CN112812136B - Novel 2, 3-indane derivative compound, preparation method and application - Google Patents

Novel 2, 3-indane derivative compound, preparation method and application Download PDF

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CN112812136B
CN112812136B CN201911117006.6A CN201911117006A CN112812136B CN 112812136 B CN112812136 B CN 112812136B CN 201911117006 A CN201911117006 A CN 201911117006A CN 112812136 B CN112812136 B CN 112812136B
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fluorobenzonitrile
acid
cyano
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CN112812136A (en
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戚祖德
袁胜峰
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Shaoxing Yatai Pharmaceutical Technology Co ltd
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Wuhan Guanggu Asia Pacific Medical Research Institute Co ltd
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Abstract

The invention discloses a novel 2, 3-indane derivative compound, and a preparation method and application thereof. The novel 2, 3-indane derivative compound can be used as an HIF-2 alpha (Hypoxia-Inducible Factors-2 alpha) inhibitor and is used for preparing a medicament for treating and/or preventing HIF-2 alpha-related diseases of mammals.

Description

Novel 2, 3-indane derivative compound, preparation method and application
Technical Field
The invention relates to a novel compound, in particular to a novel 2, 3-indane derivative compound, a preparation method and application.
Background
Renal cell carcinoma, kidney cancer for short, is one of the most fatal tumors of the urinary system and can be divided into three major histological subtypes: clear cell renal cell carcinoma (ccRCC) accounts for 70% of cases; papillary and chromophobe renal cell carcinoma, accounting for 25% of cases; medulla and tumors of the collecting system, account for 5% of cases. These subtypes are caused by distinctly different genetic factors and therefore vary in therapy.
ccRCC is the most common renal malignancy. It is estimated that 6.5 million new renal cancers in the us in 2018 died 1.4 million people; in China, the incidence rate of kidney tumor is 3.8/10 ten thousand, and the number of new patients is about 6.7 ten thousand every year, which is the country with the highest global incidence and mortality. Statistics of cancer profiles in China show that kidney morbidity has increased over the past 20 years, at an average rate of 6.5% per year, beyond the first bladder cancer in urinary tumor-related deaths. Renal cancer accounts for 80-90% of kidney malignant tumor, and can be found in people of all ages, with high incidence age mainly 50-70 years old. Because the position of the kidney is hidden, and no obvious clinical symptoms exist in the early stage of the kidney cancer, most of the patients with the kidney cancer have metastasis at the time of diagnosis, the prognosis of the kidney cancer is poor once the metastasis (late stage) occurs, and the 5-year survival rate is less than 10%. And is not sensitive to radiotherapy and chemotherapy unlike prostate cancer, bladder cancer and the like, which also becomes the biggest challenge of the previous renal cancer treatment. Therefore, finding and confirming a new target for the action of a specific drug for treating kidney cancer is a very urgent and significant work.
HIF-2 α (also known as hypoxia inducible factor 2 α) is a key factor in the progression of renal cancer. Because HIF is a transcription factor that responds to hypoxic stress, the alpha fragment is present in lower concentrations in normal nutrient environments, because proteins are rapidly degraded by the ubiquitin system as recognized by the E3 ligase after hydroxylation. Degradation rates decrease in hypoxic environments, leading to increased HIF function and increased expression of many proteins. This regulatory mechanism is hijacked in some tumors to increase microangiogenesis, promote cell proliferation, and differentiation. The most significant of these are RCCs, 90% of which lack the E3 ligase of VHL (Von Hippel-Lindau, a tumor suppressor), leading to uncontrolled HIF degradation. Thus, naturally some VHL-deficient people are at higher risk of renal cancer than normal people, and this type of renal cancer is known as Von Hippel-Lindau Syndrome (VHL Syndrome). HIF-2 alpha inhibitors can treat/prevent diseases caused by HIF-2 alpha overexpression, such as renal cell carcinoma.
The currently known HIF-2 alpha inhibitors are PT-2977 of Musacodont, and are currently in phase II clinical research, so that new HIF-2 alpha inhibitors are urgently needed.
Figure BDA0002274353350000021
Disclosure of Invention
The invention aims to provide a novel 2, 3-indane derivative compound, and a preparation method and application thereof. The novel 2, 3-indane derivative compound can be used as an HIF-2 alpha (Hypoxia-Inducible Factors-2 alpha) inhibitor and a medicament for treating and/or preventing HIF-2 alpha-related diseases of mammals.
The present invention includes the following.
