CN116925066A - Indole thiazole ketone compound and application thereof - Google Patents

Indole thiazole ketone compound and application thereof Download PDF

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CN116925066A
CN116925066A CN202210365683.5A CN202210365683A CN116925066A CN 116925066 A CN116925066 A CN 116925066A CN 202210365683 A CN202210365683 A CN 202210365683A CN 116925066 A CN116925066 A CN 116925066A
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张所明
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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

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Abstract

The application relates to an indolothiazolinone compound shown in a formula (I) and pharmaceutically acceptable salts, solvates, isotopic variants or isomers thereof,

Description

Indole thiazole ketone compound and application thereof
Technical Field
The application belongs to the technical field of anti-tumor compounds, and particularly relates to an indole thiazole ketone compound with aromatic hydrocarbon receptor (AhR) agonistic activity and application thereof.
Background
The aromatic hydrocarbon receptor (AhR, aryl hydrocarbon receptor) is one of the subfamily bHLH-PAS (bHLH-PER-ARNT-SIM) members of the basic helix-loop-helix (basic helix-helix) superfamily, and is the only receptor in the bHLH-PAS family known to be activated by a ligand (see Nat. Rev. Cancer,2014,14 (12), 801; nat. Rev. Cancer,2013,13 (12), 827). AhR is an intracellular transcription regulator capable of sensing foreign stimulus in the external environment and mediating toxic response. AhR after activation can regulate the expression of genes on many chromosomes and promote the metabolism of heteroplasmic substances. Previous studies have found that this signal is also involved in a number of important biological processes such as signal transduction, cell differentiation, apoptosis, etc.
The biological effects of AhR are through the binding of the receptor to the ligand and then into the nucleus. Recent studies have shown that AhR ligands have a variety of biological uses, such as compounds DIM and derivatives thereof have tumor-inhibiting activity (see Breast Cancer res. Treat.2001,66,147), which is currently in phase II clinical studies for the treatment of prostate and cervical Cancer. The AhR agonist Phortress is in phase I clinic for the treatment of solid tumors (see Br.J.Cancer,2003,88,599;Mol.Cancer Ther.2004,3,1565). The AhR antagonist SR-1 of Novartis (StemRegin-1) is undergoing phase I/II clinical use for cord blood cell transplantation after myeloablative. The Beijing Cheng Nuoji medical science and technology Co., ltd. Developed clinical researches on liver cancer and breast cancer by Icaritin, and has been marketed in batches for improving treatment of patients with advanced hepatocytes associated with hepatitis B virus in poor physical condition.
2- (1 '-H-indole-3' -carbonyl) thiazole-4-carboxylic acid methyl ester (ITE) is an AhR endogenous ligand extracted from pig lung and found in recent years, and synthesis (see CN1915991B, CN102775399A, US 20040204588) and preparation (see US20020183524 and WO 2018121434) of ITE are reported in various documents, and the structure of ITE is as follows:
Both ITE and dioxin are AhR agonists, but ITE is non-cytotoxic (see proc. Natl. Acad. Sci.2002,99,14694-9). Recent studies have demonstrated that ITE can inhibit proliferation and migration of ovarian Cancer cells (see Cancer Lett,2013,340 (1), 63-71), and also can inhibit prostate Cancer, stomach Cancer, rectal Cancer, skin Cancer, etc., see in particular documents US20130338201, WO2011/053466, US9238645B2, CN102573470, WO2016040553, etc. It can be seen from the structure of ITE, which is a biologically labile compound, is rapidly metabolized to organic acids in vivo. It is therefore important to design novel non-cytotoxic, biologically stable AhR agonists.
Disclosure of Invention
The invention aims to provide an anti-tumor compound with a novel structure and application thereof in preparing medicines for treating tumors.
The first aspect of the invention relates to an indolothiazolinone compound shown in a formula (I) and pharmaceutically acceptable salts, solvates, isotopic variants or isomers thereof,
wherein:
y and Z are each independently selected from O or S;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R is 7 Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, formyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, haloalkoxy, alkanoyl, haloalkoyl, thioalkanoyl, haloalkoxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, halocarbonylamino, haloalkylthio, carbonylamino and-S (O) n R 11 (n=0 to 2, r 11 Directly to S), wherein R 11 Selected from the group consisting of hydrogen, halogen, amino, hydroxy, mercapto, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkoyl, thioalkanoyl, halothioalkanoyl, carbonyloxy, halocarbonyloxy, carbonylAlkylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio and halothiocarbonylthio, wherein R 2 May be further selected from amino protecting groups;
R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkylhydroxy, alkylamino, carbonylalkoxy, carbonylalkyl, oxycarbonylalkyl, and-S (O) n R 11 (n=0 to 2, r 11 Directly connected with S); or R is 8 、R 9 And R is 10 Together, any two or three of these form a 3-to 15-membered, preferably 3-to 12-membered, preferably 3-to 8-membered, more preferably 3-to 6-membered, monocyclic or bicyclic ring containing 0 to 2 heteroatoms selected from O, N and S, said monocyclic or bicyclic ring being unsubstituted or mono-or polysubstituted by 1 to 3 groups selected from: halogen, amino, hydroxy, cyano, formyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, haloalkoxy, alkanoyl, haloalkoyl, thioalkanoyl, halothioalkanoyl, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, carbonylalkylamino, carbonylalkyl, carbonylalkoxy and-S (O) n R 11 (n=0 to 2, r 11 Directly with S).
Pharmaceutically acceptable salts of the compounds of the invention are basic salts or acid salts. The salts may be basic salts, including salts of the compounds with inorganic bases (e.g., alkali metal hydroxides, alkaline earth metal hydroxides, etc.) or with organic bases (e.g., monoethanolamine, diethanolamine, triethanolamine, etc.). Alternatively, the salt may be an acid salt, including salts of the compound with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid, etc.) or with organic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, or citric acid, etc.).
In a preferred embodiment, the solvate of the compound of the invention is a hydrate or an alkoxide, wherein the alkoxide comprises an ethoxide.
Isotopic variations of the compounds of the present invention typically are those in which a hydrogen atom (H) is replaced by deuterium (D) which is a heavy hydrogen atom.
Also included in the compounds of the present invention may be their stereoisomers, non-stereoisomers and geometric isomers other than enantiomers, as well as mixtures of stereoisomers, non-stereoisomers and geometric isomers other than enantiomers.
Methods for selecting and preparing pharmaceutically acceptable salts or solvates or isotopic variations or isomers of the compounds are well known in the art.
In a preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 Each independently selected from the group consisting of hydrogen, alkyl, halogen, and carbonylalkylamino.
In a preferred embodiment, R 8 、R 9 And R is 10 Each independently selected from hydrogen, hydroxy, amino, alkyl, alkylhydroxy, alkoxy, alkylamino, carbonylalkoxy, carbonylalkyl and oxycarbonylalkyl, or R 8 、R 9 And R is 10 Together, any two or three of these form a 3-to 15-membered monocyclic or bicyclic ring containing 0 to 2 heteroatoms selected from O, N and S, said monocyclic or bicyclic ring being unsubstituted or mono-or polysubstituted with 1 to 3 groups selected from alkyl, carbonylalkyl, sulphonylalkyl, sulphonylamino, amino, hydroxy, carbonylalkoxy.
In a preferred embodiment, R 8 、R 9 And R is 10 Together, any two or three of these form a 3-to 15-membered monocyclic ring containing 0 to 2 heteroatoms selected from O, N and S, said monocyclic ring being unsubstituted or mono-or di-substituted by 1 to 3 groups selected from alkyl, carbonylalkyl, sulphonylalkyl, sulphonylamino, amino, hydroxy, carbonylalkoxy.
