A tetrazole compound and its application

Abstract

The present invention provides a tetrazole compound and its application. The tetrazole compound has a structural formula I as shown in the following figure: wherein Ar 1 The tetrazole compound provided by the present invention can effectively inhibit the androgen receptor, has a good inhibitory effect, and has a potential therapeutic effect on prostate cancer.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a tetrazole compound and an application thereof, and in particular to a highly active tetrazole compound and an application thereof. Background Art

[0002] Prostate cancer (PCa) is the leading cause of cancer-related death in men. The androgen receptor (AR), a member of the nuclear receptor family, plays a key role in the development of PCa. PCa is a condition involving androgen excess and overexpression of AR-mediated signaling pathways, and the proliferation and survival of PCa cells are critically dependent on AR signaling. Therefore, AR has become the main therapeutic target for the treatment of PCa, and androgen deprivation therapy with surgery or chemical castration is the standard treatment, and most patients will achieve remission. Unfortunately, the disease often progresses to an incurable stage called castration-resistant prostate cancer (CRPC), and persistent or reactivated AR signaling pathways aggravate the disease progression. Most patients initially benefit from second-generation therapies, such as enzalutamide, apalutamide, and darolutamide, but eventually develop secondary resistance to them. Therefore, new therapeutic strategies are needed to counter the AR signaling pathway.

[0003] CN111655249A discloses a drug combination of an inhibitor of an androgen receptor signaling pathway and a p38 inhibitor for treating prostate cancer in an individual, wherein the prostate tumor cells express AR-V7 variant androgen receptor protein, or for preventing the occurrence of resistance in patients with prostate cancer treated by inhibitors of the androgen receptor signaling pathway. The invention further relates to a pharmaceutical composition comprising enzalutamide, abiraterone or apalutamide and a p38 inhibitor selected from LY2228820 and ARRY-614, and at least one pharmaceutically acceptable excipient. The invention also relates to the use of a p38 inhibitor for restoring sensitivity to androgen deprivation therapy (ADT) in patients with prostate cancer who have acquired resistance to androgen deprivation therapy (ADT) after treatment with an inhibitor of the androgen receptor signaling pathway, wherein the prostate tumor cells express AR-V7 variant androgen receptor protein.

[0004] CN110327465A discloses a compound anti-prostate cancer drug, which is composed of a polymethoxyflavonoid drug and an androgen receptor inhibitor drug. The mass ratio of the polymethoxyflavonoid drug to the androgen receptor inhibitor drug is 1:1. Among them, the polymethoxyflavonoid drug is nobiletin, and the androgen receptor inhibitor drug is bicalutamide. The present invention provides a method in which the efficacy of a polymethoxyflavonoid drug and an androgen receptor inhibitor anticancer drug is significantly better than that of a single drug, and has a good inhibitory effect on inhibiting prostate cancer and preventing prostate cancer from developing into a malignant state; the drug provided by the present invention has a low dosage, reduces the concentration of a single drug, thereby reducing the toxic and side effects of the drug and reducing the harm to the human body; the economic burden of the patient is further reduced by mixed use, and a better effect is achieved than using the drug alone.

[0005] Since patients currently receive second-generation therapies and eventually develop secondary drug resistance, which affects subsequent treatment, how to provide a new AR signaling pathway inhibitor has become an urgent problem to be solved. Summary of the invention

[0006] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a tetrazole compound and its application, in particular to provide a highly active tetrazole compound and its application. The tetrazole compound provided by the present invention can effectively inhibit androgen receptors, has a good inhibitory effect, and has a potential therapeutic effect on prostate cancer.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a tetrazole compound, the structure of which is shown in Formula I:

[0009]

[0010] Among them, Ar 1 is selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted C4-C7 heterocycle, Ar 2 Selected from Any one of .

[0011] Y is selected from any one of C, O or N, and Z is selected from halogen.

[0012] Ring A is selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted C4-C7 heterocyclic ring, and a substituted or unsubstituted C3-C7 aliphatic ring.

[0013] The halogen is selected from any one of fluorine, chlorine, bromine or iodine.

[0014] The heterocycle is selected from any one of thiophene, pyridine or pyrazole.

[0015] The C3-C7 aliphatic ring is selected from any one of cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.

[0016] The C4-C7 heterocycle is selected from any one of pyridazine, pyridine or thiophene.

[0017] The compounds with the above-mentioned specific structures can effectively inhibit androgen receptors and have significant inhibitory effects.