A compound of the general formula (I),
Figure BDA0002274353350000022
wherein:
RFselected from hydrogen or halogen;
x is selected from CH or nitrogen atom;
RArselected from aryl with or without substituent having 6-14 carbon atoms, heterocyclic aryl with or without substituent having 6-14 carbon atoms, wherein the substituent is selected from fluorine, chlorine, bromine, iodine,Cyano, amino, hydroxy, C1-C4 alkyl and C1-C4 alkoxy;
w is selected from the following groups:
Figure BDA0002274353350000031
wherein denotes the point of attachment of the group to the remainder of the molecule,
R1and R2Represents cyano, trifluoromethyl, methoxy, -NH2，-NHCH3，-N(CH3)2C1-C4 alkyl, C1-C4 alkoxy; or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
Preferably, in the compounds of formula (I), RArSelected from phenyl or pyridine. Preferably, in the compounds of formula (I), W is selected from
Figure BDA0002274353350000032
Wherein R is1,R2Selected from cyano, trifluoromethyl, methoxy, C1-C4 alkyl and C1-C4 alkoxy and R1And R2Not being methyl at the same time; or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
Preferably, in the compounds of formula (I), W is selected from
Figure BDA0002274353350000033
Wherein R is1,R2Selected from cyano, trifluoromethyl, methoxy, -NH2，-NHCH3，-N(CH3)2C1-C4 alkyl, C1-C4 alkoxy; or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
Preferably, in the compounds of formula (I), W is selected from
Figure BDA0002274353350000034
Wherein R is1,R2Selected from cyano, trifluoromethyl, methoxy, -NH2，-NHCH3，-N(CH3)2C1-C4 alkyl, C1-C4 alkoxy; or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
Preferably, the compounds of the invention are selected from: 3- ((((1S, 2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy ] -5-fluorobenzonitrile, alpha-hydroxy-2, alpha-hydroxy-3-methyl-ethyl-1H-inden-4-yl) oxy-phenyl,
3- (((((5R, 6S,7S) -1- ((dimethyl (oxo) -6-sulfinylimino) amino) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopentyl ] [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile, and pharmaceutically acceptable salts thereof,
3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- (1-phosphinoxide-1-yl) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile,
(1R,2S,3S) -7- (3-cyano-5-fluorophenoxy) -1, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinic acid methyl ester,
3- (((5R,6S,7S) -1- (cyclopropyl (methyl) phosphoryl) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile, salts thereof, and pharmaceutically acceptable salts thereof,
Cyclopropyl ((1R,2S,3S) -1, 2-difluoro-7- ((5-fluoropyridin-3-yl) oxy) -3-hydroxy-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphine oxide,
3- ((((1S, 2S, 3R) -7- ((dimethyl (oxo) -6-sulfinylimino) amino ] -2, 3-difluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile, a salt thereof, a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable salt thereof,
3- ((((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- (((methyl (oxo) (trifluoromethyl) -6-sulfinyl ] amino ] -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile, and pharmaceutically acceptable salts thereof,
3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- ((1-oxotetrahydro-6-thiophen-1-ylidene)) amino) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile,
3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- ((iminodimethyl-6-sulfinyl) amino) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile,
3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- ((imino (methyl) trifluoromethyl) -6-sulfinyl) amino) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile.
Further, the present invention also includes an N-oxide, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug of any of the above compounds.
Further, the present invention also includes a process for the preparation of a compound according to any one of the above, said process selected from one of the following routes:
the first synthetic route is as follows:
Figure BDA0002274353350000051
the second synthetic route is as follows:
Figure BDA0002274353350000052
further, the present invention also includes a pharmaceutical composition comprising a compound of any of the above or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers.
Further, the present invention also includes the use of a compound described in any one of the above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of a HIF-2 α -associated disease or condition in a mammal.
Preferably, the HIF-2 α -associated disease or condition is selected from the group consisting of cancer, inflammation, metabolic disease; the cancer comprises skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck tumor; the inflammation comprises pneumonia, enteritis, nephritis, arthritis and trauma infection; the metabolic diseases comprise obesity, dyslipidemia and hyperlipidemia. In particular, the HIF-2 α -associated disease or disorder is, for example, renal cell carcinoma.
The terms mentioned herein have the following meanings:
the terms "halogen atom", "halo- (halo)" are to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
The term "C1-C4 alkyl" is understood to mean a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1,2, 3, 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
The term "C1-C4-alkoxy" is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical of the formula-O-alkyl, wherein the term "alkyl" is as defined above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, or isomers thereof.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a group selected from the group indicated, with the proviso that: not exceeding the existing normal valency of the designated atom, and which substitution results in a stable compound. Substituents and/or variables can be combined as long as such combination can result in a stable compound.
The term "optionally substituted" means optionally substituted with a specified group, radical or moiety.
Ring system substitution refers to a substituent linked to an aromatic or non-aromatic ring system that, for example, replaces an available hydrogen on the ring system.
The compounds of the present invention may contain an asymmetric sulfur atom, for example, an asymmetric sulfoxide or sulfoximine of the following structure, or the like.
Preferred compounds are those that result in more desirable biological activity. Isolated, purified, or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.
To limit the isomers to different types from each other, reference is made to IUPAC Rules Section E (Pure apple Chem 45,11-30,1976)
The present invention includes all possible stereoisomers of the compounds of the invention, which may be single stereoisomers, or any mixture of said stereoisomers in any proportion, such as the R or S isomers, or the E or Z isomers. Separation of individual stereoisomers of the compounds of the invention, for example, separation of individual enantiomers or individual diastereomers, may be achieved by any suitable art-described method, for example, chromatography, particularly chiral chromatography.
The compounds of the invention may exist in the form of N-oxides, which are defined as: at least one nitrogen of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.
The invention also relates to useful forms of the compounds disclosed herein, e.g., metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.
The compounds of the invention may exist in the form of hydrates or solvates, wherein the compounds of the invention contain polar solvents, in particular water, methanol or ethanol, for example, as structural elements of the crystal lattice of the compounds. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, such as hydrates, there may be one-half, one-and-one-half, two, three, four, five solvent compounds or hydrates, respectively, and so on. The present invention includes all such hydrates or solvates.
Further, the compounds of the present invention may exist in free form, e.g., as a free base or free acid or zwitterion, or may exist in salt form. The salt may be any salt, organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt, which is generally used pharmaceutically.
Pharmaceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of the compounds of the invention which carry a nitrogen atom in the chain or ring, for example, sufficiently basic acid addition salts of the compounds of the invention, for example, acid addition salts with inorganic acids, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, phosphoric acid or nitric acid, or acid addition salts with organic acids, for example formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanoic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, Pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.
In the context of the present invention, the term "treating" includes inhibiting, delaying, examining, alleviating, attenuating, limiting, reducing, suppressing, counteracting, or curing a disease (the term "disease" includes, but is not limited to, a condition, disorder, loss, or health problem), or the development, progression, or progression of such a condition and/or symptoms of such a condition, the term "therapy" being understood herein as synonymous with the term "treating".
The terms "prevent", "preventing" or "arresting" are used synonymously in the context of the present invention and refer to avoiding or reducing the risk of infection, experiencing, suffering from or having a disease or the development or progression of symptoms of this and/or this state.
Treatment or prevention of a disease may be partial or complete.
Advantageous effects
The compound has excellent activity of inhibiting HIF-2 alpha (Hypoxia-Inducible Factors-2 alpha), can be used as an HIF-2 alpha inhibitor, and is a medicament for treating and/or preventing HIF-2 alpha-related diseases of mammals.
Detailed Description
The technical solutions of the present invention will be described in detail with reference to specific examples, but those skilled in the art will understand that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Preparation of the Compounds
Example 1
Preparation of 3- ((((1S, 2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy ] -5-fluorobenzonitrile (Compound 1)
Figure BDA0002274353350000091
(or
Figure BDA0002274353350000092
)
Step a: (7- (3-cyano-5-fluorophenoxy) -3-oxo-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinic acid ethyl ester (1-1)
Figure BDA0002274353350000093
Under nitrogen protection, 30mg (0.04mmol) of [1, 1' -bis (diphenylphosphino) ferrocene]Complex of palladium (II) dichloride and dichloromethane (1:1, Pd (dppf) Cl2) And 165mg (1.5mmol) triethylamine were added to a suspension of (350mg,1.0mmol)3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile, (130mg,1.2mmol) ethyl methylphosphinate in 5mL pure dimethylformamide. The reaction mixture was stirred at 110 ℃ for 16 h, monitored by TLC plates, and stopped after the starting material had reacted completely, cooled to room temperature, poured into water, and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol 50:1) (vol.) to give ethyl (7- (3-cyano-5-fluorophenoxy) -3-oxo-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinate (200mg, 53% yield).
LCMS:ESI(+)(M+H)m/z＝374.2
Step b: (4- (3-cyano-5-fluorophenoxy) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -7-yl) (methyl) phosphinic acid ethyl ester (1-2)
Figure BDA0002274353350000101
To a solution of ethyl (7- (3-cyano-5-fluorophenoxy) -3-oxo-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinate and (260mg,5.2mmol) ethylene glycol in 10mL toluene at room temperature was added a catalytic amount of (24mg,0.14mmol) TsOH. After refluxing the mixture at 120 ℃ for 16 hours, TLC spot plate was used to monitor the complete reaction of the starting materials, cooled to room temperature, quenched by addition of water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol 100:1) (vol.) to give ethyl (4- (3-cyano-5-fluorophenoxy) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -7-yl) (methyl) phosphinate (400mg, yield 71%).
LCMS:ESI(+)(M+H)m/z＝418
Step c: 3- ((7- (cyclopropyl (methyl) phosphoryl) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (1-3)
Figure BDA0002274353350000111
At room temperature, (0.73g,3.5mmol) PCl5To (1.5g,3.5mmol) of (4- (3-cyano-5-fluorophenoxy) -2, 3-dihydrospiro [ indene-1, 2' - [1,3]]Dioxolanes]-7-yl) (methyl) phosphinic acid ethyl ester and 30mL of 1, 2-dichloroethane, the temperature of the mixture being kept at not more than 40 ℃ during the dropwise addition. After the addition was complete, stirring was continued for 16 hours at 25 ℃. The mixed solution is concentrated in vacuum to obtain oily substance, 20mL of ethyl acetate is added, the organic phase is washed with water, the sodium bicarbonate and the saturated sodium chloride are washed, the mixture is dried by anhydrous sodium sulfate, and the oily substance 4- (3-cyano-5-fluorophenoxy) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] is obtained by vacuum concentration]Dioxolanes]-7-yl) (methyl) phosphinic acid chloride.
At 0 deg.C, (2mL,3.75mmol,2M in THF) cyclopropyl magnesium bromide solution was added to (1.0g,2.5mmol)4- (3-cyano-5-fluorophenoxy) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -7-yl) (methyl) phosphinic chloride, and during the addition, the temperature was controlled not to exceed 0 deg.C. After the addition, stirring was continued at 25 ℃ for 16 hours, and the reaction was quenched with ammonium chloride solution. (20 mL. times.3) was extracted with ethyl acetate, the organic phase was washed with sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the crude product was purified by column chromatography (dichloromethane: methanol 50:1) (vol.) to give 3- ((7- (cyclopropyl (methyl) phosphoryl) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (600mg, 42% yield).
LCMS:ESI(+)(M+H)m/z＝414.2
1H NMR(400MHz,DMSO-d6):δ8.04(m,1H),7.7(dd,1H),7.53(m,2H),7.43(d,1H),3.03(m,2H),2.74(m,2H),2.35(m,1H),2.3(d,2H),2.2(d,2H),1.76(s,3H)
Step d:3- ((3-bromo-7- (cyclopropyl (methyl) phosphoryl) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (1-4)
Figure BDA0002274353350000121
NBS (0.707g,3.97mmol) and AIBN (0.006g,0.04mmol) were added to a mixture of 3- ((7- (cyclopropyl (methyl) phosphoryl) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (1.5g,3.61mmol) and DCE (24 mL) as a solvent at room temperature, and the reaction mixture was stirred and heated to 80 ℃ for 30 minutes. After cooling, the reaction was diluted with DCM, washed with saturated sodium bicarbonate and sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol 100:1, 50:1) (vol.) to give 3- ((3-bromo-7- (cyclopropyl (methyl) phosphoryl) -2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (1.1g, yield 61%)
LCMS:ESI(+)(M+H)m/z＝492.2
Step e: 3- ((7- (cyclopropyl (methyl) phosphoryl) -3-oxo-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (1-5)
Figure BDA0002274353350000122
At room temperature, (1.05g,3.8mmol) Ag2CO3To (1.25g,2.54mmol)3- ((3-bromo-7- (cyclopropyl (methyl) phosphoryl) -2, 3-dihydrospiro [ indene-1, 2' - [1,3]]Dioxolanes]-4-yl) oxy) -5-fluorobenzonitrile in a solution of 21mL ethylene glycol dimethyl ether (DME) and 7mL water. After the reaction mixture was reacted at 25 ℃ for 16 hours, it was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. After the crude product was dissolved in 25mL of dichloromethane, DMP (1.61g,3.8mmol) was added and the mixture was stirred at room temperature for 2 hours, the reaction was diluted with ethyl acetate, quenched with saturated sodium bicarbonate and the aqueous solution was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol 100:1, 50:1) (vol/vol) to give 3- ((7- (cyclopropyl (methyl) phosphoryl) -3-oxo-2, 3-dihydrospiro [ indene-1, 2' - [1,3]]Dioxolanes]-4-yl) oxy) -5-fluorobenzonitrile (0.4g, yield 36%)
LCMS:ESI(+)(M+H)m/z＝428.1
Step f: 3- ((7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-oxo-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (1-6)
Figure BDA0002274353350000131
Under the protection of nitrogen, (1.1g,2.5mmol)3- ((7- (cyclopropyl (methyl) phosphoryl) -3-oxo-2, 3-dihydrospiro [ indene-1, 2' - [1,3]]Dioxolanes]-4-yl) oxy) -5-fluorobenzonitrile was added to a solution of triethylamine (2.1mL,15mmol) in 25mL of dichloromethane. After the mixture was cooled to 0 deg.C, (0.85mL,3.7mmol) [ tert-butyl (dimethyl) silyl ]]Triflic acid, after addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. Diluting with ethyl acetate, washing the organic phase with water and saturated sodium chloride, and removing waterDried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in 25mL acetonitrile and added (1.14g,3.2mmol)
Figure BDA0002274353350000132
After stirring the reaction mixture at room temperature for 1 hour, the reaction mixture was concentrated in vacuo. The crude product was diluted with dichloromethane, washed with water, saturated sodium chloride, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate: petroleum ether; 5:1, 1:1) (volume ratio) to give 3- ((7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-oxo-2, 3-dihydrospiro [ indene-1, 2' - [1,3]]Dioxolanes]-4-yl) oxy) -5-fluorobenzonitrile (0.6g, 54% yield) LCMS ESI (+) (M + H) M/z 446.1
Step g: 3- ((((2R, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-hydroxy-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (1-7)
Figure BDA0002274353350000141
To a solution of 10mL of dichloromethane was added (220mg,0.5mmol)3- ((7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-oxo-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile, cooled to 0 ℃ and the mixture was purged with nitrogen for 5 minutes. During this procedure, formic acid (60. mu.L, 1.5mmol), (105. mu.L, 0.75mmol) triethylamine was added stepwise. After the nitrogen gas blowing was completed, (10mg,0.015mmol) (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride was added to the above reaction solution, and the system was cooled to 0 ℃ and reacted at this temperature for 16 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (ethyl acetate: petroleum ether; 5:1, 1:1) (vol.) to give 3- (((2R, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-hydroxy-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile as a solid (120mg, 54% yield).
LCMS:ESI(+)(M+H)m/z＝448.2
Step h: 3- ((((2R, 3S) -7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-hydroxy-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (1-8)
Figure BDA0002274353350000142
(230mg,0.5mmol)3- ((((2R, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-hydroxy-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile at 25 ℃ was added to a solution of (510mg,1.93mmol) triphenylphosphine and (330mg,2.0mmol) 4-nitrobenzoic acid in 10mL anhydrous tetrahydrofuran, under nitrogen, diethyl azodicarboxylate was added (380. mu.L, 1.9mmol) and the reaction mixture was stirred at 25 ℃ for 2 hours, filtered, the cake was rinsed twice with ethyl acetate, the organic phase was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the crude product was purified by column chromatography, the excess triphenylphosphine and triphenoxyphos were removed from the reaction, the intermediate obtained was concentrated and dissolved in 10mL tetrahydrofuran, an aqueous solution of hydrated lithium hydroxide (20mg, 0.5mmol) dissolved in 2.5mL of water was added. After stirring at 25 ℃ for 1 hour, an additional portion (10mg,0.25mmol) of aqueous solution of hydrated lithium hydroxide dissolved in 1.2mL of water was added and stirred for 1 hour. The reaction was monitored by TLC, and after completion of the reaction, 2mL of saturated ammonium chloride solution was added, extracted with ethyl acetate, and the organic phase was washed with sodium bicarbonate and saturated sodium chloride, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (ethyl acetate: petroleum ether; 5:1, 1:1) (vol.) to give solid 3- (((2R, 3S) -7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-hydroxy-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (80mg, 35% yield)
LCMS:ESI(+)(M+H)m/z＝448
Step i: 3- ((((2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (1-9)
Figure BDA0002274353350000151
(100mg,0.22mmol)3- ((((2R, 3S) -7- (cyclopropyl (methyl) phosphoryl) -2-fluoro-3-hydroxy-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile was dissolved in 8mL dichloromethane under nitrogen protection, after the system was cooled to 0 ℃, after slow addition (90. mu.L, 0.67mmol) of diethylaminosulfur trifluoride (DAST), the reaction was stirred at room temperature for 3 hours, 2mL sodium bicarbonate solution was carefully added to bring the solution to basic conditions, extraction was performed with dichloromethane (2X 10mL), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the crude product was purified with (ethyl acetate: petroleum ether; 5:1, 1:1), solid 3- ((((2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile was obtained (65mg, 65% yield).
LCMS:ESI(+)(M+H)m/z＝450.2
Step j: 3- ((((1S, 2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-1-hydroxy-2, 3-dihydro-1H-indan-4-yl) oxy ] -5-fluorobenzonitrile (1)
Figure BDA0002274353350000161
(65mg,0.16mmol) of 3- ((((2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile was added to 5mL of dichloromethane at room temperature, the mixture was cooled to 0 ℃ and 70% aqueous perchloric acid was slowly added thereto, the reaction system was warmed to 50 ℃ and reacted for 3 hours, monitored by TLC, after completion of the reaction of the starting materials, cooled to 0 ℃ and neutralized with 10mL of aqueous sodium bicarbonate, dichloromethane (3X 10mL) was extracted, the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, concentrated in vacuo, the crude product was dissolved in 10mL of methanol, 10mg of the above solution was added, 0.25mmol) of NaBH4, stirred at room temperature for 30 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 10mL), the organic phase washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, concentrated in vacuo, and the crude product purified with (ethyl acetate: petroleum ether; 5:1, 1:1) to give 3- (((((1S, 2S, 3R) -7- (cyclopropyl (methyl) phosphoryl) -2, 3-difluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy ] -5-fluorobenzonitrile (20mg, 30% yield) as a solid.
LCMS：ESI(+)(M+H)m/z＝408.2
1HNMR(400MHz,CDCl3):δ7.92(d,1H),7.68(d,1H),7.45(dd,1H),7.09(d,1H),6.76(d,1H),6.09-5.91(m,1H),5.87-5.80(m,1H),5.25-5.05(m,1H),2.95(d,1H),2.2(d,2H),2.1(d,2H),1.79(s,3H).
Example 2
Preparation of 3- ((((5R, 6S,7S) -1- ((dimethyl (oxo) -6-sulfinylimino) amino) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile (Compound 2)
Figure BDA0002274353350000171
Step a:
3- ((1-bromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (2-1)
Figure BDA0002274353350000172
The method comprises the following steps:
17.9g (0.288mol) of ethylene glycol, 1.49g (0.0086mol) of p-methylbenzenesulfonic acid and 10g (0.0288mol) of 3- ((1-bromo-7-oxo-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile (0.0288mol) were added to 30mL of toluene, refluxed at elevated temperature for 12 hours, cooled to room temperature, diluted with ethyl acetate, the organic layer was washed with 5% of an anhydrous sodium bicarbonate solution and water, respectively, dried over sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol ═ 20:1 to 40:1) to give 3- ((1-bromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (9.0g, yield: 80%)
LCMS:ESI(+)(M+H)m/z＝391.2，393.1
The method 2 comprises the following steps:
under the protection of nitrogen, 10g (28.8mmol) of 3- ((1-bromo-7-oxo-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile and 8.3g (40.4mmol) of 1, 2-bis (trimethylsiloxy) ethane are dissolved in 100ml of dichloromethane, 2.04g (9.23mmol) of trimethylsilyl trifluoromethanesulfonate is added dropwise when the temperature is reduced to-78 ℃, after the dropwise addition is finished, the temperature is naturally raised to room temperature for reaction for 4.5 hours, triethylamine is added dropwise for quenching reaction, dichloromethane is concentrated under reduced pressure, ethyl acetate is used for dilution, a saturated sodium chloride solution is used for washing, an organic layer is concentrated to obtain a crude product, the crude product is purified through dichloromethane (dichloromethane: methanol: 20:1-40:1) to obtain 3- ((1-bromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (6.7g, yield: 60%)
LCMS:ESI(+)(M+H)m/z＝391.2，393.1
Step b: 3- ((1, 5-dibromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (2-2)
Figure BDA0002274353350000181
Under the protection of nitrogen, (6g,15.3mmol)3- ((1-bromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile, 0.25g (1.53mmol) azobisisobutyronitrile, 1.85g (45.9mmol) magnesium oxide, 3.54g (19.9mmol) N-bromosuccinimide and 150ml 1, 2-dichloroethane are heated, refluxed for 3h, supplemented with 0.25g (1.53mmol) azobisbutyronitrile and 3.54g (19.9mmol) N-bromosuccinimide, stirred for 1.5h, the reaction solution is naturally cooled to room temperature overnight, the reaction solution is filtered, the filter cake is washed with dichloromethane, the filtrates are combined, 50ml of a saturated sodium bicarbonate solution is added to the filtrate, stirred for 30 min, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane: methanol 20:1-40:1) to give 3- ((1, 5-dibromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (3.5g, yield: 49%)
LCMS:ESI(+)(M+H)m/z＝469,471,473
Step c: 3- ((1-bromo-7-oxo-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile 3- (((1-bromo-5-oxo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (2-3)
Figure BDA0002274353350000191
Adding 3.69g (30mmol) of silver carbonate into a 1, 2-dichloroethane/water (37ml/7ml) solution of 3- ((1, 5-dibromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile at room temperature, heating to reflux and stirring for reaction for 12 hours, cooling to room temperature, diluting the reaction solution with 20ml of ethyl acetate, filtering, separating an organic phase from the filtrate, concentrating to obtain a yellow semisolid product, dissolving the crude product in 40ml of dichloromethane again, adding 3.8g (9.0mmol) of Dess-Martin reagent, stirring at room temperature for reaction for 1.5 hours, adding 10ml of saturated sodium thiosulfate solution and 10ml of saturated sodium bicarbonate solution dropwise into the reaction solution, continuing stirring for 10 minutes, separating to obtain a lower organic layer, concentrating, and purifying by column chromatography to obtain 3- ((1-bromo-7-oxo-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile 3- (((1-bromo-5-oxo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (1.1g, yield 36%)
LCMS:ESI(+)(M+H)m/z＝405,407
Step d 3- ((1-bromo-6-fluoro-5-oxo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (2-4)
Figure BDA0002274353350000192
Dissolving 1.1g (2.7mmol) of 3- ((1-bromo-7-oxo-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile 3- (((1-bromo-5-oxo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile and 1.36g (13.5mmol) of triethylamine in 30ml of dichloromethane, cooling to 0 ℃ in an ice bath, dropwise adding 2.85g (10.8mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate at a temperature of not more than 5 ℃, keeping the temperature and stirring for 30 minutes after dropwise adding, naturally heating to room temperature and stirring for 5 hours, pouring the reaction solution into 20ml of a saturated aqueous sodium bicarbonate solution, stirring for 10 min, separating a dichloromethane layer from the reaction liquid, extracting an aqueous phase with dichloromethane 15ml x 2, combining organic phases, washing with brine, drying with anhydrous sodium sulfate, concentrating, drawing dry with an oil pump, dissolving the obtained product in 10ml acetonitrile, dropwise adding 0.96g (2.7mmol) of a fluorine reagent at room temperature, continuing stirring for 3h after the dropwise adding is finished, adding water for 30ml to quench the reaction, extracting and separating with 50ml of ethyl acetate, washing the organic phase with brine, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the product, namely 3- ((1-bromo-6-fluoro-5-oxo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (0.82g, yield of 72%)
LCMS:ESI(+)(M+H)m/z＝423,425
Step f: 3- (((((5R, 6R) -1-bromo-6-fluoro-5-hydroxy-5, 6-dihydrospiro ] [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (2-5)
Figure BDA0002274353350000201
Under the protection of nitrogen, 0.82g (1.9mmol) of 3- ((1-bromo-6-fluoro-5-oxo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile is dissolved in 15ml of dichloromethane, the temperature is reduced to 0 ℃,0.14 g (2.9mmol) of formic acid is added dropwise, 24mg (0.038mmol) of (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride is added with stirring, the mixture is kept at the constant temperature and stirred overnight, the reaction solution is decompressed and concentrated, and purified by column chromatography to obtain 3- (((((5R, 6R) -1-bromo-6-fluoro-5-hydroxy-5, 6-Dihydroppiro ] [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile (0.74g, yield 90%)
LCMS:ESI(+)(M+H)m/z＝425,427
Step g: (5S, 6R) -1-bromo-4- (3-cyano-5-fluorophenoxy) -6-fluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -5-yl 4-nitrobenzoic acid methyl ester (2-6)
Figure BDA0002274353350000211
Under the protection of nitrogen, 0.74g (1.7mmol) of 3- ((((((5R, 6R) -1-bromo-6-fluoro-5-hydroxy-5, 6-dihydrospiro ] [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile, 1.78g (6.8mmol) of triphenylphosphine and 1.14g (6.8mmol) of 4-nitrobenzoic acid are dissolved in dichloromethane, the temperature is reduced to 0 ℃, 1.37g (6.8mmol) of diisopropyl azodicarboxylate is added dropwise, the mixture is naturally heated to room temperature and stirred for reaction for 2 hours, the filter cake is filtered, the filter cake is washed by ethyl acetate, the filtrate is combined and purified by column chromatography after concentration to obtain (5S, 6R) -1-bromo-4- (3-cyano-5-fluorophenoxy) -6-fluoro-5, 6-Dihydropiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -5-yl 4-nitrobenzoic acid methyl ester (0.74g, yield: 76%)
LCMS:ESI(+)(M+H)m/z＝574,576
Step j: 3- (((5S, 6R) -1-bromo-6-fluoro-5-hydroxy-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan-4-yl) oxy) -5-fluorobenzonitrile (2-7)
Figure BDA0002274353350000212
0.74g (1.3mmol) of (5S, 6R) -1-bromo-4- (3-cyano-5-fluorophenoxy) -6-fluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -5-yl 4-nitrobenzoic acid methyl ester is dissolved in 10ml of tetrahydrofuran, the temperature is reduced to 0 ℃, lithium hydroxide aqueous solution is dripped under stirring (46.5mg of lithium hydroxide is dissolved in 6ml of water), after the dripping is finished, the temperature is kept and the stirring is carried out until the TLC monitoring reaction is completed, 20ml of water is added for dilution, 30ml of ethyl acetate is used for extraction, brine is used for washing, organic phase is concentrated and separated by column chromatography to obtain 3- (((5S, 6R) -1-bromo-6-fluoro-5-hydroxy-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] Dioxolan-4-yl) oxy) -5-fluorobenzonitrile (0.46g, yield 84%)
LCMS:ESI(+)(M+H)m/z＝425,427
Step k: 3- ((5R, 6S) -1-bromo-5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (2-8)
Figure BDA0002274353350000221
Dissolving 0.46g (1.1mmol) of 3- (((5S, 6R) -1-bromo-6-fluoro-5-hydroxy-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan-4-yl) oxy) -5-fluorobenzonitrile in 15mL of dichloromethane, dropwise adding 0.35g (2.2mmol) of diethylaminosulfur trifluoride at 25 ℃, stirring and reacting at the temperature for 30 minutes, quenching the reaction solution with 5mL of saturated sodium bicarbonate solution and stirring for 30 minutes, supplementing 30mL of dichloromethane and 15mL of water, extracting and separating the solution, washing the organic layer with 15mL of saturated saline, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column separation to obtain 3- ((5R, 6S) -1-bromo-5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (0.31g, yield: 65%)
LCMS:ESI(+)(M+H)m/z＝427,429
Step l: 3- ((5R, 6S) -1- ((dimethyl (oxo) -l 6-sulfinyl) amino)) -5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (2-9)
Figure BDA0002274353350000222
0.31g (0.72mmol) of 3- ((5R, 6S) -1-bromo-5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile, 86mg (0.93mmol) of dimethylsulfinimide, 0.05g (0.05mmol) of Pd2(dba)3, 0.04g (0.14mmol) of John Phos and 0.1g (1.0mmol) of sodium tert-butoxide are dissolved in 10ml of dioxane, heated to 80 ℃ for reaction for 4.5h, cooled to room temperature, diluted with 20ml of ethyl acetate and 10ml of water, extracted and separated, the aqueous phase is extracted once with 20ml of ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and purified by column chromatography after concentration to give the product 3- ((5R, 6S) -1 dimethyl (oxo) -6-sulfinyl) amino)) -5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile (0.27g, yield 85%)
LCMS:ESI(+)(M+H)m/z＝440.2
Step m: 3- ((((5R, 6S,7S) -1- ((dimethyl (oxo) -6-sulfinylimino) amino) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile (2)
Figure BDA0002274353350000231
Adding 0.27g (0.61mmol) of 3- ((5R, 6S) -1- ((dimethyl (oxo) -6-sulfino) amino)) -5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolane ] -4-yl) oxy) -5-fluorobenzonitrile into 15ml of dichloromethane, cooling to 0 ℃, slowly dropwise adding 3ml of 70% perchloric acid aqueous solution, heating to 40 ℃, stirring for 3 hours, cooling to 0 ℃, dropwise adding 10ml of saturated sodium bicarbonate aqueous solution, adding 20ml of dichloromethane into the reaction mixed solution, performing liquid separation extraction, concentrating an organic phase, and purifying by column chromatography to obtain a product 3- ((((5R, 6S,7S) -1- ((dimethyl (oxo) -6-sulfinyl imino) amino) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile (0.16g, yield 68%)
LCMS:ESI(+)(M+H)m/z＝398.2
1HNMR(400MHz,CDCl3):δ8.1(s,1H),7.45(dd,1H),7.09(d,1H),6.76(d,1H),6.09-5.91(m,1H),5.87-5.80(m,1H),5.25-5.05(m,1H),2.4(s,6H).
Example 3
Preparation of 3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- (1-phosphino-1-yl) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile (Compound 3)
Figure BDA0002274353350000241
The same operation as in example 1 was performed except for replacing 3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile in step a with 3-fluoro-5- ((7- (1-phosphinyl oxide-1-yl) -1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile, and omitting the reaction of the substrate with methyl grignard reagent in step c, to obtain compound 3.
EXAMPLE 4 preparation of methyl ((1R,2S,3S) -7- (3-cyano-5-fluorophenoxy) -1, 2-difluoro-3-hydroxy-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinate (Compound 4)
Figure BDA0002274353350000242
The same procedures as in example 1 were repeated except for replacing 3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile in step a with methyl (7- (3-cyano-5-fluorophenoxy) -3-oxo-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinate and omitting the reaction of the substrate with the methyl formatting reagent in step c to obtain compound 4.
Example 5
Preparation of 3- (((5R,6S,7S) -1- (cyclopropyl (methyl) phosphoryl) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile (Compound 5)
Figure BDA0002274353350000251
The same procedure as the two synthetic routes of example 2 was followed, except that 3- ((((5R, 6S) -1- ((dimethyl (oxo) -6-sulfinyl ] amino) amino ] -5, 6-difluoro-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2' - [1,3] dioxolan-4-yl) oxy) -5-fluorobenzonitrile in step I was replaced with 3- ((((5R, 6S,7S) -1- (cyclopropyl (methyl) phosphoryl) -5, 6-difluoro-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ c ] pyridin-4-yl) oxy) -5-fluorobenzonitrile, compound 5 is obtained.
Example 6 preparation of cyclopropyl ((1R,2S,3S) -1, 2-difluoro-7- ((5-fluoropyridin-3-yl) oxy) -3-hydroxy-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphine oxide (Compound 6)
Figure BDA0002274353350000252
The same procedures used in example 1 except for replacing ethyl (7- (3-cyano-5-fluorophenoxy) -3-oxo-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinate in step a by ethyl (7- ((5-cyanopyridin-3-yl) oxy) -3-oxo-2, 3-dihydro-1H-inden-4-yl) (methyl) phosphinate gave compound 6.
Example 7
Preparation of 3- ((((1S, 2S, 3R) -7- ((dimethyl (oxo) -6-sulfinylimino) amino ] -2, 3-difluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile (Compound 7)
Figure BDA0002274353350000261
In the same manner as in example 2 except for replacing 3- ((1-bromo-5, 6-dihydrospiro [ cyclopenta [ c ] pyridine-7, 2'- [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile in step a with 3- ((7-bromo-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dioxolan ] -4-yl) oxy) -5-fluorobenzonitrile and replacing pyridine in the pyridine derivative in the remaining steps with benzene, compound 7 was obtained.
Example 8
Preparation of 3- ((((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- (((methyl (oxo) (trifluoromethyl) -6-sulfinyl ] amino ] -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile (Compound 8)
Figure BDA0002274353350000262
The same procedures as in example 1 were followed except for replacing 3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile in step a with 3-fluoro-5- ((7- ((methyl (oxo) (trifluoromethyl) -6-sulfinylimino) amino) -1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile to give compound 8.
Example 9
Preparation of 3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- ((1-oxidehydro-6-thiophen-1-ylidene)) amino) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile (Compound 9)
Figure BDA0002274353350000271
The same procedures as in example 1 were repeated except for replacing 3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile in step a with 3-fluoro-5- ((7- (((1-oxotetrahydro-6-thiophen-1-yl) amino) -1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile to give compound 9.
Example 10
Preparation of 3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- ((iminodimethyl-6-sulfinyl) amino) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile (Compound 10)
Figure BDA0002274353350000272
The same procedures used in example 1 were repeated except for replacing 3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile in step a with 3-fluoro-5- ((7- ((iminodimethyl-6-sulfinylimino) amino) -1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile to give compound 10.
Example 11
Preparation of 3- ((1S, 2S, 3R) -2, 3-difluoro-1-hydroxy-7- ((imino (methyl) trifluoromethyl) -6-sulfinyl) amino) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile (Compound 11)
Figure BDA0002274353350000281
The same procedures as in example 1 were repeated except for replacing 3- ((7-bromo-1-oxo-2, 3-dihydro-1H-4-yl) oxy) -5-fluorobenzonitrile in step a with 3-fluoro-5- ((7- ((imino (methyl) (trifluoromethyl) -6-sulfinylimino) amino) -1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile to obtain compound 11.
