CN117069714A - Bis (pyrazolyl) methane derivative and application thereof - Google Patents

Bis (pyrazolyl) methane derivative and application thereof Download PDF

Info

Publication number
CN117069714A
CN117069714A CN202310773449.0A CN202310773449A CN117069714A CN 117069714 A CN117069714 A CN 117069714A CN 202310773449 A CN202310773449 A CN 202310773449A CN 117069714 A CN117069714 A CN 117069714A
Authority
CN
China
Prior art keywords
compound
synthesis
preparation
dmso
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310773449.0A
Other languages
Chinese (zh)
Inventor
尤启冬
郭小可
蔡媛倩
王颖哲
张艳
马赛
姜正羽
徐晓莉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN202310773449.0A priority Critical patent/CN117069714A/en
Publication of CN117069714A publication Critical patent/CN117069714A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a bis (pyrazolyl) methane derivative and application thereof. The bis (pyrazolyl) methane derivatives of the invention are a potent class of IGF 2 BP 2 Small molecule inhibitors of IGF 2 BP 2 Has obvious inhibition activity, inhibits RNA reading on protease level, and modifies and regulates m 6 A levels, useful in therapy and IGF 2 BP 2 Related diseases such as breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myelogenous leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma, etc.

Description

Bis (pyrazolyl) methane derivative and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a bis (pyrazolyl) methane derivative and application thereof.
Background
N 6 Methyl adenosine (m) 6 A) Is the most abundant modification in eukaryotic RNA, which is a dynamic reversible RNA modification, including writers, erasers, and readers. m is m 6 The A modification plays a role in promotion or inhibition of cell cycle regulation, cell differentiation, change in cell state, stress reaction, and the like. More and more researches find that m 6 The A modification plays an increasingly important regulatory role in the development of tumors and cancers, and has potential to become a biomarker for cancers. Human insulin-like growth factor 2 (IGF 2 ) mRNA binding protein 2 (IGF) 2 BP 2 ) Is an RNA binding protein that regulates a variety of biological processes. In recent years, studies have found IGF 2 BP 2 Plays a number of roles in various biological processes, particularly in tumors, and speculates on the mechanism by which it plays an anticancer role. In addition, targeting IGF 2 BP 2 Or downstream mechanisms thereof, have also received great attention as an effective therapeutic approach to the treatment of different types of tumors.
IGF 2 BP 2 In breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myelogenous leukemia, T-cell acute lymphoblastic leukemia, and other forms of cancer,Important functions in various tumors such as nasopharyngeal carcinoma. Thus, the use of small molecule inhibitors IGF 2 BP 2 Is useful for therapy and IGF 2 BP 2 Indications associated with protein dysfunction.
Currently, there is no highly active IGF 2 BP 2 Small molecule inhibitors are reported.
Disclosure of Invention
The invention designs and synthesizes a series of derivatives based on the Miao compound of substituted bis (pyrazolyl) methane, and carries out preliminary structure-activity relationship discussion to finally obtain the novel IGF with relatively activity 2 BP 2 Small molecule inhibitors can significantly inhibit IGF in vitro 2 BP 2 For m 6 The methylation reading activity of A is expected to become an anti-tumor candidate drug with better prospect.
It is an object of the present invention to provide a compound of formula i:
R 1 selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl or heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl or aryl;
R 3 and R is 4 Independently selected from H, substituted or unsubstituted C1-C10 alkyl;
R 2 and R is 5 Independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl or heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl or aryl, or a combination of two rings;
R 6 and R is 7 Independently selected from H, substituted or unsubstituted C1-C10 alkyl, oxy.
In certain preferred embodiments of the present invention,
R 1 selected from H, substituted or unsubstituted C1-C7 alkyl, substituted or unsubstituted 5-8 membered heteroaryl or aryl;
R 3 and R is 4 Independently and separatelySelected from H, substituted or unsubstituted C1-C7 alkyl;
R 2 and R is 5 Independently selected from a substituted or unsubstituted five-membered or six-membered nitrogen containing heterocycle or aromatic ring, or a combination of a five-membered heteroaromatic ring and a six-membered heteroaromatic ring;
R 6 and R is 7 Independently selected from H, substituted or unsubstituted C1-C5 alkyl, oxy.
In certain further preferred embodiments of the present invention,
R 1 selected from H, methyl, ethyl, isopropyl, tert-butyl,
R 3 and R is 4 Selected from H, difluoromethyl, trifluoromethyl, methyl, ethyl;
R 2 and R is 5 Selected from the group consisting of
R 6 And R is 7 Selected from H, hydroxy, methoxy, ethoxy;
at R 1 、R 2 And R is 5 Wherein R is a Is mono-or polysubstituted, and the substituent is selected from H, halogen, hydroxy, alkyl, nitro, amino, methoxy, trifluoromethyl, difluoromethyl, carboxyl, difluoromethoxy, trifluoromethoxy, mercapto or cyano.
The compounds of the general formula I according to the invention mentioned above may also be present in the form of their salts, which are converted in vivo into compounds of the formula I. For example, within the scope of the present invention, the compounds of the present invention are converted to pharmaceutically acceptable salt forms and used in salt form according to procedures known in the art.
The second object of the present invention is to provide a pharmaceutical composition, the active ingredient of which comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
It is a further object of the present invention to provide a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of IGF 2 BP 2 Use in medicine for treating protein dysfunction related diseases. Said and IGF 2 BP 2 The protein dysfunction related diseases are breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myelogenous leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma and other tumors.
The beneficial effects are that: the compound of the formula I or the pharmaceutically acceptable salt thereof provided by the invention is an effective IGF 2 BP 2 Small molecule inhibitors of IGF 2 BP 2 Has obvious inhibition activity, inhibits RNA reading on protease level, and modifies and regulates m 6 A levels, useful in therapy and IGF 2 BP 2 Related diseases such as breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, acute myelogenous leukemia, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma, etc.
Detailed Description
Preferred embodiments of the present invention will be described in detail below with reference to examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention may be made by those skilled in the art without departing from the spirit and scope of this invention.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
In some embodiments of the invention, the compound is selected from the following compounds:
example 1
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 1
Step 1: synthesis of Compounds 1-2
Compound 1-1 (500 mg,2.33 mmol) was dissolved in 15mL of 1, 4-dioxane, and thiocarbamide (211.89 mg,2.33 mmol) was added and reacted at room temperature for 12 hours. TLC monitored the reaction was complete and passed through the column. Purification by silica gel column chromatography (PE: ea=3:1) gave 1-2 as a pale green solid in 70.22% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),8.62(t,J＝3.4Hz,1H),7.66(dd,J＝8.7,1.2Hz,1H),7.31-7.20(m,1H),7.13(s,1H),7.06(ddd,J＝9.0,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 1
Compound 1-2 (150 mg, 723.76. Mu. Mol) was dissolved in 10ml of glacial acetic acid, and ethyl acetoacetate (94.19 mg, 723.76. Mu. Mol) was added thereto and reacted at 80℃for 6 hours. TLC monitoring reaction is finished, spin-drying solvent, adding absolute ethyl alcohol 15ml to dissolve, adding p-bromobenzaldehyde (66.96 mg,361.88 mu mol), reacting at 78 ℃ for 4 hours, precipitating white solid, suction filtering, drying to obtain white solid 1, the yield is 60.22%. 1 H NMR(300MHz,DMSO-d 6 )δ12.33(s,1H),10.45(s,1H),8.11(d,J＝7.8Hz,2H),7.87(s,2H),7.53(d,J＝8.0Hz,2H),7.31-7.14(m,4H),7.03-6.86(m,4H),5.12(s,1H),2.17(s,6H)。
Example 2
Preparation of 4,4' - (4-bromophenyl) methylene) bis (3-methyl-1- (4-phenylthiazol-2-yl) -1H-pyrazol-5-ol) 2
Step 1: synthesis of Compound 2-2
Compound 2-1 (500 mg,2.33 mmol) was dissolved in 15mL of 1, 4-dioxane, and thiocarbamide (211.89 mg,2.33 mmol) was added and reacted at room temperature for 12 hours. TLC monitored the reaction was complete and passed through the column. Purification by silica gel column chromatography (PE: ea=3:1) gave 2-2 as a pale green solid in 60.25% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.4Hz,1H),7.82(dd,J＝7.5,1.6Hz,2H),7.54-7.43(m,2H),7.47-7.36(m,1H),7.13(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 2
Compound 2-2 (150 mg, 723.76. Mu. Mol) was dissolved in 10ml of glacial acetic acid, and ethyl acetoacetate (94.19 mg, 723.76. Mu. Mol) was added thereto to react at 80℃for 6 hours. TLC monitoring reaction is finished, spin-drying solvent, adding absolute ethyl alcohol 15ml to dissolve, adding p-bromobenzaldehyde (66.96 mg,361.88 mu mol), reacting at 78 ℃ for 4 hours, precipitating white solid, suction filtering, drying to obtain white solid 2, the yield is 70.23%. 1 H NMR(500MHz,Chloroform-d)δ7.95(t,J＝3.4Hz,1H),7.85-7.79(m,2H),7.53-7.45(m,2H),7.44-7.37(m,1H),7.14(s,1H),4.56(dd,J＝8.3,3.4Hz,1H),4.49(dd,J＝8.3,3.4Hz,1H)。
Example 3