[0018] Preferably, the substituted substituent is selected from any one of halogen, halogen substituted or unsubstituted C1-C6 alkyl, and halogen substituted or unsubstituted C1-C6 alkoxy.

[0019] The C1-C6 alkyl group may be, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl or n-hexyl, and the C1-C6 alkoxy group may be, for example, methoxy, ethoxy, propoxy or isopropoxy.

[0020] Preferably, the substituted substituents are selected from halogen.

[0021] Preferably, the Ar 1 is selected from substituted or unsubstituted benzene rings.

[0022] Preferably, the Ar 1 is selected from substituted benzene rings.

[0023] Preferably, Y is selected from O.

[0024] Preferably, the Ar 2 Selected from Any one of the foregoing, wherein Y, Z, and ring A have the same limited ranges as above.

[0025] Preferably, the tetrazole compound is selected from Any one of .

[0026] When Y is selected from O, the tetrazole compound can be prepared by a method comprising the following steps: Reaction with HONH2 hydrochloride to obtain compound Then, it reacts with N-chlorosuccinimide in acetonitrile solution under hydrochloric acid conditions to obtain compound Then react with NaN3 in benzene to obtain compound Then react with CH3COCl in benzene to obtain the intermediate Finally, the intermediate Respectively Reaction to obtain the tetrazole compound.

[0027] When Y is selected from N, the tetrazole compound can be prepared by a method comprising the following steps: Under the condition of sodium carbonate, it reacts with hydroxylamine sulfonic acid in water to obtain the compound Afterwards, respectively Reaction to obtain the tetrazole compound.

[0028] Among them, Ar 1 , Z, and ring A have the same ranges as described above.

[0029] In a second aspect, the present invention provides use of the tetrazole compound described above in the preparation of an androgen receptor inhibitor.

[0030] In a third aspect, the present invention also provides the use of the tetrazole compounds described above in the preparation of drugs for treating prostate cancer.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The present invention provides a tetrazole compound with a specific structure, which has a significant inhibitory effect on androgen receptor and can be used to prepare androgen receptor inhibitors and prostate cancer therapeutic drugs. DETAILED DESCRIPTION

[0033] In order to further explain the technical means and effects adopted by the present invention, the technical solution of the present invention is further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0034] Example 1

[0035] This embodiment provides a tetrazole compound 1, the specific structure of which is as follows:

[0036]

[0037] The preparation steps are as follows:

[0038] (1) Hydroxylamine hydrochloride (10.42 g, 150 mmol) was added to a stirred mixture of 4-chlorobenzaldehyde (7.0 g, 50 mmol), sodium acetate (24.6 g, 150 mmol) and anhydrous ethanol (300 mL), and then refluxed for 2 hours. The solvent was removed under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain (E)-4-chlorobenzaldehyde oxime (7.7 g, 49.5 mmol, 99%);

[0039] (2) To a stirred solution of (E)-4-chlorobenzaldehyde oxime (7.7 g, 49.5 mmol) in 40 mL of acetonitrile (containing 5 drops of concentrated hydrochloric acid), N-chlorosuccinimide was added in portions at a rate that maintained the blue-green color fading before each subsequent addition. The solution was allowed to stand for 30 minutes. 80 mL of water was added and extracted with benzene (2×40 mL). The combined organic phases were dried and filtered to obtain alpha-4-dichlorobenzaldehyde oxime;

[0040] (3) Sodium azide (6.5 g, 0.1 mol) was dissolved in water (35 mL) and slowly added to a benzene solution of alpha-4-dichlorobenzaldehyde oxime stirred under an ice bath. The mixture was stirred at room temperature for 48 hours. The organic phase was washed with water (2×100 mL), dried over sodium sulfate and quickly used in the next reaction (to obtain alpha-azido-4-chlorobenzaldehyde oxime);

[0041] (4) The benzene solution containing alpha-azido-4-chlorobenzaldehyde oxime was slowly added to a benzene (20 mL) solution containing excess acetyl chloride (20 mL) stirred in an ice bath. After the addition was completed, the reaction mixture was slowly warmed to room temperature and allowed to stand for 48 hours. The mixture was partially evaporated (to 30 mL), carefully diluted with water (10 mL), and stirred at 60°C for 2 hours. The resulting mixture was cooled to room temperature, diluted with ice water (100 mL), and extracted with ether (100 mL). The organic phase was washed with water and then extracted with saturated sodium bicarbonate (2×100 mL). The sodium bicarbonate extracts were combined and acidified to pH=1 with concentrated hydrochloric acid. The solid was filtered, and the filter cake was washed with water and dried to obtain 5-(4-chlorophenyl)-1-hydroxytetrazole;