In a preferred embodiment of the present invention, Is one of the following groups:
in a preferred embodiment of the present invention,is one of the following groups:
the second aspect of the present invention relates to a process for preparing an indolothiazolidone compound according to the first aspect of the present invention, comprising the step of reacting compound M with compound S, wherein:
the compound M is:
the compound S is:
x is a leaving group which may be selected from, for example, chlorine, bromine, iodine, -OS (O) 2 CH 3 and-OS (O) 2 C 6 H 4 CH 3 。
In a preferred embodiment, the leaving group is chloro or bromo.
The third aspect of the invention relates to a pharmaceutical composition, which comprises the indolothiazolidone compound or the pharmaceutically acceptable salt or solvate or isotopic variant or isomer thereof as described in the first aspect of the invention, and pharmaceutically acceptable auxiliary materials.
The fourth aspect of the invention relates to the use of an indolothiazolidone compound according to the first aspect of the invention or a pharmaceutically acceptable salt or solvate or isotopic variant or isomer thereof, or a pharmaceutical composition according to the third aspect of the invention, for the preparation of a medicament for the treatment of tumors.
The medicament can be any clinically applied dosage form, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated tablets, granules, dry powder, oral solutions, small injection needles, freeze-dried injection powder or large infusion. Depending on the particular dosage form and mode of administration, the pharmaceutically acceptable carrier or excipient in the medicament may comprise one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, pigments and the like.
In a preferred embodiment, the tumor comprises: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, brain cancer, colon cancer, ovarian cancer, cancer of the shoulder, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchi cancer, bone cell carcinoma, epithelial cancer, bile duct cancer, choriocarcinoma, embryo cancer, seminoma, wilms' carcinoma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma, ependymoma, pineal tumor, hemangioblastoma, vocal cord neuroma, meningioma, neuroblastoma, retinoblastoma, neurofibromatoma, fibrosarcoma, fibromatoma, fibroadenoma, fibromatoma, fibrocyst, fibromyxoma, fibroosteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, myxocyst, myxochoma, myxochondrosarcoma, myxochoma, myxoadenoma, myxoblastoma, liposarcoma, lipoma, lipoadenoma, lipomatoma, lipoblastoma, lipofibroma, lipoma, chondrosarcoma, chondrioma, chondromyoma, chordoma, choriadenoma, chorioallantoic tumor, chorioallantoic cell tumor, osteosarcoma, osteoblastoma, osteochondrofibroma, osteochondral sarcoma, osteochondroma, osteosarcoma, osteoodontoma, osteofibroma, osteosarcoma, hemangiosarcoma, hemangioma, vascular lipoma, hemangioblastoma, hemangiokeratoma, angioglioma, vascular endothelial tumor, vascular fibroma, vascular myomas, vascular lipomas, vascular lymphomas, vascular liposmooth myomas, vascular myxomas, vascular reticuloendotheliomas, lymphangiosarcomas, lymphogranulomas, lymphopipe tumors, lymphomas, lymphomyxomas, lymphosarcomas, lymphangiofibromas, lymphocytomas, lymphoepitheliomas, lymphoblastomas, endotheliomas, endothelioblastomas, synoviomas, synovial sarcomas, mesotheliomas, connective tissue tumors, ewing's tumors, smooth myomas, leiomyomas, smooth myofibromas, rhabdomyomas, rhabdomyxomas, acute lympholeukemias, acute myelogenous leukemia, chronic disease cells, erythrocytosis, lymphomas, endometrial cancer, gliomas, colorectal cancer, thyroid cancer, urothelial carcinoma, or multiple myeloma, and the like.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The experimental methods in the following examples are all conventional methods unless otherwise specified, and all performed at normal temperature and pressure. The raw materials and reagent materials used in the examples below are all commercially available products unless otherwise specified.
Definition of the definition
"hydroxy", "mercapto", "cyano", "nitro" and "formyl" refer to-OH, -SH, -CN, -NO, respectively 2 and-CHO.
"alkyl" refers to groups of 1 to 12, preferably 1 to 8, more preferably 1 to 6 hydrogen saturated carbons linked in a linear, branched, or cyclic manner, including combinations of linear, branched, and cyclic linkages.
"halogen" means any of halogen atoms fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
"haloalkyl" refers to an alkyl group substituted with one or more halogens.
"alkenyl" refers to a group containing a hydrocarbon of 2 to 12, preferably 2 to 8, more preferably 2 to 6 carbons, which is linear, branched, cyclic, or a combination thereof, having at least one carbon-carbon double bond.
"haloalkenyl" refers to alkenyl groups substituted with one or more halogens.
"alkynyl" refers to a group containing a hydrocarbon of 2 to 12, preferably 2 to 8, more preferably 2 to 6 carbons, which is straight chain, branched, cyclic, or a combination thereof, having at least one carbon-carbon triple bond.
"haloalkynyl" refers to an alkynyl group substituted with one or more halogens.
"amino protecting group" means any group commonly used to protect an amino function. Such protecting groups are discussed by P.G.M.Wuts in "Protective Groups in Organic Synthesis, 5 th edition" John Wiley and Sons, inc., new York, ISBN-13:978-1118057483 (incorporated herein by reference in its entirety). Exemplary amino protecting groups include alkyl carbamates, portions of the corresponding amides, and the like, such as allyl carbamate (Alloc), t-butyl carbamate (BOC), 9-fluorenylmethyl carbamate (FMOC), benzyl carbamate (Cbz), acetamide, chloroacetamide, trifluoroacetamide (TFA), phthalimide, benzylamine, triphenylmethylamine (tritylamine), benzylideneamine, p-toluenesulfonamide, and the like.
"amino" means-NR a R b Wherein R is a And R is b Are all directly attached to N and can be independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, formyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkoyl, thioalkanoyl, halothioalkanoyl, haloalkoyl, haloalkylthio, Carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, nitrogen protecting group, or-S (O) n R 11 (n=0 to 2, r 11 Directly to S), wherein R 11 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, haloalkoxy, alkanoyl, haloalkoyl, thioalkanoyl, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, halocarbonylthio, carbonylphenyl or sulfinylalkyl.
"alkoxy" refers to an alkyl (-O-alkyl) group attached to an oxygen atom.
"haloalkoxy" refers to a haloalkyl (-O-haloalkyl) attached to an oxygen atom.
"thioalkoxy" refers to an alkyl (-S-alkyl) group attached to a sulfur atom.
"halothioalkoxy" refers to a haloalkyl (-S-haloalkyl) attached to the sulfur atom.
"carbonyl" refers to- (CO) -, where (CO) represents oxygen linked to carbon via a double bond.
"alkanoyl (or acyl)" refers to an alkyl [ - (CO) -alkyl ] group attached to a carbonyl group.
"haloalkoyl (or haloacyl)" refers to a haloalkyl [ - (CO) -haloalkyl ] attached to a carbonyl group.
"thiocarbonyl" refers to- (CS) -, where- (CS) -means that sulfur is linked to carbon via a double bond.
"thioalkanoyl (or thioacyl)" refers to an alkyl [ - (CS) -alkyl ] group attached to a thiocarbonyl group.
"halothioalkanoyl (or halothioacyl)" refers to a haloalkyl [ - (CS) -haloalkyl ] attached to a thiocarbonyl group.
"carbonyloxy" refers to alkanoyl (or acyl) [ -O- (CO) -alkyl ] attached to an oxygen atom.