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (2-methoxyphenyl) thiazol-2-yl) -3-methylpyrazol-5-ol) 3
Step 1: synthesis of Compound 3-2
The synthesis was carried out according to the preparation method of example 1. Compound 3-2 was obtained as an off-black solid in 70.12% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.4Hz,1H),7.77(dd,J＝8.5,1.3Hz,1H),7.38(td,J＝7.6,1.3Hz,1H),7.31-7.11(m,2H),6.90(dd,J＝7.7,1.4Hz,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 3
Reference examples1, and synthesizing the preparation method. Compound 3 was obtained as an off-white solid in 75.45% yield. 1H NMR (300 MHz, DMSO-d) 6 )δ12.20(s,1H),8.27(d,J＝8.7Hz,2H),7.78(s,2H),7.51(d,J＝8.5Hz,2H),7.38-7.29(m,2H),7.25(d,J＝8.4Hz,2H),7.14(d,J＝8.0Hz,2H),7.06(t,J＝7.5Hz,2H),5.08(s,1H),3.93(s,6H),2.12(s,6H)。
Example 4
Preparation of 4- (bis (5-hydroxy-1- (4- (3-methoxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-4-yl) methyl) benzoic acid 4
Step 1: synthesis of Compound 4-2
The synthesis was carried out according to the preparation method of example 1. Compound 4-2 was obtained as an off-black solid in 71.26% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.49(t,J＝3.4Hz,1H),7.71-7.53(m,1H),7.42-7.30(m,2H),7.20(s,1H),7.05-6.88(m,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 4
The synthesis was carried out according to the preparation method of example 1. Except that p-bromobenzaldehyde was changed to p-carboxybenzaldehyde. Compound 4 was obtained as an off-white solid in 72.21% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.39(s,1H),10.63(s,2H),7.99-7.90(m,2H),7.64(ddd,J＝8.7,2.1,1.2Hz,2H),7.43-7.28(m,8H),6.96(ddd,J＝8.0,2.1,1.2Hz,2H),4.98(s,1H),3.82(s,6H),2.27(s,6H).。
Example 5
Preparation of 4,4' - ((4-chlorophenyl) methylene) bis (1- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 5
Step 1: synthesis of Compound 5-2
The synthesis was carried out according to the preparation method of example 1. The compound 5-2 was obtained as a pale green solid in a yield of 71.89%. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.4Hz,1H),7.78-7.63(m,2H),7.15(s,1H),7.01-6.79(m,2H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 5
The synthesis was carried out according to the preparation method of example 1. The difference is that p-bromobenzaldehyde is changed into p-chlorobenzaldehyde. Compound 5 was obtained as an off-white solid in 74.36% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.20(s,1H),7.93(d,J＝8.8Hz,4H),7.70-7.45(m,4H),7.24(d,J＝8.1Hz,2H),7.01(d,J＝8.9Hz,4H),5.08(s,1H),3.80(s,6H),2.11(s,6H)。
Example 6
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (2-chlorophenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 6
Step 1: synthesis of Compound 6-2
The synthesis was carried out according to the preparation method of example 1. Compound 6-2 was obtained as a black solid in 68.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.52(t,J＝3.4Hz,1H),7.72-7.61(m,1H),7.52-7.33(m,3H),7.26(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 6
The synthesis was carried out according to the preparation method of example 1. Compound 6 was obtained as an off-white solid in 66.34% yield, 1 H NMR(300MHz,DMSO-d 6 )δ12.30(s,2H),7.97(d,J＝7.5Hz,2H),7.76(s,2H),7.48(ddd,J＝34.8,17.6,7.6Hz,8H),7.24(d,J＝8.1Hz,2H),5.09(s,1H),2.10(s,6H)。
example 7
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (3, 4-dichlorophenyl) thiazol-2-yl) -3-methylpyrazol-5-ol) 7
Step 1: synthesis of Compound 7-2
The synthesis was carried out according to the preparation method of example 1. The compound 7-2 was obtained as a gray black solid in 69.09% yield, 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.3Hz,1H),8.04(d,J＝1.9Hz,1H),7.83(dd,J＝8.7,1.9Hz,1H),7.58(d,J＝8.7Hz,1H),7.22(s,1H),4.88(d,J＝3.3Hz,2H)。
step 2: synthesis of Compound 7
The synthesis was carried out according to the preparation method of example 1. Compound 7 was obtained as an off-white solid in 77.01% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.28(s,1H),8.23(d,J＝2.1Hz,2H),7.99-7.91(m,4H),7.69(d,J＝8.5Hz,2H),7.51-7.43(m,2H),7.19(d,J＝8.2Hz,2H),5.04(s,1H),2.09(s,6H)。
Example 8
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4-chlorophenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 8
Step 1: synthesis of Compound 8-2
The synthesis was carried out according to the preparation method of example 1. The compound 8-2 was obtained as a dark green solid in a yield of 67.78%. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.3Hz,1H),7.70(d,J＝8.5Hz,2H),7.53-7.43(m,2H),7.16(s,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 8
The synthesis was carried out according to the preparation method of example 1. Compound 8 was obtained as an off-white solid in 78.44% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.27(s,2H),8.07-7.99(m,4H),7.84(s,2H),7.56-7.48(m,6H),7.24(d,J＝8.1Hz,2H),5.08(s,1H),2.12(s,6H)。
Example 9
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (3-chlorophenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 9
Step 1: synthesis of Compound 9-2
The synthesis was carried out according to the preparation method of example 1. The compound 9-2 was obtained as a pale green solid in 73.11% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.4Hz,1H),7.72-7.59(m,2H),7.43-7.30(m,2H),7.21(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 9
The synthesis was carried out according to the preparation method of example 1. Compound 9 was obtained as an off-white solid in 69.04% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.28(s,2H),8.10(s,2H),8.02-7.88(m,4H),7.55-7.39(m,6H),7.25(d,J＝8.1Hz,2H),5.09(s,1H),2.13(s,6H)。
Example 10
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 10
Step 1: synthesis of Compound 10-2
The synthesis was carried out according to the preparation method of example 1. The compound 10-2 was obtained as a pale green solid in a yield of 77.79%. 1 H NMR(300MHz,DMSO-d 6 )δ9.67(s,1H),9.03(s,1H),8.53(t,J＝3.4Hz,1H),7.67-7.57(m,2H),7.16(s,1H),6.94-6.84(m,2H),4.88(s,1H)。
Step 2: synthesis of Compound 10
The synthesis was carried out according to the preparation method of example 1. Compound 10 was obtained as an off-white solid in 59.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.18(s,1H),9.64(s,2H),7.81(d,J＝8.2Hz,4H),7.51(d,J＝9.7Hz,4H),7.24(d,J＝8.0Hz,2H),6.82(d,J＝8.3Hz,4H),5.07(s,1H),2.10(s,6H)。
Example 11
Preparation of 4,4' - (4-bromophenyl) methylene) bis (3-methyl-1- (4- (4-trifluoromethylphenyl) thiazol-2-yl) -1H-pyrazol-5-ol) 11
Step 1: synthesis of Compound 11-2
The synthesis was carried out according to the preparation method of example 1. Compound 11-2 was obtained as an off-white solid in 77.78% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.4Hz,1H),7.81(d,J＝11.3Hz,2H),7.69(d,J＝11.4Hz,2H),7.16(s,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 11
The synthesis was carried out according to the preparation method of example 1. Compound 11 was obtained as an off-white solid in 73.34% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.34(s,2H),8.23(d,J＝8.1Hz,4H),8.02(s,2H),7.84(d,J＝8.2Hz,4H),7.52(d,J＝8.2Hz,2H),7.25(d,J＝8.1Hz,2H),5.11(s,1H),2.14(s,6H)。
Example 12
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (3-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 12
Step 1: synthesis of Compound 12-2
The synthesis was carried out according to the preparation method of example 1. Compound 12-2 was obtained as an off-black solid in 70.47% yield. 1 H NMR(300MHz,DMSO-d 6 )δ9.40(s,1H),8.49(t,J＝3.4Hz,1H),7.59-7.49(m,1H),7.28(t,J＝8.4Hz,1H),7.23-7.12(m,2H),6.87-6.77(m,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 12
The synthesis was carried out according to the preparation method of example 1. Compound 12 was obtained as an off-white solid in 88.87% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.19(s,1H),9.53(s,2H),7.67(s,2H),7.51(d,J＝8.4Hz,2H),7.44-7.38(m,4H),7.23(t,J＝7.9Hz,4H),6.79-6.71(m,2H),5.08(s,1H),2.12(s,6H)。
Example 13
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1- (4- (3-trifluoromethylphenyl) thiazol-2-yl) -1H-pyrazol-5-ol) 13
Step 1: synthesis of Compound 13-2
The synthesis was carried out according to the preparation method of example 1. Compound 13-2 was obtained as an off-black solid in 67.43% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.3Hz,1H),8.28(q,J＝1.3Hz,1H),7.75-7.63(m,3H),7.19(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 13
The synthesis was carried out according to the preparation method of example 1. Compound 13 was obtained as an off-white solid in 64.57% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),8.27(q,J＝1.5Hz,2H),7.73-7.65(m,8H),7.51(d,J＝8.1Hz,2H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.12(s,6H)。
Example 14
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1- (4- (2-trifluoromethylphenyl) thiazol-2-yl) -1H-pyrazol-5-ol) 14
Step 1: synthesis of Compound 14-2
The synthesis was carried out according to the preparation method of example 1. Compound 14-2 was obtained as a black solid in 71.85% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.67(t,J＝3.4Hz,1H),7.89-7.81(m,1H),7.67-7.55(m,2H),7.48(ddd,J＝7.9,4.7,3.4Hz,1H),7.27(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 14
The synthesis was carried out according to the preparation method of example 1. Compound 14 was obtained as an off-white solid in 78.51% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),7.88-7.80(m,2H),7.67-7.56(m,6H),7.49(ddt,J＝11.1,7.9,2.4Hz,4H),7.20(d,J＝8.0Hz,2H),4.97(s,1H)。
Example 15
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (2-fluorophenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 15
Step 1: synthesis of Compound 15-2
The synthesis was carried out according to the preparation method of example 1. Compound 15-2 was obtained as a reddish brown solid in 75.49% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.62(t,J＝3.4Hz,1H),7.72-7.63(m,1H),7.34(ddd,J＝9.9,5.3,2.0Hz,1H),7.33-7.22(m,2H),7.15(s,1H),4.88(d,J＝3.3Hz,2H),2.12(s,3H)。
