO), which has estimated 15 million deaths due to cancer worldwide by 2030.^[1] Despite the development of many novel anticancer drugs over the years, numerous drugs in clinical practice have produced multi-drug resistance as well as fatal side effects.^[2] Therefore, it is great significantly to developing more efficient and safer antitumor drugs. Pyrimidine skeleton has received great attention, which is an elemental structural motif of several synthetic and natural occurring products with remarkable biological activities, including antiviral, ^[3] antifungal, ^[4] anti-inflammatory, ^[5] anticancer^[6] and so on.^{[7, 8]} For example (shown in the Figure 1), osimertinib (1) has a breakthrough effect in the treatment of non-small cell lung cancer, ^[9] and imatinib (2) is mainly used to treat chronic myeloid cell leukemia and acute lymphocytic leukemia.^[10] Besides, the incorporation of trifluoromethyl into organic compounds as a powerful tool has accelerated the new drug development.^{[11, 12]} IC₅₀ value of compound 3 against hedgehog (Hh) signaling pathway is 1.44 nmol/L, ^[13] and trifluridine (4) can selectively treat certain viruses, such as herpes simplex virus, adenovirus, vaccinia virus, and so on.^[14]

  Figure 1

  

  Figure 1.  Chemical structures of pyrimidine derivatives 1~4

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  At the same time, heterocycles containing benzimidazole, benzoxazole and benzothiazole are important targets in synthetic and medicinal chemistry, because these fragments are key moieties in many natural and synthetic biologically active agents, such as anti-tumor, anti-virus, anti-bacterial, anti-oxidation, anticoagulation and so on.^[15~18] Molecular hybridization strategy is a valuable structural modification approach in drug design, which based on the combination of pharmacophoric moieties of different bioactive substances to yield a new hybrid. Hybrid drug designs as a powerful strategy have accelerated the discovery of innovative anticancer agent.^{[19, 20]} Based on extensive research, it is worthy considering to synthesize some new compounds containing benzimidazole, benzoxazole, benzothiazole with 6-(trifluoromethyl)pyrimidine in a single molecule. Herein a series of novel 2, 4-substituted pyrimidine derivatives containing trifluoromethyl based on the molecular hybridization strategy in moderate yields were synthesized, their antitumor activities in vitro were also evaluated.

  2.   Results and discussion

  2.1   Chemistry

  The general synthetic route was illustrated in Scheme 1. Firstly, compound 9 was prepared via cyclization reaction of 4, 4, 4-trifluoromethylacetoacetate with thiourea in the presence of potassium hydroxide reflux in ethanol for 3 h.^[21] Key intermediates 2-chloromethylbenzimidazole 10a, ^[22] and its bio-isosteric benzoxazole^[23] as well as benzothiazole^[24] were synthesized according to relevant literatures. The obtained benzimidazole derivatives and its biologically active isosteres 10a~10c reacted with compound 9 in the mixed solvent of water and dioxane to give compounds 11a~11c, then compounds 11a~11c were added to phosphorus oxychloride and were heated at 90 ℃ for 2 h to yield compounds 12a~12c. Next, compounds 12a~12c and appropriate aniline were added to ethanol obtaining the target compounds 13a~13d, 13h~13k and 13p~13s, compounds 12a~12c and 2-mercapto heterocyclic substitutes were added in acetonitrile to get the target compounds 13e~13g, 13l~13o and 13t~13w. Finally, the structures of compounds 13a~13w were fully characterized by ¹H NMR, ¹³C NMR and HRMS.

  Scheme 1

  

  Scheme 1.  Synthesis of compounds 13a~13w

  Reagents and condition: (ⅰ) KOH, C₂H₅OH, 80 ℃, 3 h; (ⅱ) chloroacetyl chloride, HCl, 110 ℃, 6 h; chlorobenzene, pyridine, p-toluene sulfonic acid, 140 ℃, 6 h; acetic acid, 90 ℃, 2 h; (ⅲ) KOH, H₂O, dioxane, 65 ℃, 2 h; (ⅳ) POCl₃, 90 ℃, 5 h; (ⅴ) C₂H₅OH, K₂CO₃, reflux, 4 h; CH₃CN, Et₃N, reflux

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  2.2   Antitumor activity

  The target compounds were evaluated for their antitumor activity against human cancer cell lines of different origins, including EC-109 (human esophageal cancer cell line), MGC-803 (human gastric cancer cell line), PC-3 (human prostate cancer cell line) and HepG-2 (human liver cancer cell line) via MTT assay. 5-Fluorouracil (5-Fu) was used as positive control. The antitumor activities results are summarized in Table 1.