"halocarbonyloxy" refers to a haloalkoyl (or haloacyl) [ -O- (CO) -haloalkyl ] attached to an oxygen atom.
"carbonyl sulfide" refers to an alkanoyl (or acyl) [ -S- (CO) -alkyl ] attached to a sulfur atom.
"halocarbonylthio" refers to a haloalkoyl (or haloacyl) [ -S- (CO) -haloalkyl ] attached to a sulfur atom.
"thiocarbonyloxy" refers to a thioalkanoyl (or thioacyl) [ -O- (CS) -alkyl ] group attached to an oxygen atom.
"halothiocarbonyloxy" refers to a halothioalkanoyl (or halothioacyl) [ -O- (CS) -haloalkyl ] attached to an oxygen atom.
"thiocarbonylthio" refers to a thioalkanoyl (or thioacyl) [ -S- (CS) -alkyl ] group attached to a sulfur atom.
"halothiocarbonylthio" refers to a halothioalkanoyl (or halothioacyl) [ -S- (CS) -haloalkyl ] attached to a sulfur atom.
"leaving group" refers to a moiety that can be displaced under nucleophilic displacement conditions well known to those skilled in the art. Leaving groups include, but are not limited to, halo and-OSO 2 -R 20 Wherein R is 20 Is optionally substituted alkyl, aryl, heterocyclyl or heteroaryl.
A range of numbers as used herein is intended to include each number and subset of numbers contained within that range (whether or not specifically disclosed). Further, these numerical ranges should be construed as providing support for claims directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be interpreted as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.
Preparation example
English abbreviations description:
THF, tetrahydrofuran; DCM, dichloromethane; MTBE, methyl tert-butyl ether; meOH, methanol; DMF, N-dimethylformamide; DIPEA, N-diisopropylethylamine; HOAc, acetic acid; EA, acetic acid ethyl ester An ester; PE, petroleum ether; TMSCHN 2 Trimethylsilyl diazomethane; HATU,2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate; DCE, dichloroethane; NMP, methyl pyrrolidone; NBS, N-bromosuccinimide; TFAA, trifluoroacetic anhydride; eq, equivalent weight, i.e. molar ratio.
Other unexplained abbreviations or terms are explained or otherwise operated in accordance with definitions or instructions in the handbook of organic chemistry or organic synthesis.
Example 1
The first step: starting materials S1 and 1-bromo-2, 3-butanedione (M1) were synthesized according to the method disclosed in WO2018121434 (which is incorporated herein by reference in its entirety) to give compound 1a. LCMS (ESI) m/z 271[ M+1 ]] + 。
And a second step of: compound 1a (100 mg,0.37 mmol) was dissolved in 15mL dry THF, and 0.4mL of 2M solution of methyl magnesium bromide was added dropwise at room temperature and stirred overnight. Quenching with aqueous ammonium chloride, extraction with ethyl acetate (10 ml×3), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the crude product by silica gel column chromatography (PE: ea=5:1 to 1:1, volume ratio) gave compound 1 (40 mg, yield 37.4%). 1 H NMR(400MHz,DMSO-d 6 )δ＝12.21(s,1H),9.15(d,J＝3.6Hz,1H),8.33(dd,J＝6.4Hz,J＝3.2Hz,1H),7.82(s,1H),7.58(dd,J＝5.6Hz,J＝2.0Hz,1H),7.26～7.31(m,2H),5.40(s,1H),1.59(s,6H)。LCMS(ESI)m/z:287[M+1] + 。
Example 2
The first step: 2- (benzoylamino) -cyclopropanoic acid (1.00 g,4.97 mmol) was dissolved in 10mL THF, DIPEA (1.09 g,8.45 mmol) was added at 0 ℃, isobutyl chloroformate (1.01 g,7.45 mmol) was added dropwise, the reaction was kept at 0 ℃ for 4h, acetonitrile 5mL was added, 4.97mL of a mixture of trimethylsilylated diazomethane (2 mol/L) was diluted with 8mL of methanol/THF (v/v=1/1), the reaction solution was added dropwise at 0 ℃ for about 30 minutes, after stirring at natural temperature for 5h, 40% hbr aqueous solution 0.5mL was added under ice salt bath, the reaction was completed after the completion of the dropwise, MTBE and sodium bicarbonate aqueous solution were immediately extracted, anhydrous sodium sulfate was dried, and concentrated under reduced pressure to obtain 220mg of oily liquid compound M2, which was directly used for the next reaction.
And a second step of: compound M2 (200 mg,0.72 mmol) was dissolved in ethanol (10 mL), starting material S1 (147 mg,0.72 mmol) was added with stirring, heated to 80℃and reacted for 2h, cooled to room temperature, filtered and washed with ethanol to give compound 2a (0.6 g, yield 45%). 1 H NMR(400MHz,DMSO-d 6 )δ12.19(d,J＝2.4Hz,1H),9.35(s,1H),8.96(d,J＝3.2Hz,1H),8.31(m,1H),7.94(d,J＝7.2Hz,2H),7.62-7.55(m,2H),7.50(t,J＝7.2Hz,2H),7.26～7.28(m,2H),1.62(dd,J＝4.8,7.6Hz,2H),1.37(dd,J＝4.8,7.6Hz,2H)。LCMS(ESI)m/z:388.1[M+1] + 。
And a third step of: to compound 2a, 10mL of a mixed solvent of concentrated hydrochloric acid and dioxane (v/v=1:1) was added, the mixture was reacted at 100℃for 24 hours, concentrated under reduced pressure, extracted with ethyl acetate, the aqueous phase was adjusted to pH 9 to 11 with NaOH solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethanol to give compound 2 (20 mg). 1 H NMR(400MHz,DMSO-d 6 ):δ12.17(s,1H),8.97(s,1H),8.29～8.32(m,1H),7.84(s,1H),7.55～7.58(m,1H),7.24～7.30(m,2H),2.75(br,2H),1.24～1.27(dd,J＝6.8,4.0Hz,2H),1.04～1.07(dd,J＝6.8,4.0Hz,2H)。LCMS(ESI)m/z:284.1[M+1] + 。
Example 3
The first step: cyclopropylaminohydrochloride (10.7 g,77.9 mmol) was dissolved in 90mL of acetic acid and aqueous sodium nitrite (10.8 g,155.8 mmol) was added dropwise with ice water cooling, dissolved in 10mL of water. After the completion of the dropwise addition, the temperature was automatically raised overnight under stirring. The reaction solution was concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (10% to 30% EA/PE) to give Compound 3a (3.5 g, yield 31.2%) as an oil. LCMS (E)SI)m/z:145[M+Na] + 。
And a second step of: compound 3a (2.02 g,14.0 mmol) was dissolved in 50mL of DCM, a few drops of DMF under nitrogen protection, oxalyl chloride (1.11 mL,16.9 mmol) was added dropwise at 0deg.C, stirred for 1h, concentrated to dryness under reduced pressure, acetonitrile (17.6 mL) and trimethylsilyl diazomethane (17.6 mL (2M, 35.3 mmol) were added. The reaction mixture was stirred for 4h. Acetic acid (2.5 mL) and 7.5mL HBr (48%, 42.3 mmol) were then added at 0deg.C. The reaction was carried out at room temperature for 30min, and the mixture was poured into 100mL of water and extracted with DCM (70 mL. Times.3). The organic phases were combined, washed with 100mL of saturated brine, and dried over Na 2 SO 4 Drying, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography (10% -20% EA/PE) to obtain colorless oily M3 (550 mg, yield 17.8%). LCMS (ESI) m/z 221/223[ M+H ]] + 。
Thirdly, canzhao example 2 in the second step, compound M3 was reacted with starting material S1 to give compound 3b (0.2 g).