Step 2: synthesis of Compound 15
The synthesis was carried out according to the preparation method of example 1. Compound 15 was obtained as an off-white solid in 87.90% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),7.68(d,J＝1.3Hz,1H),7.65(s,1H),7.56-7.47(m,2H),7.34(ddd,J＝8.5,5.9,3.0Hz,2H),7.33-7.24(m,6H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.57(s,3H),1.93(s,3H)。
Example 16
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1- (4-o-tolyl) thiazol-2-yl) -1H-pyrazol-5-ol) 16
Step 1: synthesis of Compound 16-2
The synthesis was carried out according to the preparation method of example 1. Compound 16-2 was obtained as a white solid in 71.54% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.72(t,J＝3.4Hz,1H),7.84(ddd,J＝9.6,5.0,1.3Hz,1H),7.47(dddd,J＝8.8,7.7,5.0,1.3Hz,1H),7.30(ddd,J＝9.8,8.5,1.6Hz,1H),7.25-7.14(m,2H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 16
The synthesis was carried out according to the preparation method of example 1. Obtaining compound 16 as off-whiteThe yield of the coloured solid was 77.89%. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),7.82(ddd,J＝9.5,5.0,1.3Hz,2H),7.65(d,J＝2.0Hz,2H),7.55-7.42(m,4H),7.35-7.16(m,6H),4.97(s,1H),1.93(s,6H)。
Example 17
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4- (3-fluorophenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 17
Step 1: synthesis of Compound 17-2
The synthesis was carried out according to the preparation method of example 1. The compound 17-2 was obtained as a pale yellow green solid in 69.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.4Hz,1H),7.78(dt,J＝8.4,1.5Hz,1H),7.65(dt,J＝8.0,1.9Hz,1H),7.48(td,J＝8.1,5.0Hz,1H),7.22(s,1H),7.17(ddt,J＝9.4,7.9,1.4Hz,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 17
The synthesis was carried out according to the preparation method of example 1. Compound 17 was obtained as an off-white solid in 79.95% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),7.81-7.75(m,2H),7.61(dt,J＝8.0,2.1Hz,2H),7.55-7.43(m,4H),7.40(s,2H),7.24-7.12(m,4H),4.97(s,1H),2.31(s,6H)。
Example 18
Preparation of 3,3' - ((4-bromophenyl) methylene) bis (5-hydroxy-3-methyl-1H-pyrazole-4, 1-diyl) bis (thiazole-2, 4-diyl)) dibenzoic acid 18
Step 1: synthesis of Compound 18-2
The synthesis was carried out according to the preparation method of example 1. Compound 18-2 was obtained as a reddish brown solid in 88.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.3Hz,1H),8.32(t,J＝1.9Hz,1H),7.98(dt,J＝8.0,1.5Hz,1H),7.80(dt,J＝8.8,1.5Hz,1H),7.70-7.58(m,1H),7.19(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 18
The synthesis was carried out according to the preparation method of example 1. Compound 18 was obtained as a yellow solid in 80.52% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),8.22(t,J＝2.1Hz,2H),8.03-7.94(m,2H),7.84-7.76(m,2H),7.69-7.59(m,4H),7.55-7.47(m,2H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.31(s,6H)。
Example 19
Preparation of 3,3' - ((4-bromophenyl) methylene) bis (5-hydroxy-3-methyl-1H-pyrazole-4, 1-diyl) bis (thiazole-2, 4-diyl)) dibenzonitrile 19
Step 1: synthesis of Compound 19-2
The synthesis was carried out according to the preparation method of example 1. Compound 19-2 was obtained as a dark red solid in 88.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.50(t,J＝3.4Hz,1H),8.07(t,J＝1.9Hz,1H),7.83(dt,J＝7.7,1.5Hz,1H),7.70(dt,J＝6.5,1.5Hz,1H),7.58(dd,J＝7.6,6.4Hz,1H),7.19(s,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 19
The synthesis was carried out according to the preparation method of example 1. Compound 19 was obtained as an off-white solid in 64.77% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),8.04(t,J＝2.1Hz,2H),7.87-7.79(m,2H),7.74-7.64(m,4H),7.63-7.46(m,4H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.30(s,6H)。
Example 20
Preparation of 3- (bis (5-hydroxy-1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-4-yl) methyl) benzoic acid 20
Step 1: synthesis of Compound 20-2
The synthesis was carried out according to the preparation method of example 1. The compound 20-2 was obtained as a reddish brown solid in a yield of 69.14%. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),8.62(t,J＝3.4Hz,1H),7.66(dd,J＝8.7,1.2Hz,1H),7.31-7.20(m,1H),7.13(s,1H),7.06(ddd,J＝9.0,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 20
The synthesis was carried out according to the preparation method of example 1. The difference is that the second step of para-bromobenzaldehyde is changed into meta-carboxybenzaldehyde to obtain compound 20 as off-white solid with a yield of 85.20%. 1 H NMR(300MHz,DMSO-d 6 )δ12.57(s,1H),10.62(d,J＝1.4Hz,4H),8.01(t,J＝2.3Hz,1H),7.90(ddd,J＝7.9,2.3,1.3Hz,1H),7.62-7.50(m,3H),7.45(dt,J＝7.7,1.9Hz,1H),7.32(s,2H),7.30-7.20(m,2H),7.06(ddd,J＝9.0,7.7,1.4Hz,2H),6.94(dd,J＝8.2,1.4Hz,2H),4.99(s,1H),2.12(s,6H).。
Example 21
Preparation of 4,4' - (4- (trifluoromethyl) phenyl) methylenebis (1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methylpyrazol-5-ol) 21
Step 1: synthesis of Compound 21-2
The synthesis was carried out according to the preparation method of reference example 21. Compound 21-2 was obtained as a reddish brown solid in 70.42% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),8.62(t,J＝3.4Hz,1H),7.66(dd,J＝8.7,1.2Hz,1H),7.31-7.20(m,1H),7.13(s,1H),7.06(ddd,J＝9.0,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 21
The synthesis was carried out according to the preparation method of example 1. The difference is that the second step of para-bromobenzaldehyde is replaced by para-trifluoromethylbenzaldehyde to give compound 21 as an off-white solid in 67.50% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.33(s,1H),10.45(s,1H),8.11(d,J＝7.8Hz,2H),7.87(s,2H),7.53(d,J＝8.0Hz,2H),7.31-7.14(m,4H),7.03-6.86(m,4H),5.12(s,1H),2.17(s,6H)。
Example 22
Preparation of 4,4' -p-tolylmethylene bis (1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methylpyrazol-5-ol) 22
Step 1: synthesis of Compound 22-2
The synthesis was carried out according to the preparation method of reference example 21. Compound 22-2 was obtained as a reddish brown solid in 70.47% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),8.62(t,J＝3.4Hz,1H),7.66(dd,J＝8.7,1.2Hz,1H),7.31-7.20(m,1H),7.13(s,1H),7.06(ddd,J＝9.0,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 22
The synthesis was carried out according to the preparation method of example 1. The difference is that the second step of para-bromobenzaldehyde is replaced by para-methylbenzaldehyde to obtain compound 22 as off-white solid with a yield of 74.33%. 1 H NMR(300MHz,DMSO-d 6 )δ12.33(s,1H),10.45(s,1H),8.11(d,J＝7.8Hz,2H),7.87(s,2H),7.53(d,J＝8.0Hz,2H),7.31-7.14(m,4H),7.03-6.86(m,4H),5.12(s,1H),2.19(s,3H),2.17(s,6H)。
Example 23
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1-phenylpyrazol-5-ol) 23
The synthesis was carried out according to the preparation method of example 1. The difference was the starting material purchased in the first step, resulting in compound 23 as an off-white solid in a yield of 78.45%. 1 H NMR(300MHz,DMSO-d 6 )δ7.78(dd,J＝7.3,1.4Hz,6H),7.50(dd,J＝7.7,6.1Hz,6H),7.43-7.32(m,2H),5.48(d,J＝8.0Hz,1H),1.93(s,6H)。
Example 24
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1-phenylpyrazol-5-ol) 24
The synthesis was carried out according to the preparation method of example 1. The difference is that the starting material purchased in the first step gave compound 23 as an off-white solid and compound 24 as an off-white solid in a 64.35% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.78(dd,J＝7.3,1.4Hz,6H),7.50(dd,J＝7.7,6.1Hz,6H),7.43-7.32(m,2H),5.48(d,J＝8.0Hz,1H),1.93(s,6H)。
Example 25
Preparation of 4,4' - ((2-chlorophenyl) methylene) bis (1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol) 25
Step 1: synthesis of Compound 25-2
The synthesis was carried out according to the preparation method of example 1. Compound 25-2 was obtained as a reddish brown solid in 69.14% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),8.62(t,J＝3.4Hz,1H),7.66(dd,J＝8.7,1.2Hz,1H),7.31-7.20(m,1H),7.13(s,1H),7.06(ddd,J＝9.0,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 25
The synthesis was carried out according to the preparation method of example 1. The difference is that p-bromobenzaldehyde is changed into o-chlorobenzaldehyde, and the compound 25 is white solid with the yield of 67.39 percent. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(d,J＝1.4Hz,4H),7.57(ddd,J＝7.4,4.5,1.5Hz,3H),7.44(dd,J＝7.4,1.7Hz,1H),7.36-7.19(m,6H),7.06(ddd,J＝9.0,7.7,1.4Hz,2H),6.94(dd,J＝8.2,1.5Hz,2H),5.37(s,1H),2.11(s,6H).。
Example 26
Preparation of 4,4' - ((4-fluorophenyl) methylene) bis (1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3- (trifluoromethyl) -1H-pyrazol-5-ol) 26
Step 1: synthesis of Compound 26-2
The synthesis was carried out according to the preparation method of example 1. Compound 26-2 was obtained as a reddish brown solid in 69.14% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),8.62(t,J＝3.4Hz,1H),7.66(dd,J＝8.7,1.2Hz,1H),7.31-7.20(m,1H),7.13(s,1H),7.06(ddd,J＝9.0,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 26
The synthesis was carried out according to the preparation method of example 1. The difference is that ethyl acetoacetate is changed into ethyl 4, 4-trifluoro-3-oxobutyrate, and p-bromobenzaldehyde is changed into p-fluorobenzaldehyde, so that the compound 26 is white solid, and the yield is 73.97%. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,2H),10.34(s,2H),7.63-7.45(m,4H),7.39-7.13(m,6H),7.06(ddd,J＝9.0,7.7,1.4Hz,2H),6.94(dd,J＝8.2,1.5Hz,2H),5.21(s,1H)。
Example 27
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1- (4- (pyridin-3-yl) thiazol-2-yl) -1H-pyrazol-5-ol) 27