  Table 1

  

  Table 1.  Antitumor activity [IC₅₀/(μmol·L^－1)] of target compounds 11a~11c, 12a~12c and 13a~13w

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  Compd.	X	R	EC-109	MGC-803	PC-3	HepG-2
  11a	NH	OH	> 50	> 50	> 50	> 50
  11b	O	OH	> 50	> 50	> 50	> 50
  11c	S	OH	> 50	> 50	> 50	> 50
  12a	NH	Cl	26.78±1.43	> 50	48.82±1.64	44.57±1.65
  12b	O	Cl	> 50	> 50	41.79±1.62	> 50
  12c	S	Cl	> 50	> 50	28.12±1.45	41.84±1.62
  13a	NH	Ph	> 50	> 50	18.42±1.07	> 50
  13b	NH	2-C2H5OC6H4	25.46±1.40	33.60±1.56	24.41±1.04	> 50
  13c	NH	3-CH3C6H4	45.55±1.06	> 50	> 50	> 50
  13d	NH	4-FC6H4	22.45±1.35	> 50	19.69±1.29	44.84±1.65
  13e	NH		17.42±1.24	8.97±0.94	7.65±0.88	10.72±1.03
  13f	NH		35.02±1.54	18.79±1.27	10.79±1.06	17.93±1.25
  13g	NH		17.63±1.25	9.85±0.99	8.79±0.92	13.84±1.14
  13h	O	Ph	37.59±1.58	33.39±1.52	16.38±1.13	> 50
  13i	O	2-CH3OC6H4	34.95±1.54	> 50	18.42±1.19	30.22±1.48
  13j	O	3-CH3C6H4	22.02±1.34	30.57±1.49	23.47±1.39	33.99±1.53
  13k	O	4-FC6H4	17.08±1.23	39.08±1.59	17.02±1.17	22.73±1.36
  13l	O		8.22±0.90	5.45±0.73	5.62±0.12	13.63±1.13
  13m	O		21.67±1.34	> 50	7.83±0.99	26.97±1.42
  13n	O		19.62±1.29	> 50	6.33±0.86	> 50
  13o	O		5.80±0.72	5.81±0.76	5.28±0.68	7.70±0.89
  13p	S	Ph	> 50	18.93±1.28	12.83±1.11	> 50
  13q	S	2-CH3OC6H4	24.38±1.39	> 50	15.27±1.21	32.59±1.51
  13r	S	3-CF3C6H4	14.48±1.16	12.11±1.08	8.09±0.89	11.30±1.05
  13s	S	4-FC6H4	12.57±1.25	14.52±1.16	8.35±0.57	26.03±1.42
  13t	S		5.79±0.75	14.49±1.15	3.67±0.57	9.92±1.09
  13u	S		18.29±1.58	> 50	5.25±1.18	21.92±1.34
  13v	S		14.16±1.15	> 50	4.79±1.14	5.14±0.71
  13w	S		4.76±0.66	8.31±0.91	1.76±0.44	11.13±1.35
  5-Fub	—	—	16.64±1.12	8.95±0.96	5.55±0.74	11.13±1.35
  a Antitumor activity was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit tumor cell proliferation by 50% IC50. Dates are presented as the mean±SDs of three independent experiments. b Positive control.

  From the preliminary results in Table 1, the antitumor activity of the intermediates 11a~11c and 12a~12c possessed relatively weak antitumor activity (IC₅₀ > 50 μmol/L) against the tested four cell lines. However, when the 4-position of pyrimidine was introduced different substitutes, the antitumor activity was obviously improved, therefore the substitutes attached certain effect on the antitumor activity. With the antitumor activity against the cancer cell lines in hand, the preliminary structure-activity relationships of the target compounds were explored. Firstly, we evaluated the antitumor activity of different aniline substituents against the tested cancer cell lines. In general, compared with compounds 13a~13d, 13h~13k and 13p~13s, different aniline substituents exerted moderate antitumor activity, especially introducing the electron-withdrawing groups (such as F and CF₃) on the phenyl ring, improved the antitumor activity against EC-109 and PC-3. Compared with compounds 13e~13g, 13l~13n and 13t~13v, when the substitution R was introduced heterocyclic substituent, the antitumor activity of thiadiazole was superior to benzoxazole and benzimidazole against these four cell lines, especially compounds 13o and 13w with tetrazolium substituent had potential antitumor activity against the tested four cell lines. Therefore, the 2-mercapto heterocyclic group is preferred for the antitumor activity over the phenyl ring and the tetrazolium substituent group has the best antitumor activity. With the volume of X increasing, the antitumor activity of the target compounds had been significantly improved. Compared compound 13s and 13k as well as 13e with the 4-F-aniline substituent, compound 13s significantly increased antitumor activity against PC-3. Therefore, the benzothiazole hybrids possess better antitumor activity. The antitumor activity greatly improved when introduced into different heterocyclic heterocycles, such as 13o (5.28 μmol/L), 13t (3.67 μmol/L), 13u (5.25 μmol/L), 13v (4.79 μmol/L) and 13w (1.76 μmol/L). Compound 13w performed excellent and broad- spectrum antitumor activity with IC₅₀ values less than 10 μmol/L, comparable to that of 5-FU. Through the above structure-activity relationship (SAR) study, it can be concluded that the benzothiazole/pyrimidine hybrid derivatives possess better antitumor activity than benzimidazole and benzoxazole derivatives, and heterocyclic substitutes are beneficial for improving antitumor activity.

  3.   Conclusion

  In summary, a series of novel 2, 4-substituted pyrimidine derivatives containing trifluoromethyl based on molecular hybridization were designed, synthesized and evaluated for their antitumor activity against EC-109 (human esophageal cancer cells), MGC-803 (human gastric cancer cells), PC-3 (human prostate cancer cells) and HepG-2 (human liver cancer cells) using MTT assay in vitro. Some compounds displayed moderate to potent antitumor activity. Especially compound 13w exhibited extremely potent antitumor activity against PC-3 with IC₅₀ values of 1.76 μmol·L^－1. They are remarkably better than 5-fluorouracil, providing a structural basis for the development of new anticancer drugs.