Fourth step, compound 3b (100 mg) was dissolved in THF/MeOH/H 2 To a mixed solvent of O (v/v/v=1:1:1, 10 ml), liOH (55 mg,2.24 mmol) was added, stirred at room temperature for 2h, neutralized to ph=7 with 1N hydrochloric acid, extracted with ethyl acetate (EtOAc), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethyl acetate to give compound 3 (81 mg, yield 93%). 1 HNMR(400MHz,DMSO-d 6 )δ12.17(s,1H),8.97(s,1H),8.29～8.32(m,1H),7.84(s,1H),7.55～7.58(m,1H),7.24～7.30(m,2H),1.75(br,1H),1.24～1.27(dd,J＝6.8,4.0Hz,2H),1.04～1.07(dd,J＝6.8,4.0Hz,2H)。LCMS(ESI)m/z:284[M+1] + 。
Example 4
Compound 2 (57 mg,0.2 mmol) and paraformaldehyde (60 mg,0.2 mmol) were dissolved in 5mL of ethanol/water (v/v=1/1) mixed solvent, sodium borohydride (108 mg,2 mmol) was added, stirred overnight at room temperature, saturated ammonium chloride solution was added, extracted with ethyl acetate (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to 1mL, left stand, filtered, washed with ethyl acetate, and dried to give compound 4 (38 mg, yield 62%).
1 H NMR(400MHz,DMSO-d 6 ):δ12.15(s,1H),8.98(d,J＝2.8Hz,1H),8.29～8.31(m,1H),7.78(s,1H),7.55～7.57(m,1H),7.26～7.28(m,2H),2.35(s,3H),1.23(brs,1H),1.19～1.21(m,2H),1.04～1.06(m,2H)。MS(ESI)m/z:298.1[M+1] + 。
Example 5
Compound 2 (57 mg,0.2 mmol) and paraformaldehyde (60 mg,2 mmol) were dissolved in 5mL of ethanol/water (v/v=1/1) mixed solvent, sodium borohydride (108 mg,2 mmol) was added, stirred overnight at room temperature, saturated ammonium chloride solution was added, extracted with ethyl acetate (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to 1mL, left standing, filtered, washed with ethyl acetate, and dried to give compound 5 (45 mg, yield 72%). 1 H NMR(400MHz,CD 3 OD):δ9.12(s,1H),8.36～8.39(m,1H),7.71(s,1H),7.49～7.51(m,1H),7.26～7.30(m,2H),2.47(s,6H),1.09～1.11(m,2H),1.07～1.085(m,2H)。MS(ESI)m/z:312.1[M+1] + 。
Example 6
The first step: boc-D-proline (5.0 g,23.23 mmol) was dissolved with THF (25 mL) under stirring, DIPEA (5.1 g,39.47mmol,1.7 eq) was added, cooled to below 0deg.C, a solution of isobutyl chloroformate (4.9 g,35.88mmol,1.54 eq) in THF (25 mL) was added dropwise to the reaction solution, reacted at 0deg.C for 4 hours, acetonitrile (25 mL) was added dropwise below 0deg.C, and trimethylsilylated diazomethane (23.5 mL) in THF/methanol=1/1 (16 mL/16 mL) was added dropwise slowly, and the reaction was continued at below 0deg.C for 3.5 hours after the completion of the addition, followed by overnight at room temperature. The reaction was concentrated to dryness, MTBE (25 mL) was added and dissolved with stirring, cooled to below 0 ℃, hydrobromic acid (0.15 g,0.74mmol,0.88 eq) was added dropwise, the reaction was continued at 0 ℃ for 5 min, neutralized to ph=7 with saturated aqueous sodium bicarbonate, the organic phase was separated, the aqueous phase was extracted 3 times with MTBE, the MTBE phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give crude intermediate M6 (2.6 g, yield 35%).
And a second step of: reference is made to the second step of example 2. Intermediate M6 was reacted with starting material S1 (181 mg,0.89mmol,1 eq) to give compound 6a (180 mg, yield 68%). LCMS (ESI) m/z 398.2[ M+1 ]] + 。
In the third step, compound 6a (100 mg) was dissolved in 5ml of dioxane, 5ml of 2N hydrogen chloride dioxane solution was added, stirring was conducted at room temperature for 4 hours, and the solid was filtered and washed with dioxane to give Compound 6 hydrochloride (73 mg, yield 87%). 1 H NMR(400MHz,DMSO-d 6 ):δ12.48(s,1H),10.22(brs,1H),9.29(d,J＝4.8Hz,1H),9.21(brs,1H),8.31～8.33(m,1H),7.78(s,1H),7.57～7.60(m,1H),7.26～7.32(m,2H),4.90(m,1H),3.31～3.40(m,2H),2.45～2.52(m,1H),2.02～2.10(m,3H)。LCMS(ESI)m/z:298.2[M+1] + 。
Example 7
Synthetic method referring to example 6, boc-L-proline was used instead of Boc-D-proline. Intermediate M7 (4.1 g, 55% yield) was obtained in the first step. Compound 7a (430 mg, 84% yield) was obtained in the second step, LCMS (ESI) m/z:398.2[ M+1 ]] + . The third step gave compound 7 hydrochloride (306 mg, 85% yield). 1 H NMR(400MHz,DMSO-d 6 ):δ12.45(s,1H),10.21(brs,1H),9.29(d,J＝4.8Hz,1H),9.22(brs,1H),8.31～8.32(m,1H),7.78(s,1H),7.57～7.60(m,1H),7.25～7.32(m,2H),4.91(m,1H),3.31～3.41(m,2H),2.44～2.52(m,1H),2.00～2.10(m,3H)。LCMS(ESI)m/z:298.2[M+1] + 。
Example 8
The first step: 1-Boc-4-piperidinecarboxylic acid (1 g,4.36 mmol) was dissolved with THF (10 mL) under stirring, DIPEA (0.98 g,7.56mmol,1.7 eq) was added, a solution of isobutyl chloroformate (0.91 g,6.72mmol,1.54 eq) in THF (5 mL) was added dropwise to the reaction solution, reacted at 0℃for 4 hours, acetonitrile (5 mL) was added dropwise below 0℃and then trimethylsilanized diazomethane (0.99 g,8.73mmol,2 eq) in THF/methanol=1 (3.2 mL/3.2 mL) was slowly added dropwise, and the reaction was continued at 0℃for 3.5 hours again after the completion of the dropwise addition, followed by overnight at room temperature. The reaction was concentrated to dryness and the crude product was purified by column chromatography (DCM dissolution wet column, PE/ea=6/1 to 4/1, volume ratio) to give compound M8a (50 mg, yield 4.5%).
And a second step of: compound M8a (50 mg,0.20 mmol) was dissolved with MTBE (5 mL) under stirring, cooled to below 0deg.C, hydrobromic acid (35 mg,0.17mmol,0.88 eq) was added dropwise, the reaction was continued at 0deg.C for 5 min, the MTBE phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound M8 (52 mg, yield 82.7%).