Step 1: synthesis of Compound 27-2
The synthesis was carried out according to the preparation method of example 1. Compound 27-2 was obtained as a pale green solid in 59.98% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.99(t,J＝2.0Hz,1H),8.73(t,J＝3.3Hz,1H),8.63(dt,J＝4.9,1.9Hz,1H),8.20(dt,J＝8.5,2.2Hz,1H),7.44(dd,J＝8.5,4.8Hz,1H),7.16(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 27
The synthesis was carried out according to the preparation method of example 1. Compound 27-2 was obtained as a green solid in 63.26% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),8.99-8.87(m,2H),8.71-8.59(m,2H),8.20(dt,J＝8.5,2.1Hz,2H),7.58-7.39(m,6H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.31(s,6H)。
Example 28
Preparation of 4,4' - ((4-bromophenyl) methylene) bis (5-hydroxy-3-methyl-1H-pyrazole-4, 1-diyl) bis (thiazole-2, 4-diyl) dibenzoic acid 28
Step 1: synthesis of Compound 28-2
The synthesis was carried out according to the preparation method of example 1. Compound 28-2 was obtained as a reddish brown solid in 60.82% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.71(s,1H),8.53(t,J＝3.4Hz,1H),7.95(d,J＝8.9Hz,2H),7.86(d,J＝8.9Hz,2H),7.16(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 28
The synthesis was carried out according to the preparation method of example 1. Compound 28 was obtained as a yellow solid in 72.57% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.40(s,2H),10.63(s,2H),7.89(q,J＝9.0Hz,8H),7.62-7.46(m,2H),7.40-7.13(m,4H),4.97(s,1H),2.25(s,1H)。
Example 29
Preparation of 4,4' - ((4-bromophenyl) methylene) bis (5-hydroxy-3-methyl-1H-pyrazole-4, 1-diyl) bis (thiazole-2, 4-diyl)) dibenzonitrile 29
Step 1: synthesis of Compound 29-2
The synthesis was carried out according to the preparation method of example 1. Compound 29-2 was obtained as an off-black solid in 74.37% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.3Hz,1H),7.89(d,J＝7.2Hz,2H),7.78-7.69(m,2H),7.16(s,1H),4.88(d,J＝3.3Hz,2H)。
Step 2: synthesis of Compound 29
The synthesis was carried out according to the preparation method of example 1. Compound 29 was obtained as an off-white solid in 71.59% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.40(s,2H),7.89(q,J＝9.0Hz,8H),7.62-7.46(m,2H),7.40-7.13(m,4H),4.97(s,1H),2.25(s,1H)。
Example 30
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1- (4-p-tolyl) thiazol-2-yl) -1H-pyrazol-5-ol) 30
Step 1: synthesis of Compound 30-2
The synthesis was carried out according to the preparation method of example 1. The compound 30-2 is obtained as white solid with the yield of 74.29%, 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.4Hz,1H),7.82-7.73(m,2H),7.27(d,J＝7.2Hz,2H),7.15(s,1H),4.88(d,J＝3.4Hz,2H),2.34(s,1H)。
step 2: synthesis of Compound 30
The synthesis was carried out according to the preparation method of example 1. Compound 30 was obtained as a white solid in 78.94% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.40(s,2H),7.89(q,J＝9.0Hz,8H),7.62-7.46(m,2H),7.40-7.13(m,4H),4.97(s,1H),2.34(s,1H),2.25(s,1H)。
Example 31
Preparation of 4,4' - (4-bromophenyl) methylenebis (1- (4-fluorophenyl) thiazol-2-yl) -3-methylpyrazol-5-ol) 31
Step 1: synthesis of Compound 31-2
The synthesis was carried out according to the preparation method of example 1. The compound 31-2 was obtained as a pale green solid in a yield of 77.20%. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(t,J＝3.4Hz,1H),7.93(dd,J＝8.6,5.0Hz,2H),7.24(t,J＝8.4Hz,2H),7.16(s,1H),4.88(d,J＝3.4Hz,2H)。
Step 2: synthesis of Compound 31
The synthesis was carried out according to the preparation method of example 1. The obtained compound 31 was a white solid with a yield of 74.29%, 1 H NMR(300MHz,DMSO-d 6 )δ11.40(s,2H),7.89(q,J＝9.0Hz,8H),7.62-7.46(m,2H),7.40-7.13(m,4H),4.97(s,1H),2.25(s,6H)。
example 32
Preparation of 4,4' - (2, 2-dimethylpropane-1, 1-diyl) bis (3-methyl-1-pyridin-2-yl) -1H-pyrazol-5-ol) 32
The synthesis was carried out according to the preparation method of example 1. The difference was that the product of the first step was purchased starting material, giving compound 32 as a grey solid in 45.52% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.50(s,2H),8.47(dd,J＝3.4,1.7Hz,2H),7.97(td,J＝6.8,1.7Hz,2H),7.72(dd,J＝7.0,1.4Hz,2H),7.37(ddd,J＝6.8,3.3,1.4Hz,2H),4.55(s,1H),2.25(s,6H),1.07(s,9H)。
Example 33
Preparation of 4,4' - (4-bromophenyl) methylenebis (3-methyl-1-pyridin-3-yl) -1H-pyrazol-5-ol) 33
The synthesis was carried out according to the preparation method of example 1. The difference is that the product of the first step is purchased starting material, compound 33 as a pale yellow solid in 70.58% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.73-8.66(m,2H),8.47-8.38(m,2H),7.87(dt,J＝7.2,2.1Hz,2H),7.56-7.47(m,2H),7.41(dd,J＝7.2,3.7Hz,2H),7.20(d,J＝8.0Hz,2H),4.94(s,1H),2.25(s,6H)。
Example 34
Preparation of 4,4' - ((4-bromophenyl) methylene) bis (3-methyl-1- (pyridin-4-yl) -1H-pyrazol-5-ol) 34
The synthesis was carried out according to the preparation method of example 1. The difference is that the product of the first step is purchased starting material, compound 34 is white orange solid in 76.32% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.65-8.40(m,4H),7.51(d,J＝8.1Hz,2H),7.45-7.30(m,4H),7.20(d,J＝8.0Hz,2H),4.94(s,1H),2.25(s,6H)。
Example 35
Preparation of 4,4' - ((4-bromophenyl) methylene) bis (3-methyl-1- (pyrimidin-2-yl) -1H-pyrazol-5-ol) 35
The synthesis was carried out according to the preparation method of example 1. The difference is that the product of the first step is purchased starting material, compound 35 is a pink solid in a yield of 79.82%. 1 H NMR(300MHz,DMSO-d 6 )δ11.12(s,2H),8.76(d,J＝3.3Hz,4H),7.58-7.45(m,2H),7.30(t,J＝3.3Hz,2H),7.20(d,J＝8.0Hz,2H),5.00(s,1H),2.25(s,6H)。
Example 36
Preparation of((4-bromophenyl) methylene) bis (5-hydroxy-3-methyl-1H-pyrazol-4, 1-diyl)) bis (pyridin-2-yl methanone) 36
The synthesis was carried out according to the preparation method of example 1. The difference is that the product of the first step is purchased starting material, compound 36 as a pale orange solid in 65.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.51(s,2H),8.74(dd,J＝4.3,1.7Hz,2H),8.05(dd,J＝6.7,1.5Hz,2H),7.94(td,J＝7.0,1.7Hz,2H),7.60-7.47(m,4H),7.20(d,J＝8.0Hz,2H),5.01(s,1H),2.25(s,6H)。
Example 37
Preparation of 4- ((4-bromophenyl) (1- (4- (4-chlorophenyl) thiazol-2-yl) -5-hydroxy-3-methyl-1H-pyrazol-4-yl) methyl) -1- (4- (tetrafluorophenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol 37
Step 1: synthesis of Compound 37-3
The synthesis was carried out according to the preparation method of example 1.
The difference is in step two, when ethyl acetoacetate is added for reaction, the TLC plate monitors that the reaction is finished, the solvent is dried by rotation, and the mixture is passed through a column. Purification by silica gel column chromatography (DCM: meoh=100:1) gave 37-3 as a pale green solid in 70.22% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.93(dd,J＝8.6,5.0Hz,2H),7.30(s,1H),7.24(t,J＝8.3Hz,2H),5.38(s,1H),2.30(s,3H)。
Step two: synthesis of Compound 37-4
37-3 (50.00 mg, 181.62. Mu. Mol), p-bromobenzaldehyde (84.01 mg, 454.05. Mu. Mol) and a few drops of piperidine were added to 15ml of isopropanol, and after the completion of the reaction, which was monitored by TLC plate under reflux for 4 hours at 60 ℃, the reaction was filtered and dried to give compound 37-4 as pale green in 68.72% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.92(dd,J＝8.6,5.0Hz,2H),7.81(d,J＝8.6Hz,2H),7.59(dd,J＝7.3,1.5Hz,3H),7.46(s,1H),7.24(t,J＝8.3Hz,2H),1.93(s,3H)。
Step three: synthesis of Compound 37-5
Reference examples 37-1 to 37-3. Compound 37-5 was obtained as a pale green solid in 78.35% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.61(d,J＝8.5Hz,2H),7.52-7.43(m,2H),7.30(s,1H),5.38(s,1H),2.31(s,3H)。
Step four: synthesis of Compound 37
37-4 (50.00 mg, 112.53. Mu. Mol) and similar compound 37-5 (49.25 mg, 168.80. Mu. Mol) synthesized in the previous two steps of reference example 37 were added to absolute ethanol, refluxed at 78℃for 6 hours, and after completion of the reaction, filtered and dried by TLC plate, compound 37 was obtained as a white solid in a yield of 68.79%. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),7.97-7.88(m,2H),7.61(d,J＝8.5Hz,2H),7.54-7.44(m,4H),7.34-7.16(m,6H),4.97(s,1H)，2.25(s,6H)。
Example 38
Preparation of 4- (2- (4- (4-bromophenyl) (1- (4- (4-bromophenyl) thiazol-2-yl) -5-hydroxy-3-methyl-1H-pyrazol-4-yl) methyl) -5-hydroxy 3-methyl-1H-pyrazol-1-yl) thiazol-4-yl) benzoic acid 38
/>
Step 1: synthesis of Compound 38
The synthesis was carried out according to the preparation method of reference example 37.
Compound 38-3 was obtained as a pale yellow solid in 74.28% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.72(d,J＝8.7Hz,2H),7.64-7.55(m,2H),7.30(s,1H),5.38(s,1H),2.31(s,3H)。
Compound 38-4 was obtained as a white solid in 83.92% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.76(dd,J＝25.8,8.6Hz,3H),7.64-7.55(m,4H),7.39(s,1H),7.34(s,1H),2.23(s,3H)。
Compound 38-5 was obtained as a white solid in 83.92% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.73(s,1H),11.95(s,1H),7.89(q,J＝9.0Hz,4H),7.30(s,1H),5.38(s,1H),2.18(s,3H)。
Compound 38 was obtained as a white solid in 76.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,2H),7.89(q,J＝8.9Hz,4H),7.72(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),7.54-7.47(m,2H),7.30(d,J＝0.8Hz,2H),7.20(d,J＝8.0Hz,2H),4.97(s,1H)，2.25(s,6H)。
Example 39
Preparation of 4- ((4-chlorophenyl) (5-hydroxy-1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-4-yl) methyl) -3-methyl-1- (4- (p-tolyl) thiazol-2-yl) -1H-pyrazol-5-ol 39
Step 1: synthesis of Compound 39
The synthesis was carried out according to the preparation method of reference example 37.