  4.   Experimental section

  4.1   Materials

  Silica gel: China Qingdao Ocean Chemical Group Corporation. Column chromatography silica gel: Shanghai May Fourth Chemical Reagent Factory. Potassium hydroxide: Tianjin Chemical Reagent Supply and Marketing Company. Anhydrous Ethanol: Tianjin Yongda Chemical Reagent Company Limited. 1, 4-Dioxane: Tianjin Yongda Chemical Reagent Company Limited. All reagents and solvents were purchased from commercial sources and were used without further purification. Melting points were determined on an X-5 micro melting apparatus and are uncorrected. ¹H NMR and ¹³C NMR spectra were measured using a DPX-DPX-400 superconducting nuclear magnetic resonance instrument, Chemical shifts (δ) are given relative to TMS. High-resolution mass spectrometry was measured using a Waters-Micromass Q-TofMicro High Resolution Determination of tetragonal-flight time tandem mass spectrometer.

  2-Mercapto-6-(trifluoromethyl)pyrimidin-4-ol (9), ^[21] 2- (chloromethyl)-1H-benzo[d]imidazole (10a), ^[22] 2-(chloro- methyl)benzo[d]oxazole (10b), ^[23] 2-(chloromethyl)benzo- [d]thiazole (10c), ^[24] were synthesized according to the literature.

  4.2   General procedure for the synthesis of compounds 11a~11c

  Compounds 11a~11c was synthesized according to the literature ^[22]. To a well-stirred solution of compound 9 (0.024 mol) in H₂O (10 mL), an equimolar amount of solution of compounds 10a~10c in 1.4-dioxane (5 mL) was added. The reaction mixture was stirred and heated under 65 ℃ for 2~4 h. Upon completion, the system was adjusted to pH 6 with dilute hydrochloric acid. The precipitated product was filtered off and washed with H₂O and vacuum drying to give compounds 11a~11c.

  2-(((1H-Benzo[d]imidazol-2-yl)methyl)thio)-6-(trifluoromethyl)pyrimidin-4-ol (11a): yellow solid, yield 90.05%. m.p. 221.0~221.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.51 (dd, J＝5.9, 3.2 Hz, 2H), 7.17 (dd, J＝6.0, 3.1 Hz, 2H), 6.67 (s, 1H), 4.68 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 165.26, 163.58, 149.59, 138.44, 131.46, 128.62, 121.89, 114.80, 107.27, 27.78; HR-MS (ESI) calcd for C₁₃H₁₀F₃N₄OS [M+H]⁺ 327.0527, found 327.0528.

  2-((Benzo[d]oxazol-2-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-ol (11b): yellow solid, yield 58.2%. m.p. 193.5~193 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 13.62 (s, 1H), 8.06 (d, J＝8.0 Hz, 1H), 7.96 (d, J＝8.1 Hz, 1H), 7.50 (dd, J＝11.2, 4.2 Hz, 1H), 7.43 (t, J＝7.6 Hz, 1H), 6.70 (s, 1H), 4.89 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) 167.59, 152.32, 135.13, 127.26, 127.04, 126.24, 125.30, 124.51, 122.43, 122.15, 121.78, 119.05, 31.85; HR-MS (ESI) calcd for C₁₃H₉F₃N₃O₂S [M+H]⁺ 328.0368, found 328.0366.

  2-((Benzo[d]thiazol-2-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-ol (11c): yellow solid, yield 89.5%. m.p. 191.0~191.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 13.60 (s, 1H), 8.06 (d, J＝8.0 Hz, 1H), 7.96 (d, J＝8.1 Hz, 1H), 7.54~7.47 (m, 1H), 7.45~7.40 (m, 1H), 6.70 (s, 1H), 4.89 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 167.58, 164.60, 152.32, 151.23, 135.13, 126.24, 125.31, 122.43, 122.15, 121.77, 119.04, 107.55, 31.85; HR-MS (ESI) calcd for C₁₃H₉F₃N₃OS₂ [M+H]⁺ 344.0139, found 344.0137.

  4.3   General procedure for the synthesis of compounds 12a~12c

  Compounds 11a~11c (0.015 mol) were dissolved in 30 mL of dioxane and added with phosphorus oxychloride slowly, then the temperature was raised to 90 ℃ for 5 h. The reaction system was cooled to room temperature, slowly added dropwise to ice water while stirring, and the system continued to precipitate milky white solid. The solid was filtered, washed with 10% sodium hydroxide (100 mL). The product was washed with water to neutral. After vacuum drying, products 12a~12c were obtained.

  2-(((4-Chloro-6-(trifluoromethyl)pyrimidin-2-yl)thio)-methyl)-1H-benzo[d]imidazole (12a): yellow solid, yield 94.6%. m.p. 162.1~162.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.05 (s, 1H), 7.51 (dd, J＝5.9, 3.2 Hz, 2H), 7.16 (dd, J＝6.0, 3.2 Hz, 2H), 4.73 (s, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ: 172.18, 162.87, 155.74, 149.57, 137.62, 122.31, 118.28, 114.69, 114.36, 28.33. HR- MS (ESI) calcd for C₁₃H₉ClF₃N₄S [M+H]⁺ 345.0189, found 345.0186.