[0042] (5) 5-(4-chlorophenyl)-1-hydroxytetrazolyl (500 mg, 2.55 mmol), 1-(bromomethyl)-4-chlorobenzene (498 mg, 2.42 mmol), potassium carbonate (769 mg, 5.86 mol) were added to acetonitrile (10 mL) and stirred at room temperature overnight. The solvent was spin-dried, water (20 mL) was added to the residue, and extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated brine (20 mL), dried and evaporated. The crude material was purified by chromatography on silica gel, followed by recrystallization with DCM and petroleum ether to obtain compound 1 with a yield of 82%.

[0043] The characterization data are as follows:

[0044] Mp216℃.

[0045] 1HNMR(400MHz, CDCl-d6)7.18(2H,d,J 8.44Hz,ArH),7.44(2H,d,J 8.6Hz,ArH),7.18(2H,d,J 8.4Hz,ArH),7.06–7.23(2H,d,J 8.48,ArH),5.39(2H,benzylic CH2). 13 CNMR(150MHz,DMSO-d6)155.09,151.60,141.04,137.16,133.06,129.29,128.50,1 26.83,123.88,123.33,119.36,113.16,53.83,44.10,42.10,35.95,13.09,11.55. HRMS(ESI):m / zcalcd for C 20 H 24 N5O2 32 S:398.1651[M+H] + ;found:398.1657.

[0046] Example 2

[0047] This embodiment provides a tetrazole compound 2, the specific structure of which is as follows:

[0048]

[0049] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-chlorobenzene.

[0050] Finally, compound 2 was obtained with a yield of 88%.

[0051] The characterization data are as follows:

[0052] 1 H NMR (400MHz, CDCl3)7.81-7.74(2H,m,ArH),7.48-7.41(2H,m,ArH),7.31-7.25(1H,m,ArH),7.19-7.12(2H,m,ArH),6.98-6.99(1H,m,ArH),5.39(2H,s). 13 C NMR (150MHz, CDCl3) 146.76, 138.26, 134.91, 132.81, 130.51, 130.35, 130.24, 129.44, 129.33, 128.23, 120.38, 82.63. HRMS(ESI):m / z calcd for C 14H 10 Cl2N4O:320.0232[M+H] + ;found:321.17.

[0053] Example 3

[0054] This embodiment provides a tetrazole compound 9a, the specific structure of which is as follows:

[0055]

[0056] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-4-fluorobenzene.

[0057] Finally, compound 9a was obtained with a yield of 51%.

[0058] The characterization data are as follows:

[0059] 1 H NMR (400MHz, CDCl3)7.81-7.79(2H,m,ArH),7.49-7.42(2H,m,ArH),7.19-7.11(2H,m,ArH),6.91-6.85(2H,m,ArH),5.41(2H,s). 13 C NMR (150MHz, CDCl3)164.95,162.96,146.83,138.21,132.58,132.51,129.44,129.36,127.00,126.98,120.62,116.21,116.21,116.04,82.80. 19 F NMR spectrum for 9a (376MHz; CDCl3) 109.49. HRMS(ESI):m / z calcdfor C 14 H 10 ClFN4O:304.0527[M+H] + ;found:305.18.

[0060] Example 4

[0061] This embodiment provides a tetrazole compound 9b, the specific structure of which is as follows:

[0062]

[0063] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-fluorobenzene.

[0064] Finally, compound 9b was obtained with a yield of 27%.

[0065] The characterization data are as follows:

[0066] 1 H NMR (400MHz, CDCl3)7.89-7.81(2H,m,ArH),7.49-7.43(2H,m,ArH),7.29-7.21(1H,m,ArH),7.05-6.97(1H,m,ArH),6.96-6.85(2H,m,ArH),5.43(2H,s). 13 C NMR (150MHz, CDCl3)163.74,161.76,146.67,138.30,133.28,133.23,130.78,130.7 1,129.51,129.36,125.87,125.85,120.51,117.60,117.43,117.22,117.04,82.63. 19 F NMR spectrum for 9a (376MHz; CDCl3)111.38. HRMS(ESI):m / z calcd for C 14 H 10 ClFN4O:304.0527[M+H] + ;found:305.19.