Compound 39-3 was obtained as a white solid in 63.23% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.78-7.69(m,2H),7.33-7.22(m,3H),5.38(s,1H),2.40(s,3H),2.23(s,3H)。
Compound 39-4 was obtained as a white solid in 68.71% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.79(dd,J＝12.8,8.0Hz,3H),7.59(dd,J＝7.2,1.4Hz,2H),7.40(s,4H),7.27(d,J＝7.2Hz,1H),2.40(s,6H)。
Compound 39-5 was obtained as a pink solid in 68.71% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),10.62(s,1H),7.57(dd,J＝8.7,1.3Hz,1H),7.32(s,1H),7.25(td,J＝8.0,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),5.38(s,1H),2.20(s,3H)。
Compound 39 was obtained as a white solid in 57.83% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(d,J＝1.5Hz,3H),7.73(d,J＝7.4Hz,2H),7.61-7.47(m,3H),7.34-7.17(m,7H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),4.97(s,1H)，2.4(s,3H)，2.25(s,6H)。
Example 40
Preparation of 4- ((4-bromophenyl) (1- (4- (3-chlorophenyl) thiazol-2-yl) -5-hydroxy-3-methyl-1H-pyrazol-4-yl) methyl) -1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol 40
Step 1: synthesis of Compound 40
The synthesis was carried out according to the preparation method of reference example 37.
Compound 40-3 was obtained as a white solid in 78.37% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.72-7.59(m,2H),7.43-7.31(m,3H),5.38(s,1H),2.25(s,3H)。
Compound 40-4 was obtained as a white solid in 83.84% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.81(d,J＝8.6Hz,2H),7.71-7.61(m,1H),7.66-7.55(m,4H),7.51(s,1H),7.43-7.31(m,2H),2.21(s,3H)。
Compound 40-5 was obtained as a pink solid in 75.27% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),10.62(s,1H),7.57(dd,J＝8.7,1.3Hz,1H),7.32(s,1H),7.25(td,J＝8.0,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),5.38(s,1H),2.20(s,3H)。
Compound 40 was obtained as a white solid in 45.87% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(d,J＝1.5Hz,3H),7.70-7.47(m,6H),7.41-7.16(m,6H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.6Hz,1H),4.97(s,1H)，2.25(s,6H)。
Example 41
Preparation of 4- ((4-bromophenyl) (5-hydroxy-1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-4-yl) methyl) -3-methyl-1- (pyridin-2-yl) -1H-pyrazin-5-ol 41
Step 1: synthesis of Compound 41-1
The synthesis was carried out according to the preparation method of reference example 37.
Compound 41-3 was obtained as a pink solid in 48.35% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),10.62(s,1H),7.57(dd,J＝8.7,1.3Hz,1H),7.32(s,1H),7.25(td,J＝8.0,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),5.38(s,1H),2.20(s,3H)。
Compound 41-4 was obtained as an orange solid in 74.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),7.81(d,J＝8.6Hz,2H),7.58(td,J＝6.8,1.3Hz,4H),7.52(s,1H),7.25(td,J＝7.9,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),2.21(s,3H)。
The difference from example 37 was that compound 41-5 was directly reacted with ethyl acetoacetate using the purchased starting material to give compound 41-5 as a white solid in 57.29% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.96(s,1H),8.46(dd,J＝3.4,1.7Hz,1H),7.96(td,J＝6.9,1.7Hz,1H),7.73(dd,J＝7.0,1.5Hz,1H),7.37(ddd,J＝6.8,3.3,1.5Hz,1H),5.43(s,1H),2.15(s,3H)。
Compound 41 was obtained as a white solid in 57.28% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.21(s,1H),10.62(d,J＝1.5Hz,2H),8.47(dd,J＝3.3,1.7Hz,1H),7.97(td,J＝6.9,1.7Hz,1H),7.72(dd,J＝7.0,1.5Hz,1H),7.60-7.48(m,3H),7.37(ddd,J＝6.8,3.3,1.5Hz,1H),7.32(s,1H),7.29-7.17(m,3H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.3,1.6Hz,1H),4.98(s,1H),2.25(s,6H)。
Example 42
Preparation of 4- ((4-bromophenyl) (5-hydroxy-1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-4-yl) methyl) -3-methyl-1- (4-phenylthiazol-2-yl) -1H-pyrazol-5-ol 42
Step 1: synthesis of Compound 42
The synthesis was carried out according to the preparation method of reference example 41.
Compound 42-3 was obtained as a pink solid in 48.35% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),10.62(s,1H),7.57(dd,J＝8.7,1.3Hz,1H),7.32(s,1H),7.25(td,J＝8.0,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),5.38(s,1H),2.20(s,3H)。
Compound 42-4 was obtained as an orange solid in 74.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),7.81(d,J＝8.6Hz,2H),7.58(td,J＝6.8,1.3Hz,4H),7.52(s,1H),7.25(td,J＝7.9,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),2.21(s,3H)。
Compound 42-5 was obtained as a white solid in 57.29% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.81(dd,J＝7.5,1.6Hz,2H),7.54-7.43(m,2H),7.47-7.36(m,1H),7.30(s,1H),5.38(s,1H),2.13(s,6H)。
Compound 42 was obtained as a white solid in 48.57% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(d,J＝1.5Hz,3H),7.81(dd,J＝7.5,1.6Hz,2H),7.57(dd,J＝8.7,1.2Hz,1H),7.54-7.38(m,5H),7.34-7.15(m,5H),7.06(ddd,J＝8.9,7.7,1.4Hz,1H),6.94(dd,J＝8.2,1.4Hz,1H),4.97(s,1H),2.12(s,6H).。
Example 43
Preparation of 4- ((3-chlorophenyl) (1- (4- (3-fluorophenyl) thiazol-2-yl) -5-hydroxy-3-methyl-1H-pyrazol-4-yl) methyl) -1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3-methyl-1H-pyrazol-5-ol 43
Step 1: synthesis of Compound 43
The synthesis was carried out according to the preparation method of reference example 41.
Compound 43-3 was obtained as a pink solid in 48.35% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),10.62(s,1H),7.57(dd,J＝8.7,1.3Hz,1H),7.32(s,1H),7.25(td,J＝8.0,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),5.38(s,1H),2.20(s,3H)。
Compound 43-4 was obtained as an orange solid in 74.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),7.98-7.86(m,1H),7.79(t,J＝1.6Hz,1H),7.65-7.49(m,3H),7.46-7.34(m,2H),7.25(td,J＝7.9,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),2.23(s,3H)。
Compound 43-5 was obtained as a white solid in 76.21% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.78(dt,J＝8.4,1.6Hz,1H),7.61(dt,J＝8.0,1.9Hz,1H),7.48(td,J＝8.0,5.0Hz,1H),7.40(s,1H),7.23-7.11(m,1H),5.38(s,1H),2.13(s,6H)。。
Compound 43 was obtained as a white solid in 48.36% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(d,J＝1.4Hz,2H),7.78(dt,J＝8.3,1.6Hz,1H),7.66-7.11(m,11H),7.17-7.00(m,1H),6.94(dd,J＝8.2,1.4Hz,1H),5.03(s,1H),2.25(s,6H)。
Example 44
Preparation of 3- (2- (4- (4-bromophenyl) (5-hydroxy-3-methyl-1- (pyrimidin-2-yl) -1H-pyrazol-4-yl) methyl) -5-hydroxy-3-methyl-1H-pyrazin-1-yl) thiazol-4-yl) benzonitrile 44
Step 1: synthesis of Compound 44
The synthesis was carried out according to the preparation method of reference example 41.
Compound 44-3 was obtained as a white solid in 76.37% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),8.04(t,J＝1.9Hz,1H),7.83(dt,J＝7.7,1.5Hz,1H),7.75-7.64(m,2H),7.58(dd,J＝7.6,6.4Hz,1H),5.38(s,1H),2.31(s,3H)。
Compound 44-4 was obtained as an off-white solid in 65.07% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.04(t,J＝1.9Hz,1H),7.82(dd,J＝8.0,6.3Hz,3H),7.70(dt,J＝6.5,1.5Hz,1H),7.64-7.52(m,4H),7.50(s,1H),2.28(s,3H)。
Compound 44-5 was obtained as a dark red solid in 88.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.71(s,1H),8.76(d,J＝3.2Hz,2H),7.29(t,J＝3.3Hz,1H),5.50(s,1H),2.31(s,3H)。
Compound 44 was obtained as a white solid in 51.47% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.12(s,1H),10.63(s,1H),8.76(d,J＝3.3Hz,2H),8.04(t,J＝1.9Hz,1H),7.83(dt,J＝7.7,1.6Hz,1H),7.73-7.65(m,2H),7.61-7.47(m,3H),7.30(t,J＝3.3Hz,1H),7.20(d,J＝8.0Hz,2H),5.01(s,1H),2.25(s,6H)。
Example 45
Preparation of 4- ((4-bromophenyl) (1- (4- (3-bromophenyl) thiazol-2-yl) -5-hydroxy-3-methyl-1H-pyrazol-4-yl) methyl) -3-methyl-1- (pyridin-4-yl) -1H-pyrazin-5-ol 45
Step 1: synthesis of Compound 45
The synthesis was carried out according to the preparation method of reference example 37.
Compound 45-3 was obtained as an off-white solid in 75.32% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),7.90(t,J＝1.9Hz,1H),7.72(dt,J＝8.5,1.6Hz,1H),7.67(s,1H),7.58(dt,J＝8.0,1.5Hz,1H),7.40(t,J＝8.2Hz,1H),5.38(s,1H),2.13(s,3H)。
Compound 45-4 was obtained as an off-white solid in 71.29% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.90(t,J＝1.9Hz,1H),7.81(d,J＝8.6Hz,2H),7.72(dt,J＝8.6,1.5Hz,1H),7.59(ddt,J＝7.0,5.5,1.6Hz,4H),7.50(s,1H),7.40(t,J＝8.2Hz,1H),2.11(s,3H)。
Compound 45-5 was obtained as a yellow solid in 68.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.66(s,1H),8.56-8.48(m,2H),7.45-7.37(m,2H),5.46(s,1H),2.12(s,3H)。
Compound 45 was obtained as a white solid in 53.20% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,1H),8.58-8.48(m,2H),7.90(t,J＝1.9Hz,1H),7.75-7.65(m,2H),7.58(dt,J＝8.0,1.5Hz,1H),7.53-7.48(m,2H),7.44-7.36(m,3H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.25(s,6H)。
Example 46
Preparation of 3- (2- (4- (4-bromophenyl) (5-hydroxy-3-methyl-1- (pyrimidin-2-yl) -1H-pyrazol-4-yl) methyl) -5-hydroxy-3-methyl-1H-pyrazin-1-yl) thiazol-4-yl) benzonitrile 46
Step 1: synthesis of Compound 46
The synthesis was carried out according to the preparation method of reference example 37.
Compound 46-3 was obtained as a white solid in 76.37% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.95(s,1H),8.04(t,J＝1.9Hz,1H),7.83(dt,J＝7.7,1.5Hz,1H),7.75-7.64(m,2H),7.58(dd,J＝7.6,6.4Hz,1H),5.38(s,1H),2.31(s,3H)。
Compound 46-4 was obtained as an off-white solid in 65.07% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.04(t,J＝1.9Hz,1H),7.82(dd,J＝8.0,6.3Hz,3H),7.70(dt,J＝6.5,1.5Hz,1H),7.64-7.52(m,4H),7.50(s,1H),2.28(s,3H)。
Compound 46-5 was obtained as a white solid in 57.29% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.53(s,1H),8.76(dd,J＝2.0,1.0Hz,1H),8.41(ddd,J＝3.7,1.9,1.0Hz,1H),7.88(dt,J＝7.2,1.9Hz,1H),7.41(dd,J＝7.2,3.7Hz,1H),5.47(s,1H),2.12(s,3H)。
Compound 46 was obtained as a white solid in 57.63% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.30(s,1H),10.63(s,1H),8.73-8.66(m,1H),8.43(dt,J＝3.8,1.9Hz,1H),8.04(t,J＝1.9Hz,1H),7.85(ddt,J＝10.7,7.6,1.9Hz,2H),7.75-7.64(m,2H),7.58(dd,J＝7.6,6.4Hz,1H),7.51(d,J＝8.2Hz,2H),7.41(dd,J＝7.2,3.7Hz,1H),7.20(d,J＝8.0Hz,2H),4.97(s,1H),2.12(s,6H)。