  2-(((4-Chloro-6-(trifluoromethyl)pyrimidin-2-yl)thio)-methyl)benzo[d]oxazole (12b): yellow solid, yield 62.6%. m.p. 101.5~101.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.02 (s, 1H), 7.71 (d, J＝1.6 Hz, 1H), 7.69 (d, J＝1.8 Hz, 1H), 7.40 (dd, J＝7.3, 1.4 Hz, 1H), 7.37~7.33 (m, 1H), 4.82 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 171.64, 162.88, 162.35, 155.69, 155.32, 150.37, 140.68, 125.21, 124.50, 119.54, 114.54, 110.65, 27.74; HR-MS (ESI) calcd for C₁₃H₇ClF₃N₃OSNa [M+Na]⁺ 367.9848, found 367.9844.

  2-(((4-Chloro-6-(trifluoromethyl)pyrimidin-2-yl)thio)-methyl)benzo[d]thiazole (12c): yellow solid, yield 46.7%. m.p. 93.1~93.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (d, J＝8.0 Hz, 2H), 7.97 (d, J＝8.1 Hz, 1H), 7.51 (t, J＝7.6 Hz, 1H), 7.43 (t, J＝7.6 Hz, 1H), 4.95 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 171.76, 167.45, 162.99, 155.80, 155.44, 152.43, 135.01, 126.27, 125.31, 122.45, 122.14, 114.64, 32.70; HR-MS (ESI) calcd for C₁₃H₈ClF₃N₃S₂ [M+H]⁺ 361.9800, found 361.9804.

  4.4   General procedure for the synthesis of 2, 4-substituted pyridine derivatives (13a~13w) containing trifluoromethyl

  Compound 12 (0.58 mmol) was dissolved in 6 mL of ethanol and potassium carbonate (0.46 mmol) was added and the mixture was heated to 85 ℃. Then different aniline (0.70 mmol) was dissolved in 4 mL of ethanol and added dropwise to the above mixture. The mixture was refluxed for 4 h, then cooled to room temperature and purified by chromatography on silica gel using ethyl acetate/petroleum ether to obtain 13a~13d, 13h~13k and 13p~13s.

  Compound 12 (0.58 mmol) was dissolved in 6 mL of acetonitrile, and triethylamine (0.46 mmol) was added. Then 2-mercapto heterocycle (0.70 mmol) was dissolved in 4 mL of acetonitrile and added dropwise to the above mixture. After refluxed for 6 h, the reaction was complete. The mixture was cooled to room temperature and purified by chromatography on silica gel using ethyl acetate/petro- leum ether to obtain 13e~13g, 13l~13o and 13t~13w.

  2-(((1H-benzo[d]imidazol-2-yl)methyl)thio-N-phenyl-6-(trifluoromethyl)pyrimidin-4-amine (13a): yellow solid, yield 83.4%. m.p. 244.9.0~245.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.79 (s, 1H), 7.74 (dd, J＝6.0, 3.1 Hz, 2H), 7.72~7.36 (m, 5H), 7.27 (s, 2H), 7.05 (s, 2H), 4.91 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 169.48, 160.37, 151.07, 137.91, 131.14, 128.80, 125.55, 121.70, 120.46, 120.42, 118.97, 113.83, 101.03, 26.37; HRMS (ESI) calcd for C₁₉H₁₅F₃N₅S [M+H]⁺ 402.1000, found 402.0992.

  2-(((1H-Benzo[d]imidazol-2-yl)methyl)thio)-N-(2-ethoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-amine(13b): yellow solid, yield 59.6%. m.p. 194.3~194.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.31 (s, 1H), 9.57 (s, 1H), 7.72 (d, J＝9.1 Hz, 1H), 7.50 (dd, J＝5.6, 3.3 Hz, 2H), 7.25~7.09 (m, 4H), 7.08 (d, J＝7.7 Hz, 1H), 6.87 (t, J＝7.1 Hz, 1H), 4.60 (s, 2H), 4.10 (q, J＝7.0 Hz, 2H), 1.31 (t, J＝6.9Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.50, 167.88, 161.02, 152.41, 152.07, 151.73, 150.42, 139.25, 126.15, 124.77, 122.04, 121.64, 120.26, 119.31, 112.72, 63.85, 27.96, 14.49; HRMS (ESI) calcd for C₂₁H₁₉F₃N₅OS [M+H]⁺ 444.1106, found 444.1116.

  2-(((1H-Benzo[d]imidazol-2-yl)methyl)thio)-N-(m-tolyl)-6-(trifluoromethyl)pyrimidin-4-amine (13c): yellow solid, yield 79.8%. m.p. 235.1~235.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.78 (s, 1H), 7.75 (dd, J＝5.8, 2.9 Hz, 2H), 7.51 (dd, J＝6.1, 3.1 Hz, 2H), 7.32 (d, J＝15.6 Hz, 2H), 7.30~6.78 (m, 4H), 4.91 (s, 2H), 2.21 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 169.42, 160.39, 151.03, 138.11, 138.07, 138.01, 137.93, 137.88, 137.68, 131.13, 128.62, 125.55, 121.71, 118.98, 113.83, 26.25, 20.97; HRMS (ESI) calcd for C₂₀H₁₇F₃N₅S [M+H]⁺ 416.1157, found 416.1150.