And a third step of: compound M8 (52 mg,0.16 mmol) was dissolved with THF (5 mL) under stirring, starting material S1 (33 mg,0.16mmol,1 eq) was added, the mixture was heated to 90℃and refluxed for 2 days, the reaction solution was concentrated to dryness under reduced pressure, and compound 8a (50 mg, yield 74.4%) was isolated and purified by thin plate chromatography. LCMS (ESI) m/z 412.11[ M+1 ]] + 。
Fourth step: compound 8a (50 mg,0.12mmol,1 eq) was dissolved in DCM (5 mL), trifluoroacetic acid (5 drops) was added with stirring, reacted overnight at room temperature, 1mL of saturated aqueous sodium bicarbonate solution was added, extracted with DCM (10 mL. Times.3), the DCM phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give crude product, and methanol was recrystallized to give compound 8 (20 mg, 52.8% yield). LCMS (ESI) m/z 312.11[ M+1 ]] + 。
Example 9
The synthesis method is described in example 8.
The first step: from 1-Boc-4-piperidinecarboxylic acid (1 g,4.97 mmol) compound M9a (100 mg, yield 8.9%).
And a second step of: crude intermediate M9 (105 mg, 81.0% yield) was obtained from 100mg of compound M9 a.
And a third step of: from intermediate M9 (105 mg,0.16 mmol) compound 9a (60 mg, yield 43.4%). LCMS (ESI) m/z 384.10[ M+1 ]] + 。
Fourth step: from compound 9a (43 mg,0.11 mmol), compound 9 (5 mg, yield 78.7%). LCMS (ESI) m/z 284.10[ M+1 ] ] + 。
Example 10
The first step: 2- (benzoylamino) -2-methylpropanoic acid (8.7 g,42 mmol) was dissolved in 15mL of DMF, HATU (19 g,50 mmol) and DIPEA (16 g,126 mmol) were added, stirred at room temperature for 2 hours and quenched with 50mL of water. Extraction with ethyl acetate (50 mLX 3), combined organic phases, washing with saturated brine (100 mL), drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, purification by silica gel column chromatography (5% to 10% EA/PE) afforded 10a (4.2 g, 53% yield) as a colorless oil. LCMS (ESI) m/z 190.2[ M+1] +.
And a second step of: compound 10a (4.2 g,22.2 mmol) was dissolved in pyridine (10 mL), N, O-dimethylhydroxylamine hydrochloride (6.5 g,66.6 mmol) was added, stirred at 90℃for 2 hours, the solvent was distilled off under reduced pressure, and the white solid 10b (4.5 g, yield 81%) was purified by silica gel column chromatography (25% EA/PE). LCMS (ESI) m/z 273.2[ M+1] +.
And a third step of: 10b (4.5 g,18 mmol) was dissolved in anhydrous THF (12 mL) and methylmagnesium chloride (3M in THF, 12mL,36 mmol) was slowly added dropwise under nitrogen with ice-bath. The mixture was stirred at 0 ℃ for ten minutes, slowly warmed to room temperature, and stirred for half an hour. The reaction was quenched by addition of saturated ammonium chloride solution in ice bath. The mixture was extracted with water (30 mL) and ethyl acetate (50 mLX 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (30% EA/PE) to give 10c (3.2 g, yield 87%) as a white solid. LCMS (ESI) m/z 206.1[ M+1] +.
Fourth step: compound 10c (3.0 g,14.6 mmol) was dissolved in 20mL of DCE and a solution of bromine (2.34 g,14.6 mmol) in DCE (10 mL) was added dropwise. After stirring at 80℃for 5 hours, a sudden discoloration was observed. The solvent was evaporated under reduced pressure, THF (10 mL) was added to the remaining solid, stirred for half an hour, filtered, and the solid was rinsed with THF (2 mLX 2) to give a white solid 23d (3.0 g, yield 72%). LCMS (ESI) m/z 284.1/286.1[ M+1] +.
Fifth step: compound 10d (2.7 g,9.54 mmol) and intermediate S1 (1.95 g,9.54 mmol) were dissolved in 20mL NMP, heated to 70℃and stirred overnight, the reaction cooled to room temperature and slowly dropped into water (20 mL), filtered, the solid was added 10mL methanol, stirred for half an hour, filtered and rinsed with methanol to give a pale yellow solid 10e (1.17 g, 32% yield).
1 H NMR:(400MHz,DMSO-d6):δ12.19(s,1H),9.03(d,J＝4.0Hz,1H),8.54(s,1H),8.32-8.30(m,1H),7.85(d,J＝8.0Hz,2H),7.79(s,1H),7.56-7.50(m,2H),7.46(t，J＝8.0Hz,2H),7.28-7.25(m,2H)。LCMS(ESI)m/z:390.3[M+1]+。
Sixth step: compound 10e (200 mg,0.514 mmol) was dissolved in 1mL THF and 1mL methanol and NaOH solution (103 mg,2.57mmol in 1mL water) was added. The reaction mixture was heated to 140 ℃ in a jar and stirred overnight. The solvent was evaporated directly under reduced pressure and purified by silica gel column chromatography (5% to 10% meoh/DCM) to give 10 as a yellow solid (45 mg, 31% yield). 1H NMR (400 MHz, DMSO-d 6): delta 12.41 (s, 1H), 9.37 (s, 1H), 8.31-8.33 (m, 1H), 8.10 (s, 1H), 7.58-7.60 (m, 1H), 7.28-7.32 (m, 2H), 1.71 (s, 6H). LCMS (ESI) m/z 286.1[ M+1] +.
Example 11
The first step: compound 2 (284 mg,1 mmol) was dissolved in 50ml of tetrahydrofuran, and potassium carbonate (10 ml of a 206mg aqueous solution) was added thereto, followed by cooling to about 0℃in an ice-water bath. 262mg of di-tert-butyl dicarbonate is added, and the temperature is controlled to be 0-3 ℃. After the addition, the ice bath was removed and stirred overnight. The reaction mixture was distilled off under reduced pressure to remove tetrahydrofuran, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give Compound 11a, MS (ESI) m/z:384.1[ M+1] +.
And a second step of: to a solution of Boc-L-valine (2.17 g,10 mmol) in DMF (20 mL) was added compound 11a (3.83 g,10 mmol), HATU (4.56 g,12 mmol) and DIPEA (2.6 g,20 mmol) with stirring, and stirring was continued overnight. The reaction solution was poured into water, extracted 2 times with ethyl acetate, the organic phase was washed 1 time with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE/ea=4/1) to give compound 11b (4.51 g, yield 77%). MS (ESI) m/z 605.3[ M+23 ]] + 。
And a third step of: compound 11b (0.58 g,0.98 mmol) was dissolved in dioxane (2 mL), a solution of hydrogen chloride dioxane (5 mL) was added dropwise, the reaction was carried out overnight at room temperature, and the hydrochloride of compound 11 (378 mg, yield 83.1%) was obtained by filtration.
1 H NMR(400MHz,DMSO-d 6 ):δ9.24(s,1H),8.94(s,1H),8.41(brs,3H),8.35(d,J＝7.6Hz,1H),7.81(d,J＝7.6Hz,1H),7.39～7.47(m,2H),6.63(brs,3H),2.07～2.12(m,1H),1.24～1.27(m,2H),1.04～1.07(m,2H),0.84(d,J＝7.2Hz,3H),0.80(d,J＝7.2Hz,3H)。MS(ESI)m/z:383.2[M+1] + 。
Example 12
The first step: synthesis of compound 12 a: 3-methyl-3-hydroxy butanone (10 mmol) was dissolved in 10ml of DCM, bromine (12 mmol) was added dropwise, stirring was carried out at room temperature for 2 hours, the solvent was removed by concentration under reduced pressure, and the crude product was used in the next step without purification.