[0067] Example 5

[0068] This embodiment provides a tetrazole compound 9c, the specific structure of which is as follows:

[0069]

[0070] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-4-bromobenzene.

[0071] Finally, compound 9c was obtained with a yield of 43%.

[0072] The characterization data are as follows:

[0073] 1 H NMR (400MHz, CDCl3)7.79-7.75(2H,m,ArH),7.41-7.45(2H,m,ArH),7.38-7.31(2H,m,ArH),7.02-6.97(2H,m,ArH),5.39(2H,s). 13C NMR (150MHz, CDCl3) 146.83, 138.25, 132.24, 131.89, 129.92, 129.43, 129.39, 125.12, 120.55, 82.78. HRMS(ESI):m / z calcdfor C 14 H 10 BrClN4O:363.9727[M+H] + ;found:367.14.

[0074] Example 6

[0075] This embodiment provides a tetrazole compound 9d, the specific structure of which is as follows:

[0076]

[0077] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-bromobenzene.

[0078] Finally, compound 9d was obtained with a yield of 46%.

[0079] The characterization data are as follows:

[0080] 1 H NMR (400MHz, CDCl3)7.75-7.85(2H,m,ArH),7.49-7.42(3H,m,ArH),7.34-7.31(1H,m,ArH),7.12-7.08(1H,m,ArH),7.07-7.01(1H,m,ArH),5.39(2H,s). 13 C NMR (150MHz, CDCl3)146.89,138.38,133.54,133.39,133.06,130.51,129.53,129.40,128.74,123.01,120.43,82.65. HRMS(ESI):m / z calcd for C 14 H 10 BrClN4O:363.9727[M+H] + ;found:367.13.

[0081] Example 7

[0082] This embodiment provides a tetrazole compound 9e, the specific structure of which is as follows:

[0083]

[0084] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3,4-dichlorobenzene.

[0085] Finally, compound 9e was obtained with a yield of 70%.

[0086] The characterization data are as follows:

[0087] 1 H NMR (400MHz, CDCl3)7.83-7.79(2H,m,ArH),7.51-7.47(2H,m,ArH),7.37-7.31(1H,m,ArH),7.30-7.29(2H,m,ArH),6.99-6.95(1H,m,ArH),5.39(2H,s). 13 C NMR (150MHz, CDCl3) 146.87, 138.49, 135.04, 133.37, 132.21, 131.03, 130.99, 129.51, 129.37, 129.27, 120.31, 81.96. HRMS(ESI):m / z calcd for C 14 H9ClN4O:353.9842[M+H] + ;found:357.13.

[0088] Example 8

[0089] This embodiment provides a tetrazole compound 9f, the specific structure of which is as follows:

[0090]

[0091] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-bromotoluene.

[0092] Finally, compound 9f was obtained with a yield of 58%.

[0093] The characterization data are as follows:

[0094] 1 H NMR (400MHz, CDCl3)7.87(2H),7.43(2H),7.25(2H),7.15(2H),5.41(2H). 13CNMR(125MHz, CDCl3)146.79,138.02,130.94,130.47,130.40,129.37,129.35,128.98,120.66,83.75,77.41,77.16,76.91. HRMS(ESI):m / z calcd for C 14 H 11 ClN4O:287.0721[M+H] + ;found:287.22.

[0095] Example 9

[0096] This example provides a tetrazole compound 9g, the specific structure of which is as follows:

[0097]

[0098] The preparation steps are the same as those in Example 1 except that the 4-chlorobenzaldehyde in step (1) is replaced by an equal amount of 4-fluorobenzaldehyde.

[0099] Finally, compound 9g was obtained with a yield of 75%.

[0100] The characterization data are as follows:

[0101] 1 H NMR (400MHz, CDCl3)7.88(2H),7.15(4H),7.06(2H),5.41(2H). 13 C NMR (125MHz, CDCl3) 166.65, 166.63, 146.79, 136.64, 131.64, 130.42, 130.35, 129.48, 129.14, 118.30, 118.27, 116.43, 116.25, 82.59. HRMS(ESI):m / z calcd for C 14 H 10 ClFN4O:304.0527[M+H] + ; found:305.17.

[0102] Example 10

[0103] This embodiment provides a tetrazole compound 9h, the specific structure of which is as follows:

[0104]

[0105] The preparation steps are the same as those in Example 9 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-chlorobenzene.

[0106] Finally, compound 9h was obtained with a yield of 74%.

[0107] The characterization data are as follows:

[0108] 1 H NMR (400MHz, CDCl3)7.89(2H),7.28(1H),7.18(4H),7.03(1H),7.01(2H),5.48(2H). 13 C NMR (125MHz, CDCl3)165.71,163.69,146.81,134.93,132.90,130.53,130.4 8,130.41,130.36,130.24,128.25,118.21,118.18,116.55,116.38,82.58. HRMS(ESI):m / zcalcd for C 14 H 10 ClFN4O:304.0527[M+H] + ;found:304.92.

[0109] Embodiment 11

[0110] This embodiment provides a tetrazole compound 9i, the specific structure of which is as follows:

[0111]

[0112] The preparation steps are the same as those in Example 9 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3,4-dichlorobenzene.

[0113] Finally, compound 9i was obtained with a yield of 70%.

[0114] The characterization data are as follows:

[0115] 1 H NMR (400MHz, CDCl3)7.86(2H),7.31(1H),7.27(1H),7.15(2H),6.92(1H),5.48(2H). 13 C NMR(125MHz, CDCl3)165.79,163.77,146.87,134.98,133.32,132.19,131.11,1 30.97,130.49,130.42,129.27,118.12,118.18,118.09,116.60,116.42,81.88. HRMS(ESI):m / z calcd for C14 H9Cl2FN4O:338.0137[M+H] + ;found:339.15.

[0116] Example 12

[0117] This embodiment provides a tetrazole compound 9j, the specific structure of which is as follows:

[0118]

[0119] The preparation steps are the same as those in Example 1 except that the 4-chlorobenzaldehyde in step (1) is replaced by an equal amount of 3-chlorobenzaldehyde.

[0120] Finally, compound 9j was obtained with a yield of 32%.

[0121] The characterization data are as follows:

[0122] 1 H NMR (400MHz, CDCl3)7.84(1H),7.75(1H),7.52(1H),7.46(1H),7.21(2H),7.11(2H),5.48(2H). 13 C NMR (125MHz, CDCl3) 146.56, 136.83, 135.14, 131.80, 131.74, 130.38, 129.35, 129.24, 127.96, 126.24, 123.68, 82.85. HRMS(ESI):m / z calcd for C 14 H 10 Cl2N4O:320.0232[M+H] + ;found:321.16.

[0123] Example 13

[0124] This embodiment provides a tetrazole compound 9k, the specific structure of which is as follows:

[0125]

[0126] The preparation steps are the same as those in Example 12 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-chlorobenzene.

[0127] Finally, compound 9k was obtained with a yield of 47%.

[0128] The characterization data are as follows:

[0129] 1H NMR (400MHz, CDCl3)7.85(1H),7.76(1H),7.52(1H),7.46(1H),7.30(1H),7.18(2H),7.03(1H),5.48(2H). 13 C NMR (125MHz, CDCl3)146.58,135.17,135.00,132.75,131.93,130.61,130.45,130.41,130.26,128.35,128.00,126.18,123.53,82.80. HRMS(ESI):m / z calcd for C 14 H 10 Cl2N4O:320.0232[M+H] + ;found:321.10.

[0130] Embodiment 14

[0131] This embodiment provides a tetrazole compound 9m, the specific structure of which is as follows:

[0132]

[0133] The preparation steps are the same as those in Example 1, except that 4-chlorobenzaldehyde in step (1) is replaced by an equal amount of 2,4-dichlorobenzaldehyde, and 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-chlorobenzene.

[0134] Finally, compound 9m was obtained with a yield of 68%.

[0135] The characterization data are as follows:

[0136] 1 H NMR (400MHz, CDCl3)7.55(1H),7.30(2H),7.18(1H),7.03(2H),6.88(1H),5.48(2H). 13 C NMR (125MHz, CDCl3)146.29,138.62,135.07,134.82,133.11,132.33,130.52,130.36,130.29,130.01,128.15,127.50,120.23,82.37. HRMS(ESI):m / z calcd forC 14 H9Cl3N4O:353.9842[M+H] + ;found:355.07.

[0137] Embodiment 15

[0138] This embodiment provides a tetrazole compound 9n, the specific structure of which is as follows:

[0139]

[0140] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-trifluoromethylbenzene.

[0141] Finally, compound 9n was obtained with a yield of 45%.

[0142] The characterization data are as follows:

[0143] 1 H NMR (400MHz, CDCl3)8.25(1H),7.86(2H),7.51(3H),7.27(2H),5.48(2H). 13 CNMR(125MHz, CDCl3)146.73,138.41,133.43,132.02,131.96,131.70,131.44,131.18,129.66,129.51,129.40,129.26,127.20,127.04,126.72 124.56,122.39,120.31,120.23,82.57. HRMS(ESI):m / z calcd for C 15 H 10 ClF3N4O:354.0495[M+H] + ;found:355.15.