  2-(((1H-Benzo[d]imidazol-2-yl)methyl)thio)-N-(4-fluorophenyl)-6-(trifluoromethyl)pyrimidin-4-amine (13d): yellow solid, yield 65.8%. m.p. 212.0~212.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.80 (s, 1H), 7.72 (dd, J＝5.9, 3.0 Hz, 2H), 7.50 (dd, J＝6.1, 3.1 Hz, 4H), 7.47 (s, 1H), 7.10 (s, 2H), 6.99 (s, 1H), 4.90 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 169.46, 160.28, 151.05, 134.19, 131.06, 125.55, 122.45, 121.69, 118.96, 115.54, 113.77, 101.03, 92.21, 26.38; HRMS (ESI) calcd for C₁₉H₁₄F₄N₅S [M+ H]⁺ 420.0906, found 420.0898.

  2-((2-(((1H-Benzo[d]imidazol-2-yl)methyl)thio)-6-(trifluoromthyl)pyrimidin-4-yl)thio)-1, 3, 4-thiadiazole(13e): yellow solid, yield 47.3%. m.p. 118.0~118.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.37 (s, 1H), 9.84 (s, 1H), 8.09 (s, 1H), 7.50 (s, 2H), 7.16 (dd, J＝5.9, 3.1 Hz, 2H), 4.58 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 187.82, 171.46, 168.71, 158.65, 155.70, 149.64, 149.34, 121.86, 118.59, 114.80, 111.24, 28.33; HRMS (ESI) calcd for C₁₅H₁₀F₃N₆S₃ [M+H]⁺ 427.0081, found 427.0082.

  2-((2-(((1H-Benzo[d]imidazol-2-yl)methyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)thio)benzo[d]thiazole(13f): yellow solid, yield 46.5%. m.p. 175.8~176.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.40 (s, 1H), 8.09 (s, 1H), 8.06 (d, J＝6.9 Hz, 2H), 8.02(d, J＝7.9 Hz, 1H) 7.54 (dd, J＝11.3, 4.1 Hz, 1H), 7.49 (dd, J＝8.1, 5.1 Hz, 2H), 7.16 (dd, J＝6.0, 3.1 Hz, 2H), 4.64 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 171.47, 169.40, 156.11, 153.44, 153.09, 151.48, 149.52, 136.22, 126.75, 126.02, 122.62, 122.03, 121.81, 118.60, 114.83, 111.22, 28.32; HRMS (ESI) calcd for C₂₀H₁₃F₃N₅S₃ [M+H]⁺ 476.0285, found 476.0284.

  2-((2-(((1H-benzo[d]imidazol-2-yl)methyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)thio)benzo[d]oxazole(13g): yellow solid, yield 44.2%. m.p. 175.1~175.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.42 (s, 1H), 8.18 (s, 1H), 7.78 (d, J＝8.3 Hz, 1H), 7.65 (d, J＝7.4 Hz, 1H), 7.51~7.44 (m, 2H), 7.40 (dd, J＝12.3, 6.5 Hz, 2H), 7.16 (dd, J＝5.8, 3.0 Hz, 2H), 4.39 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 171.39, 169.73, 154.40, 153.98, 153.63, 151.76, 149.31, 140.87, 126.60, 125.14, 121.98, 121.31, 119.98, 114.75, 111.41, 110.90, 28.02; HRMS (ESI) calcd for C₂₀H₁₃F₃N₅OS₂ [M+H]⁺ 460.0514, found 460.0511.

  2-((Benzo[d]oxazol-2-ylmethyl)thio)-N-phenyl-6-(trifluoromethyl)pyrimidin-4-amine (13h): yellow solid, yield 62.1%. m.p. 160.8~161.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.23 (s, 1H), 7.71~7.69 (m, 1H), 7.69~7.67 (m, 1H), 7.57 (d, J＝7.9 Hz, 2H), 7.41~7.27 (m, 4H), 7.10 (t, J＝7.4 Hz, 1H), 6.86 (s, 1H), 4.74 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.23, 163.14, 160.25, 150.43, 140.75, 138.06, 128.82, 125.12, 124.45, 123.91, 121.82, 120.60, 119.53, 119.09, 110.64, 100.27, 27.18; HRMS (ESI) calcd for C₁₉H₁₂F₃N₄OS [M－H]^－ 401.0684, found 401.0697.

  2-((Benzo[d]oxazol-2-ylmethyl)thio)-N-(2-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-amine (13i): yellow solid, yield 53.2%. m.p. 134.6~134.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.66 (s, 1H), 7.75 (s, 1H), 7.69 (dd, J＝8.6, 7.1 Hz, 2H), 7.39(dd, J＝7.4, 1.4 Hz, 1H), 7.38~7.31 (m, 2H), 7.15 (d, J＝7.1Hz, 1H), 7.08 (d, J＝7.9Hz, 1H), 6.86 (t, J＝7.2Hz, 1H), 4.68 (s, 2H), 3.81 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 169.84, 169.37, 163.17, 160.92, 152.29, 151.94, 150.41, 140.73, 125.97, 125.09, 124.43, 121.90, 120.13, 119.51, 119.18, 118.48, 111.63, 110.66, 55.60, 27.03; HRMS (ESI) calcd for C₂₀H₁₅F₃N₄O₂SNa [M+Na]⁺ 455.0766, found 455.0768.

  2-((Benzo[d]oxazol-2-ylmethyl)thio)-N-(m-tolyl)-6-(trifluoromethyl)pyrimidin-4-amine (13j): yellow solid, yield 47.8%. m.p. 114.4~114.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.19 (s, 1H), 7.71~7.65 (m, 2H), 7.47 (s, 1H), 7.40~7.32 (m, 3H), 7.19 (t, J＝7.8 Hz, 1H), 6.93 (d, J＝7.4 Hz, 1H), 6.86 (s, 1H), 4.76 (s, 2H), 3.37 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.16, 163.12, 160.22, 151.84, 150.39, 140.72, 140.24, 138.20, 137.98, 128.65, 125.14, 124.68, 124.46, 121.82, 119.52, 119.10, 117.83, 110.62, 27.04, 20.96; HRMS (ESI) calcd for C₂₀H₁₄F₃N₄OS [M－H]^－ 415.0841, found 415.0853.

  2-((Benzo[d]oxazol-2-ylmethyl)thio)-N-(4-fluorophenyl)-6-(trifluoromethyl)pyrimidin-4-amine (13k): yellow solid, yield 57.9%. m.p. 205.8~206.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.24 (s, 1H), 7.68 (t, J＝8.1 Hz, 2H), 7.58 (dd, J＝8.0, 5.0 Hz, 2H), 7.42~7.29 (m, 2H), 7.14 (t, J＝8.7 Hz, 2H), 6.82 (s, 1H), 4.72 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.22, 163.12, 160.24, 159.68, 150.40, 140.74, 134.35, 125.11, 124.45, 122.75, 121.80, 119.51, 119.07, 115.53, 115.31, 110.59, 27.19; HR-MS (ESI) calcd for C₁₉H₁₁F₄N₄OS [M－H]^－ 419.0590, found 419.0601.

  2-(((4-((1, 3, 4-thiadiazol-2-yl)thio)-6-(trifluoromethyl)-pyrimidin-2-yl)thio)methyl)benzo[d]oxazole (13l): yellow solid, yield 59.8%. m.p. 122.0~122.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.90 (s, 1H), 8.07 (s, 1H), 7.72~7.64 (m, 2H), 7.42~7.31 (m, 2H), 4.66 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.75, 168.99, 162.27, 158.87, 155.46, 153.34, 152.98, 150.34, 140.60, 125.20, 124.48, 121.21, 119.53, 110.74, 27.35; HRMS (ESI) calcd for C₁₅H₈F₃N₅OS₃Na [M+Na]⁺ 449.9741, found 449.9740.

  2-(((4-(benzo[d]thiazol-2-ylthio)-6-(trifluoromethyl)-pyrimidin-2-yl)thio)methyl)benzo[d]oxazole (13m): yellow solid, yield 46.7%. m.p. 148.2~148.7 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.11 (d, J＝8.0 Hz, 1H), 8.04 (d, J＝9.3 Hz, 2H), 7.68~7.60 (m, 2H), 7.60~7.49 (m, 2H), 7.38 (dd, J＝7.6, 6.2 Hz, 1H), 7.34 (dd, J＝7.3, 6.1 Hz, 1H), 4.65 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.72, 169.80, 162.28, 155.58, 153.42, 153.06, 151.69, 150.32, 140.59, 136.53, 126.77, 126.15, 125.14, 124.45, 122.79, 122.06, 119.51, 111.44, 110.65, 27.32; HR-MS (ESI) calcd for C₂₀H₁₁F₃N₄OS₃Na [M+Na]⁺ 498.9945, found 498.9943.

  2-((2-((Benzo[d]oxazol-2-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)thio)benzo[d]oxazole (13n): yellow solid, yield 49.5%. m.p. 129.2~129.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (s, 1H), 7.79 (dd, J＝7.0, 1.9 Hz, 1H), 7.73~7.68 (m, 1H), 7.66~7.59 (m, 2H), 7.49~7.39 (m, 2H), 7.39~7.31 (m, 2H), 4.43 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.90, 169.18, 167.28, 153.78, 153.42, 152.44, 146.06, 134.98, 126.26, 125.30, 122.51, 122.12, 111.47, 34.58; HR-MS (ESI) calcd for C₂₀H₁₁F₃- N₄O₂S₂Na [M+Na]⁺ 483.0173, found 483.0174.

  2-(((4-((1-Methyl-1H-tetrazol-5-yl)thio)-6-(trifluoromethyl)pyrimidin-2-yl)thio)methyl)benzo[d]oxazole (13o): yellow solid, yield 57.7%. m.p. 102.5~102.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.09 (s, 1H), 7.75~7.64 (m, 2H), 7.44~7.31 (m, 2H), 4.41 (s, 2H), 3.99 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.73, 169.08, 162.12, 153.33, 150.41, 146.02, 140.55, 125.26, 124.50, 121.23, 119.54, 111.39, 110.80, 34.54, 27.00; HR-MS (ESI) calcd for C₁₅H₁₀F₃N₇OS₂Na [M+Na]⁺ 448.0238, found 448.0237.

  2-((Benzo[d]thiazol-2-ylmethyl)thio)-N-phenyl-6-(trifluoromethyl)pyrimidin-4-amine (13p): yellow solid, yield 60.5%. m.p. 172.8~173.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.32 (s, 1H), 8.07 (d, J＝7.9 Hz, 1H), 8.02 (d, J＝7.9 Hz, 1H), 7.60 (d, J＝7.9 Hz, 2H), 7.54 (s, 1H), 7.47~7.42 (m, 1H), 7.36 (d, J＝8.0 Hz, 2H), 7.14 (t, J＝7.3 Hz, 1H), 6.93 (s, 1H), 4.90 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.24, 169.49, 160.28, 152.72, 151.88, 138.06, 134.97, 128.90, 126.20, 125.12, 123.91, 122.38, 122.14, 121.88, 120.56, 119.15, 32.37; HR-MS (ESI) calcd for C₁₉H₁₃F₃N₄S₂Na [M+Na]⁺ 441.0431, found 441.0451.

  2-((Benzo[d]thiazol-2-ylmethyl)thio)-N-(2-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-amine (13q): yellow solid, yield 45.2%. m.p. 126.0~126.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.68 (s, 1H), 8.01 (d, J＝7.8 Hz, 1H), 7.96 (d, J＝8.0 Hz, 1H), 7.73 (s, 1H), 7.54~7.46 (m, 1H), 7.41 (dd, J＝11.1, 4.0 Hz, 1H), 7.21~7.00 (m, 3H), 6.90 (t, J＝7.5 Hz, 1H), 4.80 (s, 2H), 3.83 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 169.88, 169.25, 160.98, 152.64, 152.34, 151.99, 135.05, 126.14, 126.02, 125.10, 124.71, 123.80, 122.37, 122.08, 121.98, 120.27, 119.25, 111.68, 55.64, 32.19; HR-MS (ESI) calcd for C₂₀H₁₄F₃N₄OS₂ [M－H]^－ 447.0561, found 447.0574.

  2-((Benzo[d]thiazol-2-ylmethyl)thio)-6-(trifluoromethyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-4-amine(13r): yellow solid, yield 37.7%. m.p. 173.2~173.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.57 (s, 1H), 8.11 (s, 1H), 8.01 (t, J＝7.4 Hz, 1H), 7.94 (d, J＝8.1 Hz, 1H), 7.86 (d, J＝8.3 Hz, 1H), 7.59 (t, J＝8.0 Hz, 1H), 7.50 (d, J＝7.4 Hz, 1H), 7.45 (d, J＝7.9 Hz, 1H), 7.39 (d, J＝7.2 Hz, 1H), 6.93 (s, 1H), 4.88 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.37, 170.28, 168.67, 160.30, 152.78, 152.51, 139.01, 135.01, 130.14, 126.18, 126.13, 125.17, 125.02, 124.11, 122.38, 122.28, 122.09, 120.04, 116.75, 32.28. HR-MS (ESI) calcd for C₂₀H₁₂F₆N₄S₂Na [M+Na]⁺ 509.0305, found 509.0308.

  2-((Benzo[d]thiazol-2-ylmethyl)thio)-N-4-(fluorophenyl)-6-(trifluoromethyl)pyrimidin-4-amine (13s): yellow solid, yield 54.6%. m.p. 151.1~151.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J＝8.1 Hz, 1H), 7.81 (d, J＝7.9 Hz, 1H), 7.46 (t, J＝7.6 Hz, 1H), 7.36 (t, J＝7.6 Hz, 1H), 7.30 (s, 3H), 7.07 (t, J＝8.3 Hz, 2H), 6.54 (s, 1H), 4.78 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 171.30, 169.00, 161.79, 155.39, 155.03, 152.90, 135.72, 132.56, 126.13, 125.42, 125.19, 122.81, 121.79, 121.60, 116.67, 116.45, 33.04; HR-MS (ESI) calcd for C₁₉H₁₂F₄N₄S₂Na [M+Na]⁺ 459.0337, found 459.0345.

  2-(((4-((1, 3, 4-Thiadiazol-2-yl)thio)-6-(trifluoromethyl)-pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (13t): yellow solid, yield 56.5%. m.p. 105.2~105.7 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.89 (s, 1H), 8.10 (s, 1H), 8.03 (d, J＝7.9 Hz, 1H), 7.97 (d, J＝8.0 Hz, 1H), 7.54~7.48 (m, 1H), 7.42 (dd, J＝11.1, 4.0 Hz, 1H), 4.82 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.84, 169.03, 167.56, 158.81, 155.54, 153.44, 152.43, 149.32, 134.96, 126.25, 125.28, 122.49, 122.12, 111.59, 32.38; HR-MS (ESI) calcd for C₁₅H₈F₃N₅S₄Na [M+Na]⁺ 465.9512, found 465.9512.

  2-((2-((Benzo[d]thiazol-2-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)thio)benzo[d]thiazole (13u): yellow solid, yield 48.4%. m.p. 105.2~105.7 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.13 (d, J＝7.4 Hz, 1H), 8.08 (s, 1H), 8.02 (dd, J＝13.3, 7.8 Hz, 2H), 7.91 (d, J＝8.0 Hz, 1H), 7.54 (dd, J＝3.9, 1.4 Hz, 1H), 7.49 (dd, J＝11.5, 4.2 Hz, 2H), 7.41 (t, J＝7.2 Hz, 1H), 4.82 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.85, 169.86, 167.59, 155.69, 152.43, 151.68, 136.51, 134.96, 126.79, 126.20, 125.23, 122.78, 122.43, 122.11, 111.56, 32.35; HR-MS (ESI) calcd for C₂₀H₁₂F₃N₄S₄ [M+H]⁺ 492.9897, found 492.9895.