Activity assay
VEGF ELISA measurement
Human renal clear cell adenocarcinoma (786-O) cells in logarithmic growth phase were seeded in 96-well plates (Fisher Scientific) at 7500 cells per well (180. mu.l/well), and after 4h of culture, 20. mu.l of different concentrations of compound stock solutions were added to each well to give final concentrations as follows (μm): 0.01, 0.05, 0.25, 1.25, 6.25, 30. After about 20h, the medium was removed by aspiration and 180. mu.l of growth medium was provided to each well. Mu.l of freshly prepared stock solution of test compound was added to each well, incubated for 24h under hypoxia (1% oxygen + 5% carbon dioxide), and the cell culture medium was removed. The VFGF concentration was then determined using ELISA kits purchased from R & D Systems, in a manner suggested by the manufacturer. The reaction was stopped by adding 50. mu.l of Celltiter Glo reagent to each well, and the plate was gently shaken to sufficiently perform the stop reaction. The cell-seeded plates were subjected to Celltiter Glo luminescent cell viability assay (Promega), and then the light absorption value of each well was immediately measured at a wavelength of 450nm using a microplate reader. The data were analyzed by GraphPadPrism using the dose-response-inhibition (four parameter) equation to calculate EC50, the results of which are shown in table 1.
Table 1: VFGF ELISA determination of EC50 of selected Compounds
Figure BDA0002274353350000282
Figure BDA0002274353350000291
Remarking: a < 50; 50< B < 200; c >200
(II) HIF-2 alpha proximity scintillation assay (SPA)
The total amount of solution involved in the following assay is about 100. mu.l: mu.l of test compound (DMEM solubilized), 88. mu.l (containing protein, probe) and 10. mu.l of SPA microspheres. Test compounds were diluted in 3-fold gradients from 10 μm to 5Nm for 8 dose points. The method was performed on a 96-well plate, with one column containing dmso and no compound as a positive control and one column containing no protein as a negative control. Prior to addition of test compound, the cells were equilibrated for 30 minutes with a buffer containing 25mM triisopropylethanesulfonyl (Ph 7.5), 150mM sodium chloride, 15% glycerol, 0.15% BSA, 0.001% Tween 20, 150Nm Compound 211, and 100Nm HIF-2. alpha. PAS-B binding domain protein (His-tag). The compounds to be tested were then added to a white transparent bottom Isoplate-96 SPA microplate (Perkin Elmer), 88 μm of buffer was added, a plastic lid was covered and the plate was wrapped with aluminum foil, placed in a shaker and equilibrated for 1 hour. mu.M of a 2mg/Ml solution of CuYSi-labeled SPA microspheres was added to each well, covered and allowed to stand for 2 hours. The master plate was then removed from the shaker to 1450 a multifunction liquid scintillation counter (Perkin Elmer) and the extent of probe binding was measured. The inhibition ratio and the value of EC50 were calculated by the following formula and the Dotmatics system: the inhibition ratio [ (% positive group-blank group)/(negative group-blank group) ] × 100.
Table 2: EC50 of Compounds in proximity scintillation assay (SPA)
Compound (I) SPA EC50(nm)
1 A
2 B
3 C
4 C
5 A
6 C
7 A
8 B
9 A
10 B
11 C
PT2977 A
Remarking: a < 50; 50< B < 200; c >200
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims (11)

1. A compound of the general formula (I),
Figure FDA0003523045210000011
wherein:
RFselected from hydrogen or halogen;
x is selected from CH or nitrogen atom;
RArselected from aryl with or without substituent having 6-14 carbon atoms, heterocyclic aryl with or without substituent having 6-14 carbon atoms, wherein the substituent is selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, C1-C4 alkyl and C1-C4 alkoxy;
w is selected from
Figure FDA0003523045210000012
Or
Figure FDA0003523045210000013
Wherein denotes the point of attachment of the group to the remainder of the molecule,
R1and R2Represents cyano, trifluoromethyl, methoxy, -NH2，-NHCH3，-N(CH3)2C1-C4 alkyl, C1-C4 alkoxy; or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
2. The compound of claim 1, wherein: rArSelected from phenyl with or without substituents selected from fluoro, chloro, bromo, iodo, cyano, amino, hydroxy, C1-C4 alkyl and C1-C4 alkoxy, or pyridine with or without substituents.
3. The compound of claim 1 or 2, wherein: w is selected from
Figure FDA0003523045210000014
Wherein R is1,R2Selected from cyano, trifluoromethyl, -NH2，-NHCH3，-N(CH3)2C1-C4 alkyl, C1-C4 alkoxy; or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
4. The compound of claim 1, wherein: w is selected from
Figure FDA0003523045210000015
Wherein R is1,R2Selected from cyano, trifluoromethyl, -NH2，-NHCH3，-N(CH3)2C1-C4 alkyl, C1-C4 alkoxy;or R1And R2Together represent a 4-, 5-, 6-or 7-membered heterocyclic group.
5. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0003523045210000021
6. a salt of the compound of any one of claims 1-5.
7. A process for the preparation of a compound according to any one of claims 1 to 5, characterized in that it is a route as follows:
Figure FDA0003523045210000022
wherein X represents CH or a nitrogen atom;
RArselected from aryl with or without substituent having 6-14 carbon atoms, heterocyclic aryl with or without substituent having 6-14 carbon atoms, and the substituent is selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, C1-C4 alkyl and C1-C4 alkoxy.
8. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers.
9. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or preventing a HIF-2 α -associated disease or disorder in a mammal.
10. Use according to claim 9, characterized in that: the HIF-2 alpha related diseases or conditions are selected from cancer, inflammation, metabolic diseases; the cancer comprises skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck tumor; the inflammation comprises pneumonia, enteritis, nephritis, arthritis and trauma infection; the metabolic diseases comprise obesity, dyslipidemia and hyperlipidemia.
11. Use according to claim 9 or 10, characterized in that: the HIF-2 alpha-associated disease or disorder is renal cell carcinoma.
CN201911117006.6A 2019-11-15 2019-11-15 Novel 2, 3-indane derivative compound, preparation method and application Active CN112812136B (en)

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