[0144] Example 16

[0145] This embodiment provides a tetrazole compound 9q, the specific structure of which is as follows:

[0146]

[0147] The preparation steps are the same as those in Example 1 except that the 4-chlorobenzaldehyde in step (1) is replaced by an equal amount of 4-methoxybenzaldehyde.

[0148] Finally, compound 9q was obtained with a yield of 39%.

[0149] The characterization data are as follows:

[0150] 1 H NMR (400MHz, CDCl3)7.98(2H),7.26(1H),7.18(2H),7.02(2H),5.40(2H),3.91(2H). 13C NMR (125MHz, CDCl3)162.33,147.25,136.52,131.62,129.77,129.17,114.52,114.32,82.34,77.41,77.16,76.90,55.62. HRMS(ESI):m / z calcd for C 15 H 13 ClN4O2:316.0727[M+H] + ;found:317.20.

[0151] Embodiment 17

[0152] This embodiment provides a tetrazole compound 9r, the specific structure of which is as follows:

[0153]

[0154] The preparation steps are the same as those in Example 16 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 1-(bromomethyl)-3-chlorobenzene.

[0155] Finally, compound 9r was obtained with a yield of 30%.

[0156] The characterization data are as follows:

[0157] 1 H NMR (400MHz, CDCl3)7.89(2H),7.35(1H),7.29(1H),7.11(1H),7.01(2H),5.49(2H),3.91(2H). 13 C NMR (125MHz, CDCl3)162.33,147.19,134.82,133.15,130.38,130.18,129.74,128.18,114.57,114.13,82.26,77.41,77.16,76.90,55.58. HRMS(ESI):m / z calcdfor C 15 H 13 ClN4O2:317.0827[M+H] + ;found:317.20.

[0158] Embodiment 18

[0159] This embodiment provides a tetrazole compound 9t, the specific structure of which is as follows:

[0160]

[0161] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 2-(bromomethyl)-5-chlorothiophene.

[0162] Finally, compound 9t was obtained with a yield of 53%.

[0163] The characterization data are as follows:

[0164] 1 H NMR (400MHz, CDCl3)7.82(2H),7.49(2H),6.18(1H),6.14(1H),5.51(2H). 13 CNMR(125MHz, CDCl3)147.18,138.25,134.99,131.55,130.97,129.46,129.42,126.63,120.38,77.42,77.16,76.91,76.59. HRMS(ESI):m / z calcd for C 12 H8Cl2N4O2S:326.9896[M+H] + ;found:327.10.

[0165] Embodiment 19

[0166] This embodiment provides a tetrazole compound 9v, the specific structure of which is as follows:

[0167]

[0168] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 3-(bromomethyl)-6-chloropyridine.

[0169] Finally, compound 9v was obtained with a yield of 49%.

[0170] The characterization data are as follows:

[0171] 1 H NMR (500MHz, CDCl3)8.25(1H),7.86(2H),7.50(3H),7.25(1H),5.51(2H). 13 CNMR(125MHz, CDCl3)153.68,150.93,146.43,140.19,138.57,129.68,129.24,126.01,124.68,120.22,79.66,77.41,77.16,76.91. HRMS(ESI):m / z calcd for C 13H9Cl2N5O:322.0284[M+H] + ;found:322.08.

[0172] Embodiment 20

[0173] This embodiment provides a tetrazole compound 9w, the specific structure of which is as follows:

[0174]

[0175] The preparation steps are the same as those in Example 1 except that 1-(bromomethyl)-4-chlorobenzene in step (5) is replaced by an equal amount of 4-(bromomethyl)-2-chloropyridine.

[0176] Finally, compound 9w was obtained with a yield of 30%.

[0177] The characterization data are as follows:

[0178] 1 H NMR (400MHz, CDCl3)8.41(1H),7.91(2H),7.56(2H),7.29(1H),7.11(1H),5.51(2H). 13 C NMR (125MHz, CDCl3)152.27,150.43,146.20,143.06,138.62,129.73,129.23,124.10,121.95,120.02,80.14,77.42,77.16,76.91. HRMS(ESI):m / z calcd forC 13 H9Cl2N5O:322.1490[M+H] + ;found:322.18.

[0179] Embodiment 21

[0180] This embodiment provides a tetrazole compound 11, the specific structure of which is as follows:

[0181]

[0182] The preparation method is as follows:

[0183] (1) Methylmagnesium bromide (3.0 M ether solution, 12.05 mL, 37.5 mmol) was placed in a dry and nitrogen-protected round-bottom flask equipped with a magnetic stirrer. Anhydrous ether (10 mL) was added and the stirred mixture was cooled to 0°C in an ice-water bath. A solution of 4-chloroacetophenone (2.63 g, 17.0 mmol) in ether (10 mL) was added dropwise through a dropping funnel. After the addition was complete, the reaction mixture was slowly warmed to room temperature. The mixture was stirred overnight and quenched with saturated aqueous ammonium chloride solution (30 mL) and ice (5 mL). The aqueous phase was extracted with ether (3×50 mL). The combined organic phases were dried over sodium sulfate and the solvent was dried to give 2-(4-chlorophenyl)-2-propanol (2.5 g, 86%) as a colorless oil, which was used without further purification;

[0184] (2) TFA (0.3 mL) was added dropwise to a glass tube containing a mixed solution of 5-(4-chlorophenyl)-1-hydroxytetrazolyl (495 mg, 2.52 mmol, prepared by the method of Reference Example 1) and 2-(4-chlorophenyl)-2-propanol (430 mg, 2.52 mmol) in anhydrous 1,2-dichloroethane (12 mL) via a syringe. The reaction was sealed with a polytetrafluoroethylene cap and heated to 80° C. and stirred for 16 hours. The mixture was transferred to a separatory funnel, rinsed with DCM, and washed with aqueous sodium carbonate. The organic phase was collected, dried over MgSO4, and spin-dried. The residue was purified by silica gel column to obtain compound 11 (123 mg, 14%) as a white solid.

[0185] The characterization data are as follows:

[0186] 1 H NMR(500MHz,CDCl-d6)8.43(2H,d,J 8.6Hz,ArH),7.50(2H,d,J 8.6Hz,ArH),7.35(2H,d,J 8.7Hz,ArH),7.25(2H,d,J 8.7,ArH),2.16(6H,s,2CH3).

[0187] Embodiment 22

[0188] This embodiment provides a tetrazole compound 12a, the specific structure of which is as follows:

[0189]

[0190] The preparation steps except step (5) are as follows: at 0°C, under nitrogen protection, 5-(4-chlorophenyl)-1-hydroxytetrazolyl (150 mg, 0.84 mmol) is dissolved in anhydrous DMF (3 mL) and added to a stirred suspension of NaH (47 mg, 1.2 mmol) in anhydrous DMF (3 mL). Once the addition is complete, the reaction mixture is slowly warmed to room temperature. The reaction mixture is stirred at room temperature for 15 minutes and recooled to 0°C in an ice-water bath. A solution of bromodifluoromethylbenzene (207 mg, 1 mmol) in anhydrous DMF (2 mL) is added dropwise. The reaction mixture is stirred at room temperature overnight. Saturated aqueous ammonium chloride solution (8 mL) is added and the entire solution is extracted with ether (40 mL). The organic layer is washed with water (2×10 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue is purified by silica gel chromatography to obtain compound 12a as a white solid (yield 35%), the rest being consistent with Example 1.

[0191] The characterization data are as follows:

[0192] 1 H NMR (400MHz, CDCl3)7.97-7.94(2H,m,ArH),7.68-7.64(3H,m,ArH),7.59-7.55(4H,m,ArH).

[0193] Embodiment 23

[0194] This embodiment provides a tetrazole compound 13a, the specific structure of which is as follows:

[0195]

[0196] Preparation step except step (5): 5-(4-chlorophenyl)-1-hydroxytetrazolyl (150mg, 0.83mmol), t-BuOK (1M ether solution, 1.9mL, 1.9mmol) and acetonitrile (10mL) mixture was stirred at room temperature for 5 minutes. Bis(4-chlorophenyl)iodonium trifluoromethanesulfonate (665mg, 1.9mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The crude material was purified by silica gel chromatography (3%, ethyl acetate in petroleum ether) to obtain compound 13a as a light brown solid (yield 18%), the rest was consistent with Example 1.

[0197] The characterization data are as follows:

[0198] 1H NMR (500MHz, CDCl3)8.05-8.94(2H,m,ArH),7.55-7.53(2H,m,ArH),7.38-7.35(2H,m,ArH),6.92-6.89(2H,m,ArH).

[0199] Embodiment 24

[0200] This embodiment provides a tetrazole compound 20, the specific structure of which is as follows:

[0201]

[0202] The preparation steps are as follows:

[0203] (1) 5-phenyltetrazolyl (500 mg, 3.42 mmol) was dissolved in 70°C sodium carbonate aqueous solution (7.5%, 150 mL), and hydroxylamine-O-sulfonic acid (1.16 g, 10.3 mmol) was added in batches under vigorous stirring. The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature and extracted with EA (3×70 mL). The organic phases were combined, dried and spin-dried. The residue was purified by silica gel chromatography to give 1-amino-5-phenyltetrazolyl (65 mg, 12%) as a white solid;

[0204] (2) 1-amino-5-phenyltetrazolyl (60 mg, 0.37 mmol), 4-chlorobenzoyl chloride (65.5 mg, 0.37 mmol) and pyridine (1.0 mL) were added to a sealed tube and heated at 120° C. for 6 hours. The reaction solution was cooled to room temperature and pyridine was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 20 (20 mg, 18%) as a white solid.

[0205] The characterization data are as follows:

[0206] 1 H NMR (500 MHz, MeOD) 7.96 (2H, d, J 8.05 Hz, ArH), 7.90 (2H, d, J 7.3 Hz, ArH), 7.63-7.56 (5H, m, ArH).

[0207] Inhibitory effect study:

[0208] The biological activity of the compounds in Examples 1-24 was tested against CRPC cells (22RV1) with ARV7 (from the Shanghai Cell Bank of the Chinese Academy of Sciences). First, 22rv1 cells were digested and plated in a 384-well plate, with 1500 cells per well and a volume of 20 μL, and cultured in a cell culture incubator. After 24 hours, the compounds were added and incubated with the cells. The concentration of the compound mother solution was 10 mM, with 3-fold gradient dilution and 10 concentrations, and DMSO was added to the control group. The cells were cultured in a cell culture incubator for 72 hours before detection. During the detection, CellTiter-Glo reagent (Promega) was added to each well of the 384-well plate, and the plate was shaken for 10 minutes before the readings were detected in a chemiluminometer. GraphpadPrism8 software was used to calculate the fitted compound proliferation inhibition curve and calculate the IC 50 The results are as follows:

[0209]

[0210]

[0211] The above results show that the compounds provided by the present invention have an effective growth inhibitory effect on 22RV1 and show an inhibitory effect on androgen receptor. At the same time, the comparison results also show that within the preferred structural range of the present invention, the inhibitory effect is more obvious, IC 50 Can reach nm level.

[0212] The applicant declares that the present invention illustrates the tetrazolyl compounds and their applications through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0213] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0214] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A tetrazole compound, It is characterized in that The structure of the tetrazole compound is shown in Formula I: Among them, Ar 1 Selected from substituted benzene rings, Ar 2 Selected from Any one of; When Ar 2 Selected from When , Y is selected from O, and Z is selected from halogen; When Ar 2 Selected from When , Y is selected from N; Ring A is selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted C4-C7 heterocycle; The C4-C7 heterocycle is selected from any one of pyridazine, pyridine or thiophene; The substituted substituent group is selected from any one of halogen, C1-C6 alkyl, and C1-C6 alkoxy; Or, Ar 1 Selected from benzene ring, Ar 2 Selected from Y is selected from N, and ring A is selected from halogen-substituted benzene rings.

2. The tetrazole compound according to claim 1, It is characterized in that Ar 2 Selected from The Y is selected from O, Z is selected from halogen, and the ring A is selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted C4-C7 heterocycle; The C4-C7 heterocycle is selected from any one of pyridazine, pyridine or thiophene; The substituted substituent group is selected from any one of halogen, C1-C6 alkyl, and C1-C6 alkoxy.

3. The tetrazole compound according to claim 1, It is characterized in that The Ar 2 Selected from Any one of the foregoing, wherein Y, Z, and ring A have the same defined ranges as in claim 1.

4. The tetrazole compound according to claim 1, It is characterized in that The substituted substituents are selected from halogen.

5. The tetrazole compound according to claim 1, It is characterized in that The tetrazole compound is selected from Any one of .

6. Use of the tetrazole compound according to any one of claims 1 to 5 in the preparation of androgen receptor inhibitors.

7. Use of the tetrazole compound according to any one of claims 1 to 5 in the preparation of a drug for treating prostate cancer.

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