Example 47
Preparation of (3-bromophenyl) (4- ((4-bromophenyl) 5-hydroxy-3-methyl-1- (pyrimidin-2-yl) -1H-pyrazol-4-yl) methyl) -5-hydroxy-3-methyl-1H-pyrazin-1-yl) methanone 47
Step 1: synthesis of Compound 47
The synthesis was carried out according to the preparation method of reference example 37.
Compound 47-2 was purchased as a starting material, giving compound 47-3 as a white solid in 63.27% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.64(s,1H),8.07(t,J＝1.9Hz,1H),7.94-7.85(m,1H),7.74-7.64(m,1H),7.45(dd,J＝8.1,7.0Hz,1H),6.08(s,1H),2.14(s,3H)。
Compound 47-4 was obtained as a white solid in 67.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.11(t,J＝1.9Hz,1H),8.02-7.92(m,1H),7.84(d,J＝8.6Hz,2H),7.74-7.65(m,1H),7.65-7.55(m,3H),7.44(dd,J＝8.1,7.0Hz,1H),2.13(s,3H)。
Compound 47-5 was obtained as a dark red solid in 88.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.71(s,1H),8.76(d,J＝3.2Hz,2H),7.29(t,J＝3.3Hz,1H),5.50(s,1H),2.31(s,3H)。
Compound 47 was obtained as white solid in 54.49% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.64(s,1H),11.12(s,1H),8.76(d,J＝3.3Hz,2H),8.07(t,J＝1.9Hz,1H),7.95-7.85(m,1H),7.74-7.64(m,1H),7.56-7.47(m,2H),7.45(dd,J＝8.1,7.0Hz,1H),7.30(t,J＝3.3Hz,1H),7.20(d,J＝8.0Hz,2H),5.01(s,1H),2.25(s,6H)。
Example 48
Preparation of 4- ((4-bromophenyl) (5-hydroxy-3-methyl-1- (pyridin-2-yl) -1H-pyrazol-4-yl) methyl) -3-methyl-3- (pyrimidin-2-yl) -1H-pyrazol-5-ol 48
Step 1: synthesis of Compound 48
The synthesis was carried out according to the preparation method of reference example 37.
Compound 48-3 was obtained as a white solid in 57.29% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.96(s,1H),8.46(dd,J＝3.4,1.7Hz,1H),7.96(td,J＝6.9,1.7Hz,1H),7.73(dd,J＝7.0,1.5Hz,1H),7.37(ddd,J＝6.8,3.3,1.5Hz,1H),5.43(s,1H),2.15(s,3H)。
Compound 48-4 was obtained as a white solid in 65.38% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.36(dd,J＝3.4,1.7Hz,1H),8.04(dd,J＝7.0,1.5Hz,1H),7.81(d,J＝8.6Hz,2H),7.66(td,J＝6.9,1.7Hz,1H),7.59(d,J＝8.7Hz,2H),7.53(s,1H),7.14(ddd,J＝6.8,3.3,1.4Hz,1H),2.13(s,3H)。
Compound 48-5 was obtained as a dark red solid in 88.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.71(s,1H),8.76(d,J＝3.2Hz,2H),7.29(t,J＝3.3Hz,1H),5.50(s,1H),2.31(s,3H)。
Compound 48 was obtained as a white solid in 53.72% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.21(s,1H),11.12(s,1H),8.76(d,J＝3.3Hz,2H),8.47(dd,J＝3.4,1.7Hz,1H),7.97(td,J＝6.8,1.7Hz,1H),7.72(dd,J＝7.0,1.3Hz,1H),7.51(d,J＝8.1Hz,2H),7.37(ddd,J＝6.8,3.3,1.3Hz,1H),7.30(t,J＝3.3Hz,1H),7.20(d,J＝8.0Hz,2H),5.01(s,1H),2.23(s,6H)。
Example 49
Preparation of 4- ((4-bromophenyl) (5-hydroxy-3-methyl-1- (pyridin-3-yl) -1H-pyrazol-4-yl) methyl) -3-methyl-3- (pyrimidin-2-yl) -1H-pyrazol-5-ol 49
Step 1: synthesis of Compound 49
The synthesis was carried out according to the preparation method of reference example 37.
Compound 49-3 was obtained as a white solid in a yield of 57.29%. 1 H NMR(300MHz,DMSO-d 6 )δ11.53(s,1H),8.76(dd,J＝2.0,1.0Hz,1H),8.41(ddd,J＝3.7,1.9,1.0Hz,1H),7.88(dt,J＝7.2,1.9Hz,1H),7.41(dd,J＝7.2,3.7Hz,1H),5.47(s,1H),2.12(s,3H)。
Compound 49-4 was obtained as a white solid in 59.29% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.88(dd,J＝2.0,1.0Hz,1H),8.51(ddd,J＝3.7,1.9,1.0Hz,1H),8.08(dt,J＝7.2,1.9Hz,1H),7.82(d,J＝8.6Hz,2H),7.59(dd,J＝7.3,1.5Hz,3H),7.46(dd,J＝7.2,3.7Hz,1H),2.13(s,3H)。
Compound 49-5 was obtained as a dark red solid in 88.89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.71(s,1H),8.76(d,J＝3.2Hz,2H),7.29(t,J＝3.3Hz,1H),5.50(s,1H),2.31(s,3H)。
Compound 49 was obtained as a white solid in 59.24% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.12(s,1H),8.76(d,J＝3.3Hz,2H),8.70(dd,J＝2.0,1.0Hz,1H),8.43(ddd,J＝3.5,2.2,1.0Hz,1H),7.87(dt,J＝7.2,2.1Hz,1H),7.56-7.47(m,2H),7.41(dd,J＝7.2,3.7Hz,1H),7.30(t,J＝3.3Hz,1H),7.20(d,J＝8.0Hz,2H),4.98(s,1H),2.24(s,6H)。
Example 50
Preparation of 4- (1- (5-hydroxy-1- (4- (2-hydroxyphenyl) thiazol-2-yl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -2, 2-dimethylpropyl) -3-methyl-1- (pyrimidin-2-yl) -1H-pyrazol-5-ol 50
Step 1: synthesis of Compound 50
The synthesis was carried out according to the preparation method of reference example 37.
The compound 50-3 was obtained as a white solid in a yield of 65.36%. 1 H NMR(300MHz,DMSO-d 6 )δ11.98(s,1H),10.62(s,1H),7.57(dd,J＝8.7,1.3Hz,1H),7.34(s,1H),7.25(td,J＝7.9,1.3Hz,1H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),6.33(s,1H).
The compound 50-4 was obtained as a white solid in a yield of 62.36%. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),7.62-7.50(m,2H),7.25(td,J＝7.9,1.3Hz,1H),7.06(ddd,J＝9.1,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),6.59(td,J＝2.1,1.1Hz,1H),1.10(d,J＝1.0Hz,9H)。
The compound 50-5 was obtained as a black-red solid with a yield of 88.89%. 1 H NMR(300MHz,DMSO-d 6 )δ11.71(s,1H),8.76(d,J＝3.2Hz,2H),7.29(t,J＝3.3Hz,1H),5.50(s,1H),2.31(s,3H)。
Compound 50 was obtained as a white solid in 57.49% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),10.42(s,1H),9.95(s,1H),8.76(d,J＝3.3Hz,2H),7.57(dd,J＝8.7,1.3Hz,1H),7.37-7.20(m,3H),7.06(ddd,J＝9.0,7.7,1.5Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),4.6(s,1H),2.26(s,3H),1.07(s,9H)。
Test examples
1、IGF 2 BP 2 Expression and purification of proteins
IGF 2 BP 2 Gene plasmids purchased from Kirsrui Biotech Co
The experimental steps are as follows:
coli BL21 (DE 3) strain was transfected with the recombinant plasmid and the cells were recovered in sterile LB medium at 37 ℃. The monoclonal is picked up to 10mL LB liquid medium (containing 50 mug/mL kanamycin, amp), shake cultured (220 rpm) at 37 ℃ for overnight, transferred to 1L LB liquid medium (containing 50 mug/mL kanamycin, amp), shake cultured (220 rpm) at 37 ℃ for 6-8 hours until OD 600 is 0.6-0.8, cooled to 12 ℃, added with 1mM IPTG (Merck) to induce expression for 16 hours (180 rpm) and then harvested, and stored at-80 ℃ for standby.
4g of the bacterial sludge obtained in the previous step is added with 40mL of a broken bacterial lysate, PMSF (Biyun Tian) is added after mixing, ultrasonic pyrolysis is carried out for 40 minutes, the cracked mixed solution is subjected to low-temperature high-speed centrifugation (10000 rpm,20min,4 ℃), supernatant is taken and filtered (0.4 mu m microporous filter membrane), and the mixture is separated and purified by AKTA pure25 (GE Healthcare, life Sciences) through His column (equilibrium solution: 20mM pH8.0Tris-HCl,300mM NaCl,10mM imidazole; eluent: 20mM pH8.0Tris-HCl,300mM NaCl,500mM imidazole), 10% SDS-PAGE confirms the molecular weight and purity of the bands, and the mixture is dialyzed overnight (20 mM pH8.0Tris-HCl,300mM NaCl). The protein obtained was measured for concentration by BCA and stored at-80℃for further use.
2. Determination of compounds versus IGF based on Fluorescence Polarization (FP) 2 BP 2 Is effective in inhibiting activity of (a)
The invention is based on IGF 2 BP 2 A combined fluorescent molecular probe used for researching the competition of the compounds for IGF 2 BP 2 And m is equal to 6 A nucleic acid binding method, determining the inhibition rate of the compound under different concentration conditions, and further calculating IC 50 Values.
The equipment and reagents used were as follows:
the instrument used in this experiment was SpectraMax Paradigm Multi-Mode Microplate Reader (Molecular Devices). The protein is IGF 2 BP 2 (laboratory self-expressed and purified protein, sequence. The probe used is fluorescence-labeled m 6 A-ssRNA (sequence) all test compounds were formulated as 10mM stock in DMSO. 384 well blackboard used for the experiment was produced by Corning.
The experimental steps are as follows:
the final volume tested was selected to be 60. Mu.L, and 20. Mu.L IGF was used at different concentrations of 20. Mu.L (10-14 gradients diluted with two-fold gradients per compound, initial concentration 100. Mu.M) 2 BP 2 Protein (300 nM, final concentration 100 nM), 20. Mu.L of fluorescent probe (300 nM, final concentration 10 nM) were added sequentially to the wells. Each experiment was run with a blank (40. Mu.L pH=7.5 Tris-HCl buffer+20. Mu.L 10nM fluorescent probe) and a negative control (20. Mu.L pH=7.5 Tris-HCl buffer+20. Mu.L IGF) 2 BP 2 Protein+20 μL 10nM fluorescent probe). Shielding 384 well plates with tinfoil paper after sample addition, incubating in a shaker at room temperature for 1 hr, reading fluorescence with excitation wavelength of 485nm and emission wavelength of 535nm by using SpectraMax Paradigm Multi-Mode Microplate Reader, calculating mP value, calculating inhibition rate by using the following formula, and calculating IC by using GraphPad Prism 5.0 50 Values.
Inhibition ratio = (compound group mP value-blank group mP value)/(negative control group mP value-blank group mP value) ×100%
The experimental results are shown in Table 1, with m without fluorescent label 6 A-ssRNA was used as a positive control, a compound of the formula was used as a lead, and then activity data thereof was used as a control,
TABLE 1 compounds of the invention are useful for treating IGF 2 BP 2 Protein IC 50 Value of
/>
As can be seen from the results of the above table, the compounds of the present invention are useful for treating IGF 2 BP 2 Has obvious inhibiting activity and can be used as IGF 2 BP 2 Protein small molecule inhibitors, inhibiting IGF 2 BP 2 Binding to mRNA.
In conclusion, the substituted bis (pyrazolyl) methane derivative compounds provided by the invention are used for treating IGF 2 BP 2 Has obvious inhibition activity, is an effective IGF 2 BP 2 An inhibitor. Therefore, the medicine containing the compound as the active ingredient can be used for preparing the medicine and IGF 2 BP 2 Related clinical symptoms.
As described above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (6)