And a second step of: method for synthesizing Compound 12 referring to Compound 1 of example 1, compound 12 (130 mg, yield 82%) was obtained by reacting Compound 12a with starting material S2. 1 HNMR(400MHz,DMSO-d 6 ):δ12.24(s,1H),9.12(d,J＝3.2Hz,1H),7.94(dd,J＝2.4,10.0Hz,1H),7.78(s,1H),7.55(dd,J＝4.8,8.8Hz,1H),7.10(ddd,J＝2.4,8.8,12Hz,1H),5.33(s,1H),1.53(s,6H)。MS(ESI)m/z:305.1[M+1] + 。
Example 13
The first step: 1-Boc-3-azetidinone (5 g,29.2 mmol) was dissolved in dichloromethane (150 mL) and tert-butylsulfinamide (4.25 g,35.05 mmol) and tetraisopropyl titanate (16.6 g,58.4 mmol), N were added at room temperature 2 Reflux overnight under protection, 200ml of dichloromethane and cold saturated sodium bicarbonate solution were added and stirred well, solids developed, celite filtered, the filtrates separated, dichloromethane extracted, the organic phases combined, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to dryness, purified by column chromatography on silica gel (PE: ea=10:1 to 1:1, volume ratio) to give 6g of white solid 13a (yield 74.88%). LCMS (ESI) m/z 275.1[ M+1 ]] + 。
And a second step of: ethyl vinyl ether (4.74 g,65.7 mmol) was weighed and 100ml of anhydrous tetrahydrofuran, N was added 2 Protecting, cooling to below-72 ℃, slowly adding tert-butyllithium (25 mL,1.3mol/L,32.8 mmol) dropwise by a syringe, keeping the dropwise temperature below-68 ℃, stirring for 20 minutes after the dropwise addition, removing a dry ice acetone bath, naturally heating to 0 ℃, keeping the temperature of the ice water bath to react for 1.5 hours until the reaction solution fades into a semitransparent colorless solution, cooling to below-72 ℃, dropwise adding a THF solution (6 g,21.9mmol dissolved in 50mL anhydrous tetrahydrofuran) of the compound 13a, stirring for 30 minutes after the dropwise addition, keeping the residual cold bath overnight, naturally heating to room temperature, adding saturated ammonium chloride solution dropwise for quenching reaction in the ice bath, extracting with methyl tert-butyl ether and saturated brine for 2 times, combining organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering and concentrating to dryness, and purifying by silica gel column chromatography (PE: EA=1:1, volume ratio) to obtain 3g oily liquid 13b (yield 39%). LCMS (ESI) m/z 347.1[ M+1 ] ] + 。
And a third step of: compound 13b (500 mg,1.44 mmol) was dissolved in dioxane (15 mL), cooled to 0℃and kept well stirred so as not to coagulate, and 10 drops of water were added dropwise, followed by a slow addition of a solution of NBS (205 mg,1.154 mmol) in dioxane (2 mL) (about 5 minutes). The mixture was stirred at low temperature for 20 minutes, the reaction mixture was directly dried over magnesium sulfate, and a crude solution of compound 13c was obtained after filtration and used directly in the subsequent reaction without purification。LCMS(ESI)m/z:341.2[M+1-56] + 。
Fourth step: the crude product 13c from the third step was dissolved in 20mL dioxane, S1 (188 mg,0.92 mmol) was added, stirred at room temperature over the weekend, insoluble impurities were filtered off, the solvent was evaporated off under reduced pressure, and silica gel column chromatography (DCM/MeOH/THF=50/1/0 to 10/1/1, volume ratio) was purified to 80mg of yellow solid 13d (yield 13.4%). LCMS (ESI) m/z 343.2[ M+1-56] + 。
Fifth step: compound 13d (26 mg) was dissolved in 4M hydrogen chloride 1, 4-dioxane solution (2 mL), stirred at room temperature overnight, solid precipitated, 10mL of MTBE was added, filtered, and the filter cake was rinsed with MTBE (5 mLX 2) to give 15mg of yellow solid 13 (yield 62%). 1 H NMR(400MHz,DMSO-d6)δ12.52(s,1H),10.14(s,1H),9.80(brs,3H),9.44(s,2H),8.57(s,1H),8.31(m,1H),7.59(m,1H),7.29(m,2H),4.68(s,2H),4.58(s,2H)。LCMS(ESI)m/z:299[M+1] + 。
Example 14
The synthesis of intermediate 14a is described in the second and third steps of example 13.
The synthesis of intermediate 14b was performed in 23% yield with reference to the fourth step of example 13. 1 H NMR(400MHz,DMSO-d 6 )δ12.31(s,1H),9.01(d,J＝2.8Hz,1H),8.31～8.33(m,1H),7.96(s,1H),7.54～7.57(m,1H),7.27～7.31(m,2H),6.71(s,1H),4.31(m,2H),4.07(m,2H),1.41(s,9H)。LCMS(ESI)m/z:400.1[M+1] + 。
The synthesis of compound 14 was carried out in 88% yield by reference to the fifth step of example 13. 1 H NMR(400MHz,DMSO-d 6 )δ12.34(s,1H),9.56(brs,2H),9.36(d,J＝3.2Hz,1H),8.32～8.34(m,1H),8.06(s,1H),7.59～7.61(m,1H),7.26～7.31(m,2H),7.17(s,1H),4.51～4.55(m,2H),4.17～4.19(m,2H)。LCMS(ESI)m/z:300.1[M+1] + 。
Example 15
The synthesis of intermediate 15a is described in the second and third steps of example 13.
The synthesis of intermediate 15b was performed in 31% yield in the fourth step of example 13. 1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),9.05(s,1H),8.00(d,J＝2.4Hz,1H),7.97(s,1H),7.58(dd,J＝4.8,8.8Hz,1H),7.15(ddd,J＝2.4,7.2,11.6Hz,1H),6.71(s,1H),4.32(d,J＝4.8Hz,2H),4.06(d,J＝8.4Hz,2H),1.41(s,9H)。LCMS(ESI)m/z:418.1[M+1] + 。
The synthesis of compound 15 was performed according to the fifth step of example 13 in 78% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.45(s,1H),9.56(brs,2H),9.41(d,J＝2.4Hz,1H),8.07(s,1H),7.99(dd,J＝2.4,8.8Hz,1H),7.62(dd,J＝4.4,8.4Hz,1H),7.17(s,1H),7.13～7.18(m,1H),4.53(d,J＝11.2Hz,2H),4.18(d,J＝11.2Hz,2H)。LCMS(ESI)m/z:318.1[M+1] + 。
Example 16
In the first step, the synthesis of intermediate 16a was carried out in 62% yield with reference to the second step of example 13. LCMS (ESI) m/z 145.2[ M+1 ]] + 。
In the second step, the synthesis of intermediate 16b was used directly in the next step without purification, as in the third step of example 13.
Third step, synthesis of intermediate 16 c: crude 16b (5 mmol) was dissolved in 20ml of anhydrous water, S1 (913 mg,4.48 mmol) was added, stirred at reflux overnight, the solvent was evaporated under reduced pressure, silica gel column chromatography (PE: EA=5:1-1:1, then DCM: meOH: THF=10:1:1 in volume ratio was used to purify yellow solid 16c (300 mg, yield 21%). LCMS (ESI) m/z:319.1[ M+1:1:1] + 。
Fourth step, synthesis of compound 16: intermediate 16c (300 mg,0.94 mmol) was dissolved in THF, 2, 6-lutidine (603.5 mg,5.64 mmol) was added, TFAA (592.2 mg,2.82 mmol) was slowly added under ice-bath, and the mixture was stirred at room temperature for 3 hours, and reversed Ethyl acetate and water were added to the reaction solution to extract 3 times, and the organic phases were combined, washed with a small amount of cold dilute hydrochloric acid of about 0.1 mol/L2 times, washed with an aqueous sodium hydrogencarbonate solution once, washed with a saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness by filtration to give intermediate 16d, which was added with methanol and an aqueous sodium hydrogencarbonate solution, stirred for 2 hours, and filtered to give compound 16 (220 mg, yield 78%). 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.16(s,1H),8.31～8.34(m,1H)，7.96(s,1H),7.57～7.59(m,1H),7.27～7.30(m,2H)，6.68(s,1H),5.00(d,J＝6.4Hz,2H),4.77(d,J＝6.8Hz,2H)。LCMS(ESI)m/z:301.1[M+1] + 。
Example 17
The synthesis of compound 17 is referred to compound 2.
The first step: reaction of starting material S2 with intermediate M2 gave compound 17a (77% yield). MS (ESI) m/z 406.1[ M+1] +.
And a second step of: the hydrolysis method of compound 17a is referred to compound 2a. 203mg of compound 17a was hydrolyzed to obtain 98mg of compound 17 in a yield of 32.4%. 1 H NMR(400MHz,DMSO-d 6 ):δ12.24(s,1H),9.12(d,J＝3.2Hz,1H),7.94(dd,J＝2.4,10.0Hz,1H),7.78(s,1H),7.55(dd,J＝4.8,8.8Hz,1H),7.10(ddd,J＝2.4,8.8,12Hz,1H),2.75(br,2H),1.24～1.27(dd,J＝6.8,4.0Hz,2H),1.04～1.07(dd,J＝6.8,4.0Hz,2H)。MS(ESI)m/z:302.1[M+1] + 。
Example 18
The first step: the synthesis of intermediate 18a was performed in the second and third steps of example 13 in 36% yield.
And a second step of: the synthesis of compound 18 was performed in 51% yield by referring to the fifth step of example 10. 1 H NMR(400MHz,DMSO-d 6 )δ12.18(s,1H),9.13(d,J＝3.2Hz,1H),8.31～8.33(m,1H),7.89(s,1H),7.57～7.59(m,1H),7.25～7.31(m,2H),5.45(s,1H),3.72～3.84(m,4H),2.18～2.25(m,2H),1.75(d,J＝12.4Hz,2H)。LCMS(ESI)m/z:329.1[M+1] + 。
Example 19
The synthesis of compound 19 was carried out according to the method of example 18, whereby compound 19 was obtained by reacting compounds S2 and 18a in a yield of 62%. 1 H NMR(400MHz,DMSO-d 6 )δ12.27(s,1H),9.16(d,J＝3.2Hz,1H),7.99(dd,J＝2.8,9.6Hz,1H),7.91(s,1H),7.60(dd,J＝4.8,8.8Hz,1H),7.15(ddd,J＝2.8,9.2,12.0Hz,1H),5.45(s,1H),3.72～3.84(m,4H),2.18～2.25(m,2H),1.75(d,J＝12.0Hz,2H)。LCMS(ESI)m/z:347.1[M+1] + 。
Example 20
The first step: tetrahydropyrone (10 g,100 mmol) was dissolved in dichloromethane (250 mL) and tert-butylsulfinamide (14.5 g,120 mmol) and tetraisopropyl titanate (56.8 g,200 mmol), N were added at room temperature 2 Reflux overnight under protection, add 300ml of dichloromethane and cold saturated sodium bicarbonate solution with stirring thoroughly, solid formation, celite filtration, filtrate separation, dichloromethane extraction, combination of organic phases, saturated brine wash, drying over magnesium sulfate, filtration concentration to dryness, purification by silica gel column chromatography (PE: ea=10:1-2:1, volume ratio), intermediate 20a (2 g, yield 10%). LCMS (ESI) m/z 204[ M+1 ]] + 。
And a second step of: the synthesis of intermediate 20b is described in the second and third steps of example 13. From 2.02g of intermediate 20a, 1.5g of intermediate 20b was obtained and used directly in the next step. LCMS (ESI) m/z 326[ M+1 ]] + 。
And a third step of: intermediate 20b (0.87 mmol) was dissolved in 10ml dioxane, S1 (177 mg,0.87 mmol) was added, stirred at RT over the weekend, ethyl acetate and sodium bicarbonate saturated solution was addedThe solution was stirred well, extracted, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and purified by column chromatography on silica gel (DCM: meoh=50:1 to 10:1) to give the product compound 20 (62 mg, yield 32%). 1 H NMR:(400MHz,DMSO-d6)δ12.47(s,1H),9.35(d,J＝3.2Hz,1H),8.87(br,3H)8.38(s,1H),8.30～8.33(m,1H),7.57～7.60(m,1H),7.28～7.32(m,2H),3.92～9.96(m,2H),3.45～3.49(m,2H),2.50～2.56(m,2H),2.18～2.25(m,2H)。LCMS:(ESI)m/z:328[M+1] + 。
Example 21
The first step: the method for synthesizing intermediate 21a was carried out with reference to intermediate 20a, and the yield was 21%. LCMS (ESI) m/z 176.1[ M+1 ]] + 。
And a second step of: the method for synthesizing intermediate 21b was carried out with reference to intermediate 20b in 42% yield.
And a third step of: synthesis of Compound 21 referring to Compound 20, compound 21 (46 mg, 18% yield) is obtained from 297mg of intermediate 21b and 177mg of S1. 1 H NMR(400MHz,DMSO-d 6 )δ12.25(s,1H),9.18(d,J＝2.4Hz，1H),8.32～8.34(m,1H)，8.00(s,1H),7.57～7.59(m,1H),7.26～7.31(m,2H),6.68(s,1H),4.95(d,J＝6.4Hz,2H),4.65(d,J＝6.4Hz,2H),2.67(brs,2H)。LCMS(ESI)m/z:300.1[M+1] + 。
Example 22
Compound 8 (31 mg,0.1 mmol) and paraformaldehyde (60 mg,0.2 mmol) were dissolved in 5mL of ethanol/water (v/v=1/1) mixed solvent, sodium borohydride (108 mg,2 mmol) was added, stirred overnight at room temperature, saturated ammonium chloride solution was added, extracted with ethyl acetate (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to 1mL, left stand, filtered, washed with ethyl acetate, and dried to give compound 22 (27 mg, yield 82%). LCMS (ESI) m/z 326.1[ M+1 ]] + 。
Effect examples
Effect example 1: biologically relevant solubility of the Compounds
The human fasting simulated gastric fluid (pH: 1.6,37 ℃) and human fasting simulated intestinal fluid (pH: 6.5,37 ℃) are prepared as dissolution media according to the requirements of pharmacopoeia. In the bio-related solubility measurement, the temperature of the dissolution medium was controlled at 37±0.5 ℃. The biologically relevant solubility measurement followed a shake flask method, which included making a solubility measurement at 24h of dissolution and at least one additional time point thereafter to confirm that the dissolution was equilibrated.
The corresponding solubilities of representative compounds of the invention and compound ITE are shown in table 1.
Table 1: solubility of the respective Compounds
As can be seen from the results in Table 1, representative compounds of the present invention have significantly better solubility relative to compound ITE, both in human fasted simulated gastric fluid (pH: 1.6,37 ℃) and in human fasted simulated intestinal fluid (pH: 6.5,37 ℃).
Effect example 2: determination of metabolic stability of liver microsomes
The in vitro liver microsomal metabolic stability assay was performed on representative compounds of the present invention and compound ITE using liver microsomal metabolic stability assay methods routinely used by those skilled in the art. Microsomes from liver cells are extracted by conventional methods, and the extracted liver microsomes contain a number of enzymes involved in drug metabolism, including cytochrome P450, flavin monooxygenase, carboxylesterase, cyclooxygenase, and the like.
Table 2: hepatic microsomal metabolic stability of Compounds
As can be seen from the results of table 2, the representative compounds of the present invention are less likely to be metabolized by the liver drug metabolizing enzyme system in the liver microsomal metabolic stability assay than the compound ITE, and have higher oral bioavailability and thus will have better drug efficacy.
Effect example 3: aromatic receptor (AhR) agonism assay
AhR agonistic activity of each compound was measured.
Test materials: a human liver cancer cell line HepG2 cell for stably expressing an AhR reporter gene. The reporter vector plasmid contains a firefly Luciferase (Luciferase) gene and a pac gene (puromycin resistance gene) linked to a dioxin-specific genetic response element (DRE, reference fundam. Appl. Toxicol.1996,30 (2), 194-203). The vector plasmid is transfected into HepG2 cells and then screened by puromycin to obtain cells stably expressing the AhR reporter gene.
Table 3 below shows the genetic background of the cell lines and standard compounds used to verify the AhR activity assay.
TABLE 3 Table 3
Treatment of the compound: after the compound is synthesized, 10mM stock solution is prepared by DMSO and stored in a dark place at 4 ℃, and the stock solution is serially diluted to a required concentration by using a cell culture medium when the compound is used.
The method comprises the following steps: specific batches of reporter cells were evaluated using standard compound ITE versus test compound controls.
The data processing method comprises the following steps: microsoft Exel was used to manage, store data, and calculate results, specific methods are referenced J.Biomol. Screen,1999,4 (2), 67-73, which is incorporated herein by reference in its entirety.
The AhR agonist assay comprises the following three steps:
(1) Report cells were resuspended in cell culture medium (MEM; containing 10% heat-inactivated fetal bovine serum) and 100. Mu.L of report cell suspension was added to a 96-well black transparent test plate to allow cells to stand inCulturing in incubator for 24 hr (37deg.C, 5% CO) 2 )。
(2) Before testing, ITE and test compound stock solutions were serially diluted with cell culture medium to 2 times the final concentration of the experiment, respectively, and a set of negative controls was additionally provided to contain DMSO only at the corresponding same concentration. Two replicates were set up for each compound and each compound was set up with a well concentration of 0 (i.e. containing medium only) to determine basal numbers. After 50ul of medium was aspirated from the 96-well plate, it was discarded, and 50ul of 2 x compound dilution was added to give the desired final concentration of compound. The cells were incubated in the incubator for 2-24 hours after compound treatment.
(3) After the incubation is completed, 100. Mu.L/well of luciferase assay reagent is added to the 96-well plate and RLU (relative fluorescence intensity) of each well is determined. RLU mean at 0 concentration per 96 well plate calculate baseline AveRLU Vehicle . RLU from test compounds at different concentrations in experimental groups TestCmpd And baseline AveRLU Vehicle According to formula (1), the activity of AhR under the action of test compounds with different concentrations is calculated, and the activation times are determined. If AhR activation occurs, the activation factor is greater than 1, and if AhR is not activated, the activation factor is equal to 1. If the activation fold is less than 1, this indicates that AhR activity is inhibited. Then the activation fold and the compound concentration are subjected to nonlinear fitting according to the formula (2) to calculate the EC of each compound 50 。
Formula (1)
Formula (2)Where y is the activation fold, x is the compound concentration, a, b are the maximum response and baseline, respectively, and a, b and EC can be calculated by nonlinear fitting 50 . In the actual calculation, if the AhR activity inhibition phenomenon does not occur, b can be directly set to 1.
EC of each compound 50 The values are shown in Table 4, where A represents 0.001. Mu.M < EC 50 Less than or equal to 1.0 mu M, B represents less than EC of 1.0 mu M 50 C represents 10.0 mu M < EC 50 ≤100μM。
Table 4: EC of each compound 50 Value of
From the results of table 4, it can be seen that each of the above compounds can bind to AhR and activate gene expression regulated by AhR. It can thus be demonstrated that the compounds of the invention are capable of modulating AhR activity, acting as AhR agonists. On this basis, those skilled in the art will recognize that these compounds are useful in the treatment of diseases associated with the AhR pathway, including but not limited to tumors.

Claims (10)

1. An indolothiazolidones compound shown in formula (I) and pharmaceutically acceptable salts or solvates or isotopic variants or isomers thereof,
wherein:
y and Z are each independently selected from O or S;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R is 7 Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkoyl, thioalkanoyl, and-S (O) n R 11 (n=0 to 2, r 11 Directly to S), wherein R 11 Selected from the group consisting of hydrogen, amino, hydroxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, thioalkoxy, and halothioalkoxy, wherein R 2 May be further selected from amino protecting groups;
R 8 、R 9 and R is 10 Each independently of the otherIs selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy; or R is 8 、R 9 And R is 10 Together any two or three of these form a 3-to 15-membered monocyclic or bicyclic ring containing 0 to 2 heteroatoms selected from O, N and S, said monocyclic or bicyclic ring being unsubstituted or mono-or polysubstituted by 1 to 3 groups selected from: halogen, amino, hydroxy, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl and haloalkoyl.
2. The indolothiazolidones according to claim 1, wherein:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 Each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, and carbonylalkylamino.
3. The indolothiazolidones according to claim 1, wherein:
wherein R is 8 、R 9 And R is 10 Each independently selected from hydrogen, hydroxy, amino, alkyl, alkylhydroxy, alkoxy, and alkylamino, or R 8 、R 9 And R is 10 Together, any two or three of these form a 3-to 15-membered monocyclic or bicyclic ring containing 0 to 2 heteroatoms selected from O, N and S, said monocyclic or bicyclic ring being unsubstituted or mono-or polysubstituted by 1 to 3 groups selected from alkyl, amino, hydroxy, carbonylalkoxy.
4. An indolothiazolidones according to claim 3, characterized in that:
wherein R is 8 、R 9 And R is 10 Together, any two or three of these form a 3-to 15-membered monocyclic ring containing 0 to 2 heteroatoms selected from O, N and S, said monocyclic ring being unsubstituted or mono-or di-substituted by 1 to 3 groups selected from alkyl, amino, hydroxy, carbonylalkoxy.
5. The indolothiazolidones according to claim 1, wherein:
wherein the method comprises the steps ofIs one of the following groups:
6. the indolothiazolidones according to claim 1, wherein:
wherein the method comprises the steps ofIs one of the following groups:
7. a process for preparing an indolothiazolidone compound according to any one of claims 1-6, comprising the step of reacting compound M with compound S, wherein:
the compound M is:
the compound S is:
wherein X is a leaving group.
8. The method of claim 7, wherein the leaving group is chlorine or bromine.
9. A pharmaceutical composition comprising an indolothiazolidone compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvate or isotopic variant or isomer thereof, and a pharmaceutically acceptable adjuvant.
10. Use of an indolothiazolinone compound according to any of claims 1-6 or a pharmaceutically acceptable salt or solvate or isotopic variant or isomer thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of tumors.
CN202210365683.5A 2022-04-08 2022-04-08 Indole thiazole ketone compound and application thereof Pending CN116925066A (en)

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