  2-((2-((Benzo[d]thiazol-2-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)thio)benzo[d]oxazole (13v): yellow solid, yield 42.2%. m.p. 125.1~125.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.19 (s, 1H), 8.00 (d, J＝7.5 Hz, 1H), 7.90 (d, J＝8.0 Hz, 1H), 7.83~7.79 (m, 1H), 7.74~7.69 (m, 1H), 7.53~7.39 (m, 4H), 4.61 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.94, 169.80, 167.15, 154.25, 153.70, 152.33, 151.82, 140.95, 134.96, 126.66, 126.18, 125.24, 125.17, 122.44, 122.07, 120.07, 111.74, 111.71, 110.98, 32.2; HR-MS (ESI) calcd for C₂₀H₁₂F₃N₄OS₃ [M+H]⁺ 477.0125, found 477.0126.

  2-(((4-((1-Methyl-1H-tetrazol-5-yl)thio)-6-((trifluoromthyl)pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (13w): yellow solid, yield 61.2%. m.p. 138.1~138.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.08~8.03 (m, 2H), 7.97 (d, J＝8.1 Hz, 1H), 7.52 (t, J＝7.6 Hz, 1H), 7.44 (t, J＝7.5 Hz, 1H), 4.62 (s, 2H), 4.01 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.90, 169.18, 167.28, 153.78, 153.42, 152.44, 146.06, 134.98, 126.26, 125.30, 122.51, 122.12, 111.47, 34.58, 32.20; HR-MS (ESI) calcd for C₁₅H₁₁F₃N₇S₃ [M+H]⁺ 442.0190, found 442.0192.

  Supporting Information  ¹H NMR and ¹³C NMR spectra of compounds 11a~11c, 12a~12c and 13a~13w are available for free download from our website (http://sioc-journal.cn/).

  
  
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• 

  Figure 1  Chemical structures of pyrimidine derivatives 1~4

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  Scheme 1  Synthesis of compounds 13a~13w

  Reagents and condition: (ⅰ) KOH, C₂H₅OH, 80 ℃, 3 h; (ⅱ) chloroacetyl chloride, HCl, 110 ℃, 6 h; chlorobenzene, pyridine, p-toluene sulfonic acid, 140 ℃, 6 h; acetic acid, 90 ℃, 2 h; (ⅲ) KOH, H₂O, dioxane, 65 ℃, 2 h; (ⅳ) POCl₃, 90 ℃, 5 h; (ⅴ) C₂H₅OH, K₂CO₃, reflux, 4 h; CH₃CN, Et₃N, reflux

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  Table 1.  Antitumor activity [IC₅₀/(μmol·L^－1)] of target compounds 11a~11c, 12a~12c and 13a~13w

  Compd.	X	R	EC-109	MGC-803	PC-3	HepG-2
  11a	NH	OH	> 50	> 50	> 50	> 50
  11b	O	OH	> 50	> 50	> 50	> 50
  11c	S	OH	> 50	> 50	> 50	> 50
  12a	NH	Cl	26.78±1.43	> 50	48.82±1.64	44.57±1.65
  12b	O	Cl	> 50	> 50	41.79±1.62	> 50
  12c	S	Cl	> 50	> 50	28.12±1.45	41.84±1.62
  13a	NH	Ph	> 50	> 50	18.42±1.07	> 50
  13b	NH	2-C2H5OC6H4	25.46±1.40	33.60±1.56	24.41±1.04	> 50
  13c	NH	3-CH3C6H4	45.55±1.06	> 50	> 50	> 50
  13d	NH	4-FC6H4	22.45±1.35	> 50	19.69±1.29	44.84±1.65
  13e	NH		17.42±1.24	8.97±0.94	7.65±0.88	10.72±1.03
  13f	NH		35.02±1.54	18.79±1.27	10.79±1.06	17.93±1.25
  13g	NH		17.63±1.25	9.85±0.99	8.79±0.92	13.84±1.14
  13h	O	Ph	37.59±1.58	33.39±1.52	16.38±1.13	> 50
  13i	O	2-CH3OC6H4	34.95±1.54	> 50	18.42±1.19	30.22±1.48
  13j	O	3-CH3C6H4	22.02±1.34	30.57±1.49	23.47±1.39	33.99±1.53
  13k	O	4-FC6H4	17.08±1.23	39.08±1.59	17.02±1.17	22.73±1.36
  13l	O		8.22±0.90	5.45±0.73	5.62±0.12	13.63±1.13
  13m	O		21.67±1.34	> 50	7.83±0.99	26.97±1.42
  13n	O		19.62±1.29	> 50	6.33±0.86	> 50
  13o	O		5.80±0.72	5.81±0.76	5.28±0.68	7.70±0.89
  13p	S	Ph	> 50	18.93±1.28	12.83±1.11	> 50
  13q	S	2-CH3OC6H4	24.38±1.39	> 50	15.27±1.21	32.59±1.51
  13r	S	3-CF3C6H4	14.48±1.16	12.11±1.08	8.09±0.89	11.30±1.05
  13s	S	4-FC6H4	12.57±1.25	14.52±1.16	8.35±0.57	26.03±1.42
  13t	S		5.79±0.75	14.49±1.15	3.67±0.57	9.92±1.09
  13u	S		18.29±1.58	> 50	5.25±1.18	21.92±1.34
  13v	S		14.16±1.15	> 50	4.79±1.14	5.14±0.71
  13w	S		4.76±0.66	8.31±0.91	1.76±0.44	11.13±1.35
  5-Fub	—	—	16.64±1.12	8.95±0.96	5.55±0.74	11.13±1.35
  a Antitumor activity was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit tumor cell proliferation by 50% IC50. Dates are presented as the mean±SDs of three independent experiments. b Positive control.

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