1. A compound of formula i:
R 1 selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl or heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl or aryl;
R 3 and R is 4 Independently selected from H, substituted or unsubstituted C1-C10 alkyl;
R 2 and R is 5 Independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl or heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl or aryl, or a combination of two rings;
R 6 and R is 7 Independently selected from H, substituted or unsubstituted C1-C10 alkyl, oxy.
2. A compound or pharmaceutically acceptable salt thereof according to claim 1,
R 1 selected from H, substituted or unsubstituted C1-C7 alkyl, substituted or unsubstituted 5-8 membered heteroaryl or aryl;
R 3 and R is 4 Independently selected from H, substituted or unsubstituted C1-C7 alkyl;
R 2 and R is 5 Independently selected from a substituted or unsubstituted five-membered or six-membered nitrogen containing heterocycle or aromatic ring, or a combination of a five-membered heteroaromatic ring and a six-membered heteroaromatic ring;
R 6 and R is 7 Independently selected from H, substituted or unsubstituted C1-C5 alkyl, oxy.
3. A compound or pharmaceutically acceptable salt thereof according to claim 2,
R 1 selected from H, methyl, ethyl, isopropyl, tert-butyl,
R 3 and R is 4 Independently selected from H, methyl, ethyl, difluoromethyl, trifluoromethyl;
R 2 and R is 5 Independently selected from
R 6 And R is 7 Independently selected from H, hydroxy, methoxy, ethoxy;
at R 1 、R 2 And R is 5 Wherein R is a Is mono-or polysubstituted, and the substituent is selected from H, halogen, hydroxy, alkyl, nitro, amino, methoxy, trifluoromethyl, difluoromethyl, carboxyl, difluoromethoxy, trifluoromethoxy, mercapto or cyano.
4. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for use in therapy with IGF 2 BP 2 Use in medicine for treating protein dysfunction related diseases.
5. A pharmaceutical composition, characterized in that the active ingredient of the pharmaceutical composition comprises a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable carrier.
CN202310773449.0A 2023-06-28 2023-06-28 Bis (pyrazolyl) methane derivative and application thereof Pending CN117069714A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310773449.0A CN117069714A (en) 2023-06-28 2023-06-28 Bis (pyrazolyl) methane derivative and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310773449.0A CN117069714A (en) 2023-06-28 2023-06-28 Bis (pyrazolyl) methane derivative and application thereof

Publications (1)

Publication Number Publication Date
CN117069714A true CN117069714A (en) 2023-11-17

Family

ID=88715940

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310773449.0A Pending CN117069714A (en) 2023-06-28 2023-06-28 Bis (pyrazolyl) methane derivative and application thereof

Country Status (1)

Country Link
CN (1) CN117069714A (en)

Similar Documents

Publication Publication Date Title
US11021475B2 (en) Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
CA2698511C (en) Substituted pyrimidinyl-amines as protein kinase inhibitors
US20110053935A1 (en) Fused pyridines active as inhibitors of c-met
BR112019010167A2 (en) pyrrolopyrimidines as cftr enhancers
CN113811300A (en) Novel small molecule inhibitors of TEAD transcription factor
JP5518887B2 (en) Tetrasubstituted pyridazine hedgehog pathway antagonist
JP2010524974A (en) Kinase inhibitors useful for the treatment of myeloproliferative disorders and other proliferative disorders
WO2002088110A1 (en) Quinoline derivative having azolyl group and quinazoline derivative
JP7288904B2 (en) Biaryl ether-type quinazoline derivatives
KR20180094880A (en) 5-membered heterocyclic amide-based WNT pathway inhibitor
WO2024088110A1 (en) Heterocyclic macrocyclic compound containing indazole structure and used as protein kinase inhibitor, and preparation method therefor
CN109734674B (en) Aniline WDR5 protein-protein interaction inhibitor and preparation method and application thereof
CN111533721B (en) Benzopyrone or quinolinone compounds and application thereof
CN117069714A (en) Bis (pyrazolyl) methane derivative and application thereof
CN116283920B (en) 2, 4-disubstituted pyridine compound and application thereof
EP2948443A1 (en) New pyrimidine derivatives as phosphodiesterase 10 inhibitors (pde-10)
CN113493437B (en) Compound containing benzimidazole structure and preparation method and application thereof
WO2002092593A1 (en) 4-(4-pyridazinyl)pyrazole derivatives
RU2652112C1 (en) Bromides of benzimidazolium derivatives as inhibitors of protein-tyrosinephosphatase 1b type (ptp1b)
WO2024114574A1 (en) High-selectivity plk4 inhibitor, preparation method therefor and use thereof
Nishad et al. DESIGN, SYNTHESIS AND CHARACTERIZATION OF SUBSTITUTED-TRIAZOLE-BASED ANTI? TUBERCULOSIS DERIVATIVES
US20240217969A1 (en) Substituted pyrrole carboxamides, process for their preparation and their use as kinase inhibitors
CN114989176A (en) Imidazopyridazine derivative and application thereof
CA3215443A1 (en) Substituted pyrrole carboxamides, process for their preparation and their use as kinase inhibitors
WO2023057371A1 (en) 1,2,4-oxadiazol-5-one derivatives for the treatment of cancer

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination