CN112538038B - 2-indolone ERR alpha inverse agonist and pharmaceutical composition and application thereof - Google Patents

2-indolone ERR alpha inverse agonist and pharmaceutical composition and application thereof Download PDF

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CN112538038B
CN112538038B CN201910894236.7A CN201910894236A CN112538038B CN 112538038 B CN112538038 B CN 112538038B CN 201910894236 A CN201910894236 A CN 201910894236A CN 112538038 B CN112538038 B CN 112538038B
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丁克
李姗
彭丽洁
司鸿飞
张章
任小梅
雷冲
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Jinan University
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Abstract

The invention provides an indolone compound with a structure shown in a formula (I) or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof and application thereof. The compound can effectively inhibit the combination of estrogen related receptor alpha (ERR alpha) and coactivator PGC-1 alpha, is a brand-new ERR alpha inverse agonist, has certain proliferation inhibition activity on tumor cells, and also has obvious improvement on the in-vivo sugar tolerance of db/db mice.
Figure DDA0002209716270000011

Description

2-indolone ERR alpha inverse agonist and pharmaceutical composition and application thereof
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to an indolone compound and application thereof.
Background
Estrogen-Related Receptors (ERRs) belong to the nuclear receptor superfamily of transcription factors, including three subtypes ERR alpha, ERR beta and ERR gamma, and are named because of high sequence and structure homology with the ERs of Estrogen Receptors. Unlike ERs, ERRs do not bind to hormonal ligands such as estrogen, and other endogenous ligands are not found at present, and are orphan nuclear receptors. Among them, ERRa (NR3B1) was first discovered by Gigurere V et al in 1988, and is widely distributed in tissues and organs with active metabolism such as skeletal muscle, heart, kidney, liver and fat tissue, and is a transcription regulatory factor for maintaining the balance of energy metabolism of cells.
Studies have shown that ERR α is expressed to varying degrees in both normal and tumor cells. In normal cells, receptor tyrosine kinases (EGFR or/and ERBB2) can up-regulate post-translational modification or phosphorylation process of ERR alpha, thereby improving the transcriptional activity of ERR alpha, promoting the combination of ERR alpha protein with coactivators (PGC-1/SRC and the like) or cosuppressing factors (RIP-140 and the like), further recognizing estrogen-related receptor response elements (ERRE) on target genes, activating the transcription level of the target genes, participating in regulating estrogen-receptor-related signal pathways, influencing the differentiation of chondrocytes, the formation of bone joints, regulating fatty acid oxidation, the biosynthesis and oxidation capacity of mitochondria, sugar metabolism and the like.
ERR alpha protein is highly expressed in ovarian cancer, endometrial cancer, prostatic cancer, colorectal cancer, especially breast cancer. In breast cancer cells, over-activation of EGFR or/and ErbB2 signaling pathway leads to over-expression of ERR alpha protein in cells, and after ERR alpha is combined with coactivator (such as PGC-1), up-regulation of a plurality of downstream target genes closely related to the occurrence and development of breast cancer, including genes PDK4 and ACADM related to oxidative metabolism and tricarboxylic acid cycle, SOD2 and UCP2 related to mitochondrial dysfunction, ENO1 and ALDOA related to sugar degradation, CCNE1 and NEK2 related to cell cycle, CXCR4 related to cell invasion and metastasis, and TFF1, S100P related to poor prognosis, etc., thereby regulating intracellular oxidative metabolic pathway, activating VEGF, aromatase, WNT signaling pathway, causing metabolic reprogramming (metabc reprogramming) of breast cancer cells, promoting cell proliferation and angiogenesis, and promoting tumor cell transformation, interstitial tumor invasion and metastasis, resulting in tumor resistance, tumor recurrence or recurrence, leading to poor prognosis.
Experiments show that ERR alpha is over-expressed in ER alpha-deleted triple-negative breast cancer cells, the expression quantity of ERR alpha is positively correlated with the malignancy degree, recurrence rate and clinical adverse prognosis of triple-negative breast cancer, and the ERR alpha is a new biomarker of breast cancer; introduction of ERR alpha small interfering RNA (siRNA) can effectively inhibit in vitro invasion and metastasis of triple negative breast cancer cell MDA-MB-231, and shows better in vivo proliferation inhibition activity. In addition, Genevieve et al found that Lapatinib can cause the degradation of ERR alpha protein in sensitive breast cancer cells, but under the pressure of continuous chemotherapy, the breast cancer cells remarkably up-regulate the expression of ERR alpha protein by activating mTOR signal pathway, recover the intracellular glutamine metabolism level, promote the energy metabolism of mitochondria and improve the ROS detoxification ability (ROS detoxification), thereby maintaining the energy steady state of the tumor cells and ensuring the survival of the cells; in a mouse model with HER2 high-expression breast cancer, the intervention of ERR alpha inverse agonist effectively breaks the energy homeostasis established by tumor cells, thereby overcoming Lapatinib drug resistance.
As the key roles played by ERR α in processes such as fatty acid oxidation, mitochondrial biosynthesis and oxidation capacity, carbohydrate metabolism, and metabolic reprogramming in tumor cells have been gradually elucidated, the application of ERR α inverse agonists in diseases such as metabolic diseases and tumors has been emphasized. However, the currently reported structural types of ERR alpha inverse agonists are rare, and no candidate molecules enter clinical research, so that the further development of ERR alpha inverse agonists is limited.
Therefore, a new type of compound, especially a compound with a novel framework, is urgently needed in the field to solve the problem of low drug potency of the ERR alpha inverse agonist at present and fill the gap of the ERR alpha inverse agonist in clinical application.
Disclosure of Invention
Aiming at the problems, the invention provides a novel indolone compound which can effectively inhibit the combination of estrogen related receptor alpha (ERR alpha) and coactivator PGC-1 alpha, is a novel ERR alpha inverse agonist and has certain proliferation inhibition activity on tumor cells.
The specific technical scheme is as follows:
an indolone compound having a structure shown in formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:
Figure BDA0002209716250000021
wherein the content of the first and second substances,
m is selected from: 0.1 and 2;
ring (C)
Figure BDA0002209716250000022
Selected from: s number of R0Substituted or unsubstituted C6-C10Aryl, s R0Substituted or unsubstituted C5-C10A heteroaryl group;
R1、R2、R3、R4、R5、R6、R7、R8、R0each independently selected from: hydrogen, halogen, cyano, nitro, amino, hydroxy, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C3-C6Cycloalkyl radical, RfSubstituted or unsubstituted C1-C6Alkoxy radical, RfSubstituted or unsubstituted C3-C6Cycloalkoxy, RfSubstituted or unsubstituted C2-C6Alkenyl radical, RfSubstituted or unsubstituted C2-C6Alkynyl, RfSubstituted or unsubstituted phenyl, - (CH)2)pNRaRb-C (═ O) OR, -CONHR, OR R3And R5By passingChemical bonds linked together to form-O-, -NH-, or- (CH)2)n；
R9Selected from: hydrogen, - (CH)2)qNRdRe、-(CH2)qORd、-(CH2)qOCRcRdRe、-(CH2)qCRcRdRe；
s is selected from: an integer of 0 to 5;
n is selected from: 1 or 2;
p is selected from; an integer of 0 to 6;
q is selected from: 1 to 6;
Ra、Rbeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C1-C6Heteroalkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted heteroatom-containing monocyclic, fused, spiro or bridged ring;
r is selected from: hydrogen, C1-C6An alkyl group;
Rcselected from: hydrogen, C1-C3An alkyl group;
Rd、Reeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C1-C6Heteroalkyl, or Rd、ReTogether with the N or C atom to which they are attached form RfA substituted or unsubstituted heteroatom-containing monocyclic, fused, spiro or bridged ring;
each RfEach independently selected from: halogen, hydroxy, amino, C1-C3Alkyl, hydroxy substituted C1-C3Alkyl radical, C1-C3Alkoxy, -NH (C)1-C3Alkyl), -N (C)1-C3Alkyl) (C1-C3Alkyl), -C (═ O) (C)1-C3Alkyl radical) And R is a substituted or unsubstituted 5-to 7-membered heterocyclic group.
In some of these embodiments, the ring
Figure BDA0002209716250000031
Selected from: a benzene ring, a pyridine ring, a naphthalene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a pyrazine ring, a pyridazine ring, an imidazole ring or a pyrimidine ring.
In some of these embodiments, R1、R2、R3、R4、R5、R6、R7、R8、R0Each independently selected from: hydrogen, halogen, cyano, nitro, amino, hydroxy, C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C3-C6Cycloalkoxy, C2-C6Alkenyl radical, C2-C6Alkynyl, phenyl, - (CH)2)pNRaRb-C (═ O) OR, -CONHR, OR R3And R5Are linked together by a chemical bond to form-O-;
Raand RbEach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C3Alkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 3-8 membered monocyclic ring containing 1,2 or 3 heteroatoms, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 8-12 membered fused, spiro or bridged ring containing 1,2 or 3 heteroatoms; the heteroatom is selected from: o, N, S are provided.
In some of these embodiments, R1、R2、R3、R4、R5、R6、R7、R8、R0Each independently selected from: hydrogen, halogen, cyano, nitro, hydroxy, C1-C3Alkyl, halo C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, phenyl, -C (═ O) OR, -CONHR, OR R3And R5Are linked together by a chemical bond to form-O-; wherein R is selected from: hydrogen, C1-C3An alkyl group.
In some of these embodiments, R1、R2、R3、R4、R5、R6、R7、R8、R0Each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, methyl, ethyl, isopropyl, propyl, cyclopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, cyclopropyloxy, vinyl, ethynyl, phenyl, - (CH)2)p-NH2、
Figure BDA0002209716250000041
Figure BDA0002209716250000042
Figure BDA0002209716250000043
-C(＝O)OH、-C(＝O)OCH3、-C(＝O)OCH2CH3、-C(＝O)OCH2(CH3)CH3、-CONH2、-CONHCH3Or R is3And R5Are linked together by a chemical bond to form-O-; wherein p is an integer of 0 to 3.
In some of these embodiments, R9Selected from: hydrogen, - (CH)2)qNRdRe(ii) a Wherein the content of the first and second substances,
q is selected from: 1.2, 3 or 4;
Rd、Reeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl, or Ra、RbTogether with the N atom to which they are attached form RfSubstituted or unsubstituted hetero atoms containing 1,2 or 3 hetero atomsA 3-8 membered monocyclic ring of a nucleus, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 8-12 membered fused, spiro or bridged ring containing 1,2 or 3 heteroatoms; the heteroatom is selected from: o, N, S are provided.
In some of these embodiments, Rd、ReEach independently selected from: hydrogen, C1-C3Alkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 5-7 membered monocyclic ring containing 1,2 or 3 heteroatoms; the heteroatom is selected from: o, N, respectively; rfSelected from: H. c1-C3Alkyl, -NH (C)1-C3Alkyl), -N (C)1-C3Alkyl) (C1-C3Alkyl), 5-to 7-membered heterocyclic group, C1-C3An alkyl-substituted 5-to 7-membered heterocyclic group.
In some of these embodiments, R9Selected from: hydrogen, - (CH)2)q-NH2、
Figure BDA0002209716250000044
Figure BDA0002209716250000051
Figure BDA0002209716250000052
-(CH2)q-OH、-(CH2)q-OCH3、-(CH2)q-OCH2CH3(ii) a Wherein q is selected from 1,2, 3 or 4.
In some of these embodiments, the ring
Figure BDA0002209716250000053
Selected from the group consisting of: benzene ring, naphthalene ring;
R1、R2、R3、R4、R5、R6、R7、R8each independently selected from: hydrogen, methoxy, hydroxy, fluoro, chloro, bromo, methyl, cyclopropyl, phenyl, or R3And R5Are linked together by a chemical bond to form-O-;
R0selected from: hydrogen, cyano, trifluoromethyl, nitro, fluoro, chloro, bromo, carboxamido, formyl, methyl formate, difluoromethyl, methoxy;
R9selected from: hydrogen, - (CH)2)q-NH2、
Figure BDA0002209716250000054
Figure BDA0002209716250000055
Figure BDA0002209716250000061
Wherein q is selected from 1,2, 3 or 4.
In some of these embodiments, the ring
Figure BDA0002209716250000062
Selected from: benzene ring, naphthalene ring;
R1、R2、R3、R4、R5、R6、R7、R8each independently selected from: hydrogen, methoxy, hydroxy, fluoro, chloro, bromo, methyl, cyclopropyl, phenyl, or R3And R5Are linked together by a chemical bond to form-O-;
R0selected from: hydrogen, cyano, trifluoromethyl, nitro, fluoro, chloro, bromo, methyl formate, difluoromethyl, methoxy;
R9selected from: hydrogen, hydrogen,
Figure BDA0002209716250000063
Figure BDA0002209716250000064
Wherein q is selected from 1,2, 3 or 4. Wherein R is4Further preferably a methoxy group.
In some embodiments, the indolone compound has a structure represented by formula (II) or formula (III):
Figure BDA0002209716250000065
wherein s is selected from: an integer of 0 to 4.
In some of these embodiments, R1、R2、R3、R4、R6、R7、R8Each independently selected from: hydrogen, methoxy, hydroxy, fluoro, chloro, bromo, methyl, cyclopropyl, phenyl;
R5selected from: hydrogen, phenyl; and when R is5When it is hydrogen, R2And R3Are not hydroxyl;
R0selected from: hydrogen, cyano, trifluoromethyl, nitro, fluoro, chloro, bromo, methyl formate, difluoromethyl, methoxy;
R9selected from: hydrogen, hydrogen,
Figure BDA0002209716250000066
Figure BDA0002209716250000067
q is selected from: 1.2, 3 or 4.
In some of these embodiments, the indolone compound is selected from the group consisting of:
Figure BDA0002209716250000071
Figure BDA0002209716250000081
the invention also provides application of the compound.
The specific technical scheme is as follows:
the application of the indolone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof in preparing ERR alpha inverse agonist.
The indolone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof can be applied to the preparation of medicines for preventing and/or treating diseases related to the abnormal expression of ERR alpha protein activity.
In some of these embodiments, the disease associated with aberrant expression of ERR α protein activity is: tumors, metabolic diseases.
In some of these embodiments, the tumor is: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, endometrial cancer, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma, malignant melanoma, renal cancer, bladder cancer, ovarian cancer, cervical cancer, laryngeal cancer, or multiple myeloma, B lymphoma, leukemia;
the metabolic disease is: hyperglycemia, diabetes, obesity, atherosclerosis, metabolic syndrome, liver fibrosis, non-alcoholic fatty liver disease, gallstone, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, hypertension, hyperinsulinemia, hyperuricemia, Parkinson's disease, and Alzheimer's disease.
The invention also provides a pharmaceutical composition for preventing or treating diseases related to the abnormal expression of ERR alpha protein activity.
The specific technical scheme is as follows:
a pharmaceutical composition for preventing and/or treating diseases related to the abnormal expression of ERR alpha protein activity is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the indolone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or prodrug molecules thereof.
Based on the technical scheme, the invention has the following beneficial effects:
the inventor of the present application has conducted extensive and intensive studies and, for the first time, has unexpectedly developed an indolone compound having a novel structure, which can exhibit an ERR α inhibitory activity of nanomolar intensity in a time-resolved fluorescence resonance energy transfer experiment. The indolone compounds can effectively inhibit the combination of estrogen related receptor alpha (ERR alpha) and coactivator PGC-1 alpha, are a brand new ERR alpha inverse agonist, and can be used for preventing or treating diseases related to the abnormal expression of ERR alpha protein activity, such as tumors or metabolic diseases and the like.
Drawings
FIG. 1 is a graph of blood glucose levels of DB/DB mice in an OGTT test 28 days after continuous dosing.
Detailed Description
In the compounds of the present invention, when any variable (e.g., R, etc.) occurs more than one time in any constituent, its definition in each occurrence is independent of its definition in every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
The phrase "R" as used hereinfSubstitution "," R-substitution "is considered equivalent to the phrase" substituted with at least one substituent ", and preferred embodiments in this case will have 1-4 substituents.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6Alkyl radical "middle" C1-C6The definition of "includes groups having 1,2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. For example, "C1-C6Alkyl "specifically includes methyl, ethyl, n-propyl, isopropylN-butyl, t-butyl, isobutyl, pentyl, hexyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "alkoxy" refers to a group having the structure-O-alkyl, such as-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2And the like. The term "heteroaryl" refers to an aromatic ring containing 1,2 or 3 heteroatoms selected from O, N or S, and heteroaryl groups within the scope of the present invention include, but are not limited to: imidazolyl, triazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl.
As understood by those skilled in the art, "halo" or "halo" as used herein means chloro, fluoro, bromo, and iodo.
Chemical bond in chemical structural formula of the invention
Figure BDA0002209716250000101
The compound refers to a single bond with unfixed direction, and the compound comprises two isomers of cis structure and trans structure. For example, the compounds of formula (I) of the invention
Figure BDA0002209716250000102
The method comprises the following two cis-trans isomers:
Figure BDA0002209716250000103
as yet another example of an implementation of the method,
Figure BDA0002209716250000104
the method comprises the following two cis-trans isomers:
Figure BDA0002209716250000111
namely, the 2-indolone compounds comprise (Z) -2-indolone compounds and (E) -2-indolone compounds, and single (Z) -2-indolone compounds or (E) -2-indolone compounds can be obtained by separation, but the two isomers can be mutually converted in a chemical solvent, namely, the 2-indolone compounds exist in a mixed form of cis-trans isomer interconversion in the chemical solvent, namely, the 2-indolone compounds exist in a mixed form of (Z) -2-indolone compounds and (E) -2-indolone compounds. The "chemical solvent" includes but is not limited to dimethyl sulfoxide, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, water.
The invention provides a compound shown in formula I, pharmaceutically acceptable salt or stereoisomer thereof or prodrug molecule thereof,
Figure BDA0002209716250000112
wherein, the first and the second end of the pipe are connected with each other,
m is selected from: 0.1 and 2;
ring (C)
Figure BDA0002209716250000113
Selected from: s number of R0Substituted or unsubstituted C6-C10Aryl, s R0Substituted or unsubstituted C5-C10A heteroaryl group;
R1、R2、R3、R4、R5、R6、R7、R8、R0each independently selected from: hydrogen, halogen, cyano, nitro, amino, hydroxy, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C3-C6Cycloalkyl radical, RfSubstituted or unsubstituted C1-C6Alkoxy radical, RfSubstituted or unsubstituted C3-C6Cycloalkoxy, RfSubstituted or unsubstituted C2-C6Alkenyl radical, RfSubstituted or unsubstituted C2-C6Alkynyl, RfSubstituted or unsubstituted phenyl, - (CH)2)pNRaRb-C (═ O) OR, -CONHR, OR R3And R5Are linked together by a chemical bond to form-O-, -NH-, or- (CH)2)n；
R9Selected from: hydrogen, - (CH)2)qNRdRe、-(CH2)qORd、-(CH2)qOCRcRdRe、-(CH2)qCRcRdRe；
s is selected from: an integer of 0 to 5;
n is selected from: 1 or 2;
p is selected from; an integer of 0 to 6;
q is selected from: 1 to 6;
Ra、Rbeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C1-C6Heteroalkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted heteroatom-containing monocyclic, fused, spiro or bridged ring;
r is selected from: hydrogen, C1-C6An alkyl group;
Rcselected from: hydrogen, C1-C3An alkyl group;
Rd、Reeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C1-C6Heteroalkyl, or Rd、ReTogether with the N or C atom to which they are attached form RfA substituted or unsubstituted heteroatom-containing monocyclic, fused, spiro or bridged ring;
each RfEach independently selected from: halogen, hydroxy, amino, C1-C3Alkyl, hydroxy substitutionC of (A)1-C3Alkyl radical, C1-C3Alkoxy, -NH (C)1-C3Alkyl), -N (C)1-C3Alkyl) (C1-C3Alkyl), -C (═ O) (C)1-C3Alkyl), R is a substituted or unsubstituted 5-to 7-membered heterocyclic group.
The invention includes the free forms of the compounds of formula (I), as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula (I). The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If the compounds of the invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, "Pharmaceutical Salts" J.pharm.Sci.' 1977: 66: 1-19 describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.
Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing polysubstitution under the definition of formula (I) above.
The compounds of formula (I) according to the invention can be prepared by the following reaction scheme:
Figure BDA0002209716250000131
wherein R is1、R2、R3、R4、R5、R6、R7、R8、R9M and
Figure BDA0002209716250000141
as defined in the preceding summary; a is selected from: chlorine, bromine, iodine.
Wherein, nucleophilic substitution reaction is carried out between the compound of formula (VI) and the compound of formula (VII) under alkaline condition, and the ether compound of formula (VIII) is obtained. The alkali used in the reaction condition can be potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and the like, the solvent used can be one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, the reaction temperature is preferably 80-120 ℃, and the reaction time is 5-12 hours.
The compound of formula (VIII) and the indolone compound of formula (VIIII) are subjected to aldol condensation reaction under the condition of acid or alkali catalysis to obtain the alpha-beta unsaturated indolone compound of formula (X). The basic catalyst used in the reaction conditions may be oxides, hydroxides, bicarbonates, carbonates and carboxylates of alkali metals or alkaline earth metals, organic amine compounds, anion exchange resins, etc., such as sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, calcium hydroxide, sodium hydride, sodium alkoxide, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, Diisopropylethylamine (DIPEA), trimethylamine, piperidine, pyrrolidine, etc.; the acid catalyst used in the reaction condition can be sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, cation exchange resin, boron trifluoride and the like, the solvent used can be methanol, ethanol and the like, the reaction temperature is preferably 60-80 ℃, and the reaction time is preferably 2-5 hours.
Nucleophilic substitution reaction is carried out on the compound in the formula (X) and the compound in the formula (XI) under alkaline conditions, and the target product in the formula (I) is obtained. The alkali used in the reaction condition can be potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and the like, the solvent used can be one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, the reaction temperature is preferably 80-120 ℃, and the reaction time is 5-12 hours.
The salt of the compound in the formula XI and the salt of the compound in the formula I are selected from inorganic acid salts or organic acid salts, such as hydrochloride, sulfate, hydrobromide, phosphate, nitrate, acetate, maleate, p-toluenesulfonate, methanesulfonate or trifluoroacetic acid.
In one embodiment, the present application provides a method of treating hyperproliferative diseases or conditions, metabolic diseases or conditions, such as tumors, in humans and other mammals, using compounds having the structure shown in formula (I) and pharmaceutically acceptable salts thereof.
In one embodiment, the compounds contemplated herein and pharmaceutically acceptable salts thereof may be used to treat or control non-small cell lung cancer, lung adenocarcinoma, squamous carcinoma of the lung, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, endometrial cancer, histiocytic lymphoma, nasopharyngeal cancer, head and neck tumors, colon cancer, rectal cancer, glioma, malignant melanoma, renal cancer, bladder cancer, ovarian cancer, cervical cancer, laryngeal cancer or multiple myeloma, B lymphoma, leukemia, hyperglycemia, diabetes, obesity, atherosclerosis, metabolic syndrome, liver fibrosis, non-alcoholic steatoliver, biliary disease, hyperlipidemia, hypercholesteremia, hyperlipoproteinemia, hypertriglyceridemia, hypertension, hyperinsulinemia, hyperuricemia, parkinson's disease, or a pharmaceutically acceptable salt thereof, Alzheimer's disease, etc.
Drug metabolites and prodrugs
Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.
Pharmaceutical composition
The invention also provides a pharmaceutical composition comprising a safe and effective amount of the active ingredient, and a pharmaceutically acceptable carrier.
The "active ingredient" of the present invention includes the compounds of formula I of the present invention.
The "active ingredients" and pharmaceutical compositions described herein are useful as ERR α inverse agonists. In another preferred embodiment, the compound is used for preparing a medicament for preventing and/or treating tumor/metabolic diseases.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient.
Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002209716250000151
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer by non-bonding. In another preferred embodiment, the compound of formula I of the present invention as a small molecule can also be linked to a macromolecular compound or a macromolecule via a chemical bond. The macromolecular compounds may be biological macromolecules such as homoglycans, proteins, nucleic acids, polypeptides, and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following:
(a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
(b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia;
(c) humectants, for example, glycerol;
(d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
(e) slow solvents, e.g., paraffin;
(f) absorption accelerators, e.g., quaternary ammonium compounds;
(g) wetting agents, for example, cetyl alcohol and glycerol monostearate;
(h) adsorbents, for example, kaolin; and
(i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
The solid dosage forms may also be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other therapeutic agents, such as glucose lowering agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Combination drug
The compounds of formula (I) may be combined with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug is maintained, while the compound of formula (I) is administered simultaneously or subsequently. When the compound of formula (I) is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. The pharmaceutical combination also comprises the administration of a compound of formula (I) in an overlapping time period with one or more other known drugs. When a compound of formula (I) is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula (I) or known drug may be lower than the dose when they are administered alone.
Drugs or active ingredients that may be used in pharmaceutical combination with the compounds of formula (I) include, but are not limited to:
estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, inhibitors of apoptosis, inhibitors of tumor growth, and the like, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and the like.
In one embodiment, the pharmaceutical or active ingredients with which the compounds of formula I may be combined include, but are not limited to: aldesleukin, alendronic acid, interferon, atrazine, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, ambrolidine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, bacillus calmette or tide bacillus calmette, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromouroxime, bortezomib, busulfan, calcitonin, alezomab injection, capecitabine, carboplatin, custard, cefesone, simon, daunorubicin, phenylbutyric acid azone, mustard, cladribine, clodronate, cyclophosphamide, alexanide, dacarbazine, actinomycin, dexamethasone, estramustin phosphate, estramustine, dexamethasone, estradiol phosphate, estradiol valerate phosphate, valproate, doxylamine, and mixtures thereof, Dinil interleukin 2, dibume, deslorelin, delazoxan, diethylstilbestrol, tolbutan, docetaxel, doxifluridine, doxorubicin, dronabinol, azulene-166-chitosan complex, eligard, labyrinase, epirubicin hydrochloride, aprepitant, epirubicin, alfafurtine, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, hydroxyphosphoric acid, pirimiphoside, etoposide, favuzole, tamoxifen formulations, filgrastim, phenastidine, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, flumetmesterone, flunomide, fulvestrant, 1-beta-D-arabinofuranosylcytisidine-5 '-stearoyl-5' -stearoyl phosphate, flutamide, fluvastatin, Fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine wafer capsule, goserelin, glanesilong hydrochloride, histrelin, and meclizine, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, temin bemomab, idarubicin, ifosfamide, interferon alpha 2A, interferon alpha 2B, interferon alpha nl, interferon alpha n3, interferon beta, interferon gamma la, interleukin 2, intron A, iressa, irinotecan, kateride, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprorelin, levamisole acetate, levamisole, calcium levofolinate, sodium levothyroxine preparation, Lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-ryopurine, mesna, methotrexate, methyl aminoacetonate, miltefosine, milbemycin, mitomycin C, mitotane, mitoxantrone, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, omprex interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate formulation, pemetrexed, domethacin, pentostatin, streptolysin formulation, pilocarpine hydrochloride, bordeauxins, plicamycin, pemetrexen, phenomycin, and prednisone, Spiprantelone, prednisone, pemetrexed, procarbazine, recombinant human erythropoietin, raltitrexed, ribi, rhenium-186 etidronate, merosal, dygulin-A, romopeptide, pilocarpine hydrochloride tablet, octreotide, samustine, semustine, Sizopyran, sobuzosin, Succinum methylprednisolone, Pafoscarnet, Stemonaccid, streptozocin, strontium chloride-89, levothyroxine sodium, tamoxifen, tamsulosin, tasolomide, Tastolactone, Tetharidin, Tecetithiozine, temozolomide, teniposide, testosterone propionate, megestrol, thioguanine, thiotepa, thyrotropine, Teluzole, topotecan, toremifene, tositumomab, Suzuzumab, Ottoepirubicin, Vavea tablet, methotrexate, trimetrexamine, triptorelin, trexate, troglib, troglitazone, trexate, trexaprop-A, tremulin, tremula, tremulin, tremula, tremulin, triptorelin pamoate, eufordine, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vinblastine amide, vinorelbine, vilulizine, dexpropinimine, neat stastine ester, pindoline, paclitaxel protein stabilizing formulations, acolbifene, interferon r-lb, affinitak, aminopterin, azoxifene, aspristil, atamestane, atrasentan, BAY43-9006, avastin, CCI-779, CDC-501, Celopabrol, cetuximab, clinacatto, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, eocharin, eflornithine, irinotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, bamine-DOTMP, holmium-phosphate, ibandron, gamma-gamma, interferon-containing, loxapine, PEG-L-1582, hematoporphyrin-L-2, and leupeptin, Lancet, lasofoxifene, libra, lonafamib, milbexifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, Orimunoson, onco-TCS, osidmem, paclitaxel polyglutamate, sodium pamoate, PN-401, QS-21, quarta, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, docosahexanoic acid paclitaxel, thymosin alpha l, Galfazolin, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-7R, vastada, pravastatin, vatalanib, valporopenpine, vinpocetine, Z-100, and lypocetine or combinations thereof.
The features mentioned above, or those mentioned in the embodiments, may be combined in any combination. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The invention has the advantages that:
(1) provides a 2-indolone compound with novel structure.
(2) The compounds can effectively inhibit the combination of estrogen related receptor alpha and coactivator PGC-1 alpha, and can be used for preparing antitumor drugs and/or drugs for treating metabolic diseases.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 14- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-86)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000191
Step 14- (4-formyl-2-methoxyphenoxy) -3- (trifluoromethyl) benzonitrile (3)
4-fluoro-3- (trifluoromethyl) benzonitrile (1,5g,26.5mmol), vanillin (2,4g,26mmol), potassium carbonate (6.1g,44mmol) were dissolved in anhydrous N, N-dimethylformamide (50mL) and stirred at room temperature overnight. When the reaction was complete, ice water (200mL) was added with stirring and a large amount of solid precipitated. Filtered under reduced pressure and dried in vacuo to give a white solid (7.6g, 92% yield).
1H NMR(400MHz,DMSO-d6):δ10.02(s,1H),8.36(d,J＝2.0Hz,1H),8.04(dd,J＝8.4,2.0Hz,1H),7.72(d,J＝2.0Hz,1H),7.66(dd,J＝8.0,2.0Hz,1H),7.45(d,J＝8.4Hz,1H),6.95(d,J＝8.8Hz,1H),3.83(s,3H).
MS(ESI):m/z 322[M+H]+.
Step 24- (4- ((5-fluoro-1-H-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-63)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
4- (4-aldehyde-2-methoxyphenoxy) -3- (trifluoromethyl) benzonitrile (3,1.08g,3.3mmol) and 5-fluoroindolone (4,0.48g,3.2mmol) were dissolved in 20 ml of anhydrous ethanol and stirred until the reaction system was clear. After a catalytic amount of piperidine was added dropwise to the reaction system, the reaction temperature was raised to 60 ℃. After the reaction was complete, cooling and a large amount of yellow solid precipitated. Filtered under reduced pressure and dried in vacuo to give a yellow solid (1.28g, yield 90%).
Isomer A1H NMR(400MHz,DMSO-d6):δ10.69(s,1H),8.77(s,1H),8.34(s,1H),8.03(d,J＝8.8Hz,1H),7.98-7.90(m,2H),7.67(dd,J＝8.8Hz,2.0Hz,1H),7.33(d,J＝8.4Hz,1H),7.10-7.02(m,1H),6.94(d,J＝8.8Hz,1H),6.83(dd,J＝8.4,4.4Hz,1H),3.81(s,3H).
Isomer B1H NMR(400MHz,DMSO-d6):δ10.68(d,J＝7.2Hz,1H),8.35(d,J＝2.0Hz,1H),8.06(dd,J＝8.8,2.0Hz,1H),7.73(s,1H),7.61(d,J＝2.0Hz,1H),7.48-7.37(m,3H),7.18-7.08(m,1H),7.02(d,J＝8.8Hz,1H),6.89(dd,J＝8.8,4.8Hz,1H),3.78(s,3H).
MS(ESI):m/z 455[M+H]+.
Step 34- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-86)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxy phenoxy)-3-(trifluoromethyl)benzonitrile
4- (4- ((5-fluoro-1-H-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-63,0.50g,1.1mmol), 4- (2-chloroethyl) morpholine hydrochloride (5,0.41g,2.2mmol) and potassium carbonate (0.46g,3.3mmol) were dissolved in 20 ml of anhydrous acetonitrile and heated to 90 ℃ for reaction overnight. Cooling to room temperature, spin-drying most of the acetonitrile solvent, extracting with dichloromethane three times, combining the organic phases, washing with saturated brine, spin-drying, and separating by column chromatography to obtain a yellow solid (0.47g, 76%).
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.34(s,2H),8.13-7.93(m,4H),7.81(s,1H),7.73(d,J＝8.8Hz,1H),7.62(s,1H),7.46(d,J＝8.8Hz,2H),7.39(d,J＝8.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.26-7.06(m,4H),7.02(d,J＝8.4Hz,1H),6.94(d,J＝8.8Hz,1H),3.95-3.83(m,4H),3.81(s,3H),3.77(s,3H),3.62-3.46(m,8H),2.54(s,4H),2.45(s,8H).
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,DMSO-d6):δ8.75(d,J＝1.6Hz,1H),8.34(d,J＝2.0Hz,1H),8.06-7.99(m,2H),7.97(dd,J＝8.8,1.7Hz,1H),7.73(dd,J＝8.8,2.4Hz,1H),7.35(d,J＝8.4Hz,1H),7.16(td,J＝8.8,2.4Hz,1H),7.09(dd,J＝8.4,4.4Hz,1H),6.95(d,J＝8.4Hz,1H),3.89(t,J＝6.8Hz,2H),3.81(s,3H),3.51(t,J＝4.0Hz,4H),2.54(t,J＝6.8Hz,2H),2.48-2.37(m,4H).
Isomer B1H NMR(400MHz,DMSO-d6):δ8.34(d,J＝1.6Hz,1H),8.05(dd,J＝8.8,2.0Hz,1H),7.81(s,1H),7.62(d,J＝2.0Hz,1H),7.49-7.43(m,2H),7.39(d,J＝8.4Hz,1H),7.21(td,J＝8.8,2.8Hz,1H),7.15(dd,J＝8.8,4.4Hz,1H),7.02(d,J＝8.8Hz,1H),3.89(t,J＝6.4Hz,2H),3.77(s,3H),3.53(t,J＝4.4Hz,4H),2.55(t,J＝6.4Hz,2H),2.47-2.39(m,4H).
HRMS(ESI):m/z 568.1838[M+H]+.
Example 24- (2-methoxy-4- ((2-indolone-3-ylide) methyl) phenoxy) -3-trifluoromethylbenzonitrile (LS 1-61)
4-(2-methoxy-4-((2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000211
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.67(s,1H),10.63(s,0.9H),8.75(d,J＝2.0Hz,1H),8.33(d,J＝1.6Hz,1.8H),8.03(td,J＝8.8,2.0Hz,2H),7.95(dd,J＝8.4,1.6Hz,1H),7.87(s,1H),7.73(d,J＝7.6Hz,1H),7.69-7.62(m,1.8H),7.59(d,J＝1.6Hz,0.9H),7.43(dd,J＝8.8,1.6Hz,0.9H),7.36(d,J＝8.4Hz,0.9H),7.31(d,J＝8.4Hz,1H),7.27-7.20(m,1.8H),7.05-6.96(m,2H),6.96-6.81(m,3.9H),3.80(s,3H),3.77(s,2.7H).
Further separation to give isomer A1H NMR(400MHz,DMSO-d6):δ10.68(s,1H),8.76(d,J＝2.0Hz,1H),8.34(d,J＝1.6Hz,1H),8.03(dd,J＝8.4,2.0Hz,1H),7.96(dd,J＝8.8,2.0Hz,1H),7.88(s,1H),7.74(d,J＝7.2Hz,1H),7.32(d,J＝8.4Hz,1H),7.24(td,J＝7.6Hz,1.2Hz,1H),7.02(td,J＝7.6Hz,0.8Hz,1H),6.94(d,J＝8.8Hz,1H),6.86(d,J＝7.6Hz,1H),3.81(s,3H).
MS(ESI):m/z 437[M+H]+.
Example 34- (4- ((5-bromo-1-H-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-59)
4-(4-((5-bromo-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000221
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.81(s,1H),10.80(s,0.4H),8.75(d,J＝2.0Hz,1H),8.39-8.30(m,1.4H),8.11-7.93(m,3.8H),7.79-7.69(m,1H),7.63(s,0.6H),7.49-7.37(m,2.4H),7.33(d,J＝8.4Hz,1H),6.96(dd,J＝17.2,8.8Hz,1.4H),6.90-6.77(m,1.4H),3.80(s,3H),3.79(s,1.2H).
MS(ESI):m/z 515[M+H]+.
Example 44- (4- ((5-fluoro-1-H-2-indolone-3-ylide) methyl) -phenoxy) -3-trifluoromethylbenzonitrile (LS1-108)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000222
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.67(s,1H),10.66(s,1H),8.58-8.49(m,2H),8.41(d,J＝2.0Hz,2H),8.19-8.09(m,2H),7.93(s,1H),7.87-7.79(m,2H),7.71(s,1H),7.66(dd,J＝9.2,2.8Hz,1H),7.40-7.20(m,7H),7.11(td,J＝8.8,2.4Hz,1H),7.08-6.99(m,1H),6.88(dd,J＝8.8,4.8Hz,1H),6.80(dd,J＝8.8,4.8Hz,1H).
MS(ESI):m/z 425[M+H]+.
Example 54- (4- ((5-fluoro-1-H-2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-104)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-3-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000231
The synthesis was as in example 1, step 2.
Column chromatography separation to obtain:
isomer A1H NMR(400MHz,DMSO-d6):δ10.58(s,1H),8.61(d,J＝8.4Hz,1H),8.40(d,J＝1.6Hz,1H),8.13(dd,J＝8.8,2.4Hz,1H),7.93(s,1H),7.58(dd,J＝8.8,2.8Hz,1H),7.25(d,J＝8.8Hz,1H),7.08-6.99(m,1H),6.98(d,J＝2.4Hz,1H),6.79(dd,J＝8.4Hz,4.4Hz,1H),6.74(dd,J＝8.8Hz,2.4Hz,1H),3.90(s,3H).
Isomer B1H NMR(400MHz,DMSO-d6):δ10.63(s,1H),8.41(d,J＝1.6Hz,1H),8.15(dd,J＝8.8,2.0Hz,1H),7.78(d,J＝8.4Hz,1H),7.67(s,1H),7.33(d,J＝8.8Hz,1H),7.19(dd,J＝9.2,2.4Hz,1H),7.15-7.04(m,2H),6.93-6.81(m,2H),3.87(s,3H).
MS(ESI):m/z 455[M+H]+.
Example 64- (4- ((5-fluoro-1-H-2-indolone-3-ylide) methyl) -3-hydroxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-109)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-3-hydroxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000232
4- (4- ((5-fluoro-1-H-2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS1-104,30mg,0.066mmol) was dissolved in anhydrous dichloromethane and 0.5 ml of 1.0M BBr was slowly added dropwise at 0 deg.C3Dichloromethane solution. The reaction was continued for about 3 hours and quenched by dropwise addition of ice water. Extraction was carried out three times with dichloromethane, the organic phases were combined, washed with saturated brine, spin-dried and separated by column chromatography to give a yellow solid (16mg, 55%).
1H NMR(400MHz,DMSO-d6):δ10.78(s,0.5H),10.77(s,1H),10.65-10.53(m,1.5H),8.76(d,J＝8.8Hz,0.5H),8.41(d,J＝2.0Hz,1H),8.20-8.10(m,1.5H),7.95(s,0.5H),7.74(d,J＝8.4Hz,1H),7.70(s,1H),7.52(dd,J＝8.8,2.4Hz,0.5H),7.37(d,J＝8.8Hz,1H),7.30(d,J＝8.8Hz,0.5H),7.25(dd,J＝9.6,2.8Hz,1H),7.08(td,J＝9.2,2.8Hz,1H),7.05-6.99(m,0.5H),6.86(dd,J＝8.4,4.4Hz,1H),6.79(dd,J＝8.4,4.4Hz,0.5H),6.76(dd,J＝8.0,2.0Hz,1H),6.69(d,J＝2.4Hz,1H),6.65(dd,J＝8.8,2.4Hz,0.5H),6.61(d,J＝2.4Hz,0.5H),6.63(s,0.5H).
MS(ESI):m/z 439[M-H]-.
Example 74- (3-methoxy-4- ((4-methyl-2-indolone-3-ylide) methyl) phenoxy) -3-trifluoromethylbenzonitrile (LS 1-128)
4-(3-methoxy-4-((4-methyl-2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000241
The synthesis was as in example 1, step 2.
Column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ8.38(d,J＝9.6Hz,1H),7.99(d,J＝1.6Hz,1H),7.95(s,1H),7.73(dd,J＝8.8,2.0Hz,1H),7.54(s,1H),7.17-7.08(m,2H),6.84(d,J＝8.0Hz,1H),6.73-6.64(m,3H),3.88(s,3H),2.61(s,3H).
Isomer B1H NMR(400MHz,CDCl3):δ8.00(d,J＝2.0Hz,1H),7.93(s,1H),7.76(dd,J＝8.4,2.0Hz,1H),7.56(s,1H),7.21-7.09(m,2H),6.99(d,J＝8.4Hz,1H),6.77(d,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,1H),6.68(d,J＝2.0Hz,1H),6.63(dd,J＝8.0,2.0Hz,1H),3.87(s,3H),1.82(s,3H).
MS(ESI):m/z 451[M+H]+.
Example 84- (4- ((4-bromo-2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS1-131)
4-(4-((4-bromo-2-oxoindolin-3-ylidene)methyl)-3-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000242
The synthesis was as in example 1, step 2.
Further column chromatography separation to obtain:
isomer A1HNMR for(400MHz,DMSO-d6):10.81(s,1H),8.79(s,1H),8.42(d,J＝8.4Hz,1H),8.40(d,J＝2.0Hz,1H),8.13(dd,J＝8.8,2.0Hz,1H),7.25(d,J＝8.8Hz,1H),7.20(dd,J＝8.0,0.8Hz,1H),7.13(t,J＝8.0Hz,1H),6.97(d,J＝2.0Hz,1H),6.85(dd,J＝7.6,1.2Hz,1H),6.73(dd,J＝8.4,2.4Hz,1H),3.89(s,3H).
MS(ESI):m/z 515[M+H]+.
Example 94- (4- ((4-fluoro-2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS1-140)
4-(4-((4-fluoro-2-oxoindolin-3-ylidene)methyl)-3-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000251
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.94-10.80(m,1.85H),8.65(d,J＝8.8Hz,1H),8.45-8.36(m,1.85H),8.19-8.10(m,1.85H),8.03(d,J＝3.2Hz,1H),7.74(s,0.85H),7.39(dd,J＝8.4,5.6Hz,0.85H),7.33-7.20(m,3H),7.18(d,J＝8.8Hz,0.85H),7.02-6.95(m,1.85H),6.82(dd,J＝10.4,8.4Hz,1H),6.77-6.67(m,4.4H),3.89(s,3H),3.84(s,2.55H).
MS(ESI):m/z 455[M+H]+.
Example 104- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-113)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-3-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000252
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.78(d,J＝9.2Hz,1H),8.01(dd,J＝8.0,1.6Hz,2H),7.93(d,J＝11.6Hz,2H),7.80(dd,J＝8.8,2.0Hz,1H),7.75(dd,J＝8.8,2.0Hz,1H),7.71(d,J＝9.2Hz,1H),7.34-7.21(m,3H),7.11(d,J＝8.4Hz,2H),7.05-6.92(m,3H),6.79-6.66(m,4H),4.19-3.96(m,4H),3.95-3.66(m,14H),3.06-2.41(m,12H).
MS(ESI):m/z 568[M+H]+.
Example 114- (4- ((4-bromo-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-123)
4-(4-((4-bromo-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-3-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000261
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.97(s,1H),8.37(d,J＝9.2Hz,1H),8.07-7.95(m,2.2H),7.80-7.69(m,1.6H),7.23(d,J＝8.0Hz,2H),7.18-7.08(m,3.2H),6.99(d,J＝8.8Hz,0.6H),6.95-6.79(m,1.6H),6.71-6.56(m,2.8H),4.06-3.84(m,6.2H),3.83(s,1.8H),3.78-3.53(m,6.4H),2.77-2.34(m,9.6H).
MS(ESI):m/z 628[M+H]+.
Example 124- (4- ((4-bromo-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-hydroxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-125)
4-(4-((4-bromo-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-3-hydroxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000262
The synthesis was as in example 6.
1H NMR(400MHz,CDCl3):δ9.95(s,1H),8.88(s,1H),8.00(d,J＝1.6Hz,1H),7.77(dd,J＝8.8,2.0Hz,1H),7.56(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,0.8Hz,1H),7.21-7.08(m,2H),6.97(d,J＝7.6Hz,1H),6.82(d,J＝2.4Hz,1H),6.76(dd,J＝8.4,2.4Hz,1H),4.02(t,J＝6.8Hz,2H),3.66(t,J＝4.4Hz,4H),2.66(t,J＝6.4Hz,2H),2.53(t,J＝4.4Hz,4H).
MS(ESI):m/z 612[M-H]-.
Example 134- (4- ((4-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-142)
4-(4-((4-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-3-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000271
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.56(d,J＝9.2Hz,0.8H),8.20(d,J＝3.2Hz,0.8H),8.09-7.93(m,2.8H),7.75(td,J＝8.8,2.0Hz,1.8H),7.35(dd,J＝9.2,5.6Hz,1H),7.30-7.15(m,1.8H),7.11(d,J＝8.8Hz,0.8H),7.04(d,J＝8.4Hz,1H),6.79-6.64(m,7.2H),3.97-3.83(m,9H),3.72-3.65(m,7.2H),2.68-2.52(m,10.8H).
MS(ESI):m/z 568[M+H]+.
Example 144- (4- ((4-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-hydroxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-143)
4-(4-((4-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-3-hydroxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000272
The synthesis was as in example 6.
1H NMR(400MHz,DMSO-d6):δ10.81(s,1H),10.63(s,0.5H),8.81(d,J＝8.8Hz,1H),8.45-8.35(m,1.5H),8.27-8.08(m,2.5H),7.85(s,0.5H),7.41-7.26(m,3H),7.22(d,J＝8.4Hz,0.5H),6.99(d,J＝8.0Hz,0.5H),6.95(d,J＝8.0Hz,1H),6.89(dd,J＝10.8,8.4Hz,1H),6.81(dd,J＝10.0,8.4Hz,0.5H),6.73-6.57(m,3H),3.99-3.79(m,3H),3.64-3.41(m,6H),2.61-2.33(m,9H).
MS(ESI):m/z 552[M-H]-.
Example 154- (4- ((5-fluoro-1- (2-ethylpiperidine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-146)
4-(4-((5-fluoro-2-oxo-1-(2-(piperidin-1-yl)ethyl)indolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000281
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.76(s,0.8H),7.99(dd,J＝7.2,2.0Hz,1.8H),7.86(s,1H),7.73(dd,J＝8.8,2.0Hz,1H),7.68(dd,J＝8.8,2.0Hz,0.8H),7.64(dd,J＝8.4,2.0Hz,0.8H),7.48(s,1H),7.41(dd,J＝8.8,2.4Hz,1H),7.38-7.24(m,4.2H),7.19(d,J＝8.4Hz,0.8H),7.07-6.99(m,1.8H),6.98-6.79(m,3H),4.21-3.85(m,6H),3.81(s,3H),2.98-2.24(m,10.8H),1.62-1.39(m,10.8H).
MS(ESI):m/z 566[M+H]+.
Example 164- (4- ((5-fluoro-1- (3-propylpiperidine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-147)
4-(4-((5-fluoro-2-oxo-1-(3-(piperidin-1-yl)propyl)indolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000282
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.76(d,J＝1.6Hz,0.8H),7.97(dd,J＝7.6,2.0Hz,1.8H),7.83(s,1H),7.71(dd,J＝8.4,2.0Hz,1H),7.66(dd,J＝8.8,2.4Hz,0.8H),7.60(dd,J＝8.4,2.0Hz,0.8H),7.46(s,0.8H),7.38(dd,J＝8.8,2.4Hz,1H),7.33-7.20(m,3.6H),7.16(d,J＝8.4Hz,0.8H),7.00(td,J＝8.4,2.4Hz,2H),6.95-6.87(m,1.8H),6.86-6.78(m,1.8H),3.89(s,2.4H),3.85(t,J＝6.8Hz,3.6H),3.79(s,3H),2.71-2.31(m,10.8H),2.11-1.88(m,5.4H),1.65-1.40(m,9H).
MS(ESI):m/z 580[M+H]+.
Example 174- (4- ((5-fluoro-1- (3-propylpyrrole) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-148)
4-(4-((5-fluoro-2-oxo-1-(3-(pyrrolidin-1-yl)propyl)indolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000291
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.68(d,J＝1.6Hz,1H),7.97(dd,J＝6.8,1.6Hz,2H),7.83(s,1H),7.75-7.60(m,3H),7.48(s,1H),7.40(dd,J＝8.8,2.4Hz,1H),7.37-7.23(m,3H),7.18(d,J＝8.4Hz,1H),7.14-6.96(m,3H),6.95-6.88(m,2H),6.87-6.78(m,2H),3.90(t,J＝6.8Hz,4H),3.88(s,3H),3.80(s,3H),3.24-2.69(m,12H),2.27-2.17(m,4H),2.07-1.96(m,8H).
MS(ESI):m/z 566[M+H]+.
Example 184- (4- ((5-fluoro-1- (3- (4-methylpiperazin-1-yl) propyl) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-149)
4-(4-((5-fluoro-1-(3-(4-methylpiperazin-1-yl)propyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000292
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.78(d,J＝2.0Hz,1H),7.97(dd,J＝7.2,1.6Hz,2H),7.83(s,1H),7.71(dd,J＝8.4,2.0Hz,1H),7.66(dd,J＝8.8,2.0Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.46(s,1H),7.39(dd,J＝9.2,2.4Hz,1H),7.34-7.27(m,2H),7.25-7.21(m,2H),7.17(d,J＝8.4Hz,1H),6.98(td,J＝8.8,2.0Hz,2H),6.92-6.77(m,4H),3.88(s,3H),3.83(t,J＝6.8Hz,4H),3.79(s,3H),2.72-2.24(m,26H),1.93-1.86(m,4H).
MS(ESI):m/z 595[M+H]+.
Example 194- (4- ((1- (3- (dimethylamino) propyl) -5-fluoro-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-150)
4-(4-((1-(3-(dimethylamino)propyl)-5-fluoro-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000301
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.76(d,J＝1.6Hz,0.8H),7.97(dd,J＝7.6,1.6Hz,1.6H),7.84(s,1H),7.71(dd,J＝8.8,2.0Hz,1H),7.66(dd,J＝8.8,2.0Hz,0.8H),7.61(dd,J＝8.0,1.6Hz,0.8H),7.46(s,1H),7.39(dd,J＝8.8,2.4Hz,1H),7.36-7.22(m,3.8H),7.17(d,J＝8.4Hz,0.8H),7.10-7.04(m,0.8H),7.00(td,J＝8.8,2.4Hz,1.6H),6.95-6.77(m,3H),3.88(m,2.4H),3.85(t,J＝6.8Hz,3.6H),3.79(s,3H),2.57-2.36(m,3.6H),2.30(d,J＝8.0Hz,10.8H),1.97-1.89(m,3.6H).
MS(ESI):m/z 540[M+H]+.
Example 204- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -benzonitrile (LS 2-16)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)benzonitrile
Figure BDA0002209716250000302
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.75(d,J＝2.0Hz,0.8H),7.85(s,1H),7.67-7.57(m,4.4H),7.47(s,0.8H),7.43(dd,J＝8.8,2.4Hz,1H),7.32-7.26(m,2.8H),7.17(d,J＝8.0Hz,1H),7.10(d,J＝8.4Hz,1H),7.05-6.95(m,5.4H),6.86-6.80(m,1.6H),3.94(t,J＝7.2Hz,3.6H),3.93(s,2.4H),3.82(s,3H),3.76-3.66(m,7.2H),2.71-2.62(m,3.6H),2.61-2.50(m,7.2H).
MS(ESI):m/z 450[M+H]+.
Example 215-fluoro-3- (3-methoxy-4- (4-nitro-2- (trifluoromethyl) phenoxy) benzyl ylide) -1- (2-ethylmorpholine) indol-2-one (LS 2-22)
5-fluoro-3-(3-methoxy-4-(4-nitro-2-(trifluoromethyl)phenoxy)benzylidene)-1-(2-morpholinoethyl)indolin-2-one
Figure BDA0002209716250000311
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.75(d,J＝2.0Hz,1H),8.58(dd,J＝6.8,2.8Hz,1.9H),8.31(dd,J＝9.2,2.8Hz,0.9H),8.26(dd,J＝9.2,2.8Hz,1H),7.84(s,0.9H),7.62(dd,J＝8.4,2.0Hz,1H),7.46(s,1H),7.40(dd,J＝8.8,2.4Hz,0.9H),7.32(dd,J＝8.0,1.2Hz,1H),7.30-7.23(m,2.8H),7.19(d,J＝8.4Hz,0.9H),7.00(td,J＝8.4,2.0Hz,1.9H),6.88-6.77(m,3.8H),3.91(t,J＝6.8Hz,3.8H),3.88(s,3H),3.79(s,2.7H),3.69(dd,J＝9.6,6.0Hz,7.6H),2.67-2.60(m,3.8H),2.59-2.49(m,7.6H).
MS(ESI):m/z 588[M+H]+.
Example 225-fluoro-3- (3-methoxy-4- (2- (trifluoromethyl) phenoxy) benzyl ylide) -1- (2-ethylmorpholine) indol-2-one (LS 2-24)
5-fluoro-3-(3-methoxy-4-(2-(trifluoromethyl)phenoxy)benzylidene)-1-(2-morpholinoethyl)indolin-2-one
Figure BDA0002209716250000312
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.72(d,J＝1.6Hz,1H),7.84(s,0.5H),7.72-7.64(m,1.5H),7.58(dd,J＝8.4,2.0Hz,1H),7.52-7.38(m,3H),7.31-7.21(m,2H),7.20-7.11(m,1.5H),7.10-7.03(m,0.5H),7.02-6.93(m,2.5H),6.87(d,J＝8.0Hz,1.5H),6.84-6.73(m,1.5H),3.95(s,3H),3.94-3.88(m,3H),3.77-3.66(m,6H),3.64(s,1.5H),2.70-2.61(m,3H),2.61-2.48(m,6H).
HRMS(ESI):m/z 543.1883[M+H]+.
Example 234- (3-methoxy-4- ((1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) phenoxy) -3-trifluoromethylbenzonitrile (LS 2-25)
4-(3-methoxy-4-((1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000321
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.75(d,J＝8.4Hz,0.5H),8.00(d,J＝2.0Hz,1H),7.98(d,J＝1.6Hz,0.5H),7.92(s,0.5H),7.89(s,1H),7.81-7.70(m,2.5H),7.61-7.51(m,1.5H),7.31-7.21(m,1.5H),7.14-7.02(m,2H),6.93-6.83(m,2.5H),6.76-6.64(m,3H),3.92(t,J＝7.2Hz,3H),3.90(s,1.5H),3.86(s,3H),3.77-3.64(m,6H),2.68-2.60(m,3H),2.60-2.47(m,6H).
MS(ESI):m/z 550[M+H]+.
Example 244- (3-hydroxy-4- ((1- (2-ethylmorpholine) -2-carbonyl-4-phenylindole-3-ylide) methyl) phenoxy) -3-trifluoromethylbenzonitrile
4-(3-hydroxy-4-((1-(2-morpholinoethyl)-2-oxo-4-phenylindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile(LS 2-37)
Figure BDA0002209716250000322
The synthesis was as in example 6.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ10.39(s,1H),7.97(d,J＝1.6Hz,1H),7.72(dd,J＝8.8,2.0Hz,1H),7.52-7.40(m,5H),7.36(t,J＝7.6Hz,1H),7.15(s,1H),7.06(d,J＝8.4Hz,1H),7.00(d,J＝8.0Hz,2H),6.77(d,J＝8.8Hz,1H),6.73(d,J＝2.4Hz,1H),6.54(dd,J＝8.8,2.8Hz,1H),4.05(t,J＝6.8Hz,2H),3.70(d,J＝4.4Hz,4H),2.71(t,J＝6.8Hz,2H),2.65-2.49(m,4H).
MS(ESI):m/z 610[M-H]-.
Example 254- (4- ((4-cyclopropyl-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-hydroxyphenoxy) -3-trifluoromethylbenzonitrile (LS 2-28A)
4-(4-((4-cyclopropyl-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-3-hydroxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000331
The synthesis was as in example 6.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ10.19(s,1H),8.43(s,1H),7.99(d,J＝1.6Hz,1H),7.76(dd,J＝8.4,2.0Hz,1H),7.48(d,J＝8.8Hz,1H),7.25(t,J＝7.6Hz,1H),7.12(d,J＝8.8Hz,1H),7.02(d,J＝8.0Hz,1H),6.88(d,J＝7.6Hz,1H),6.84(d,J＝2.4Hz,1H),6.75(dd,J＝8.8,2.4Hz,1H),4.01(t,J＝6.8Hz,2H),3.68(t,J＝4.4Hz,4H),2.67(t,J＝6.8Hz,2H),2.55(t,J＝4.0Hz,4H),1.12-1.06(m,2H),0.89-0.85(m,3H).
MS(ESI):m/z 574[M-H]-.
Example 264- (3-hydroxy-4- ((1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) phenoxy) -3-trifluoromethylbenzonitrile (LS 2-28B)
4-(3-hydroxy-4-((1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000332
The synthesis was as in example 6.
1H NMR(400MHz,CDCl3):δ8.05-7.96(m,2.5H),7.76(dt,J＝8.8,2.0Hz,1.5H),7.72-7.63(m,1.5H),7.60(d,J＝7.2Hz,0.5H),7.55(d,J＝7.6Hz,1H),7.54(d,J＝8.8Hz,0.5H),7.37-7.32(m,0.5H),7.31-7.24(m,1.5H),7.17(td,J＝7.6,0.8Hz,0.5H),7.10(d,J＝8.8Hz,1H),6.98(d,J＝8.0Hz,0.5H),6.92(td,J＝7.6,0.8Hz,1H),6.87(d,J＝7.6Hz,1H),6.81(d,J＝2.4Hz,0.5H),6.74(dd,J＝8.8,2.8Hz,0.5H),6.67-6.58(m,2H),4.01(t,J＝6.8Hz,1H),3.93(t,J＝7.2Hz,2H),3.74-3.64(m,6H),2.71-2.63(m,3H),2.61-2.48(m,6H).
MS(ESI):m/z 534[M-H]-.
Example 274- (3-hydroxy-4- ((4-methyl-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) phenoxy) -3-trifluoromethylbenzonitrile (LS 2-28C)
4-(3-hydroxy-4-((4-methyl-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000341
The synthesis was as in example 6.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ9.99(s,1H),7.99(d,J＝2.0Hz,1H),7.80(s,1H),7.75(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),7.23(t,J＝8.0Hz,1H),7.11(d,J＝8.8Hz,1H),6.95(d,J＝8.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.78(d,J＝2.4Hz,1H),6.73(dd,J＝8.4,2.4Hz,1H),4.01(t,J＝6.8Hz,2H),3.68(t,J＝4.8Hz,4H),2.67(t,J＝6.8Hz,2H),2.63(s,3H),2.59-2.52(m,4H).
MS(ESI):m/z 548[M-H]-.
Example 283- (4- (4-chloro-2- (trifluoromethyl) phenoxy) -3-methoxybenzylylide) -5-fluoro-1- (2-ethylmorpholine) indol-2-one (LS 2-54)
Figure BDA0002209716250000342
The synthesis was as in example 1.
Further column chromatography separation to obtain:
isomer A1H NMR for(400MHz,CDCl3):δ8.73(d,J＝2.0Hz,1H),7.64(d,J＝2.8Hz,1H),7.58(dd,J＝8.4,2.0Hz,1H),7.45(s,1H),7.37(dd,J＝8.8,2.4Hz,1H),7.30-7.23(m,1H),7.02(d,J＝8.0Hz,1H),7.00-6.95(m,1H),6.82-6.74(m,2H),3.97-3.86(m,5H),3.69(t,J＝4.8Hz,4H),2.64(t,J＝6.8Hz,2H),2.56(t,J＝3.6Hz,4H).
MS(ESI):m/z 577[M+H]+.
Example 294- (4- ((5-fluoro-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzamide (LS 2-62)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzamide
Figure BDA0002209716250000351
The synthesis was as in example 1, step 2.
1H NMR(400MHz,CD3OD):δ8.84(d,J＝1.6Hz,1H),8.26(dd,J＝4.0,2.0Hz,2H),8.07-7.95(m,2H),7.80(d,J＝14.0Hz,2H),7.73(dd,J＝8.4,1.6Hz,1H),7.50-7.44(m,2H),7.44-7.36(m,2H),7.30(d,J＝8.0Hz,1H),7.18(d,J＝8.4Hz,1H),7.06-6.93(m,2H),6.93-6.77(m,4H),3.86(s,3H),3.82(s,3H).
MS(ESI):m/z 473[M+H]+.
Example 303-chloro-4- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) benzonitrile (LS 2-67)
3-chloro-4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)benzonitrile
Figure BDA0002209716250000352
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.75(d,J＝1.6Hz,0.8H),7.85(s,1H),7.76(dd,J＝6.8,2.0Hz,1.8H),7.61(dd,J＝8.4,1.6Hz,0.8H),7.50-7.42(m,2H),7.44-7.35(m,1.6H),7.32-7.22(m,3H),7.18(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,0.8H),7.01(td,J＝8.8,2.8Hz,1.8H),6.88-6.82(m,1.6H),6.82-6.75(m,1.8H),4.02-3.87(m,6H),3.82(s,3H),3.78-3.66(m,7.2H),2.75-2.65(m,3.6H),2.65-2.52(m,7.2H).
MS(ESI):m/z 534[M+H]+.
Example 314- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-nitrobenzoic acid methyl ester (LS 3-53)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-nitrophenyl acetate
Figure BDA0002209716250000361
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.75(d,J＝2.0Hz,0.8H),8.66(d,J＝2.0Hz,1H),8.65(d,J＝2.4Hz,0.8H),8.14(dd,J＝8.8,2.4Hz,1H),8.09(dd,J＝8.8,2.0Hz,0.8H),7.84(s,1H),7.62(dd,J＝8.4,2.0Hz,0.8H),7.46(s,0.8H),7.40(dd,J＝8.8,2.4Hz,1H),7.35-7.23(m,3.6H),7.19(d,J＝8.4Hz,0.8H),7.00(td,J＝8.8,2.4Hz,2H),6.92(d,J＝8.8Hz,1H),6.89(d,J＝8.8Hz,0.8H),6.86-6.77(m,1.8H),4.04-3.94(m,5.4H),3.92(t,J＝6.4Hz,3.6H),3.88(s,2.4H),3.80(s,3H),3.75-3.64(m,7.2H),2.67-2.60(m,3.6H),2.60-2.49(m,7.2H).
MS(ESI):m/z 578[M+H]+.
Example 324- (4- ((5-fluoro-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -2-trifluoromethylbenzonitrile (LS3-58)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-2-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000362
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.68(s,1H),10.67(s,0.6H),8.77(d,J＝1.6Hz,1H),8.16-8.05(m,1.6H),7.95(s,1H),7.94(dd,J＝8.4,1.6Hz,1H),7.73(s,0.6H),7.66(dd,J＝8.8,2.4Hz,1H),7.60(d,J＝1.6Hz,0.6H),7.58-7.52(m,1.6H),7.48-7.39(m,1.2H),7.39-7.33(m,1.6H),7.30(dd,J＝8.4,2.4Hz,0.6H),7.25(dd,J＝8.8,2.4Hz,1H),7.12(td,J＝9.2,2.8Hz,0.6H),7.09-7.02(m,1H),6.88(dd,J＝8.4,4.4Hz,0.6H),6.83(dd,J＝8.4,4.4Hz,1H),3.82(s,3H),3.78(s,1.8H).
MS(ESI):m/z 455[M+H]+.
Example 334- (4- ((5-fluoro-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-nitrobenzonitrile (LS3-63)
4-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-nitrobenzonitrile
Figure BDA0002209716250000371
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.69(s,1H),10.67(s,1H),8.77(d,J＝1.6Hz,1H),8.66(d,J＝2.0Hz,2H),8.05(td,J＝8.8,2.0Hz,2H),7.94(s,1H),7.93(dd,J＝8.4,1.6Hz,1H),7.71(s,1H),7.66(dd,J＝8.8,2.4Hz,1H),7.60(s,1H),7.44(d,J＝0.8Hz,2H),7.44-7.35(m,2H),7.18-7.09(m,2H),7.09-7.01(m,2H),6.88(dd,J＝8.4,4.4Hz,1H),6.83(dd,J＝8.4,4.4Hz,1H),3.81(s,3H),3.78(s,3H).
MS(ESI):m/z 432[M+H]+.
Example 342- (4- ((5-fluoro-2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -5-trifluoromethylbenzonitrile (LS3-67)
2-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-5-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000372
The synthesis was as in example 1, step 2.
1H NMR(400MHz,DMSO-d6):δ10.70(s,1H),10.68(s,0.8H),8.78(d,J＝2.0Hz,1H),8.42(d,J＝2.0Hz,1.8H),7.99-7.93(m,3.8H),7.73(s,0.8H),7.66(dd,J＝8.8,2.4Hz,1H),7.62(d,J＝1.6Hz,0.8H),7.51-7.38(m,3.4H),7.12(td,J＝9.2,2.8Hz,0.8H),7.09-7.03(m,1H),7.01(d,J＝9.2Hz,0.8H),6.94(d,J＝8.8Hz,1H),6.89(dd,J＝8.4,4.4Hz,0.8H),6.83(dd,J＝8.4,4.4Hz,1H),3.83(s,3H),3.79(s,2.4H).
MS(ESI):m/z 455[M+H]+.
Example 354- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -2-trifluoromethylbenzonitrile (LS 3-65)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-2-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000381
The synthesis was as in example 1.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,DMSO-d6):δ8.75(d,J＝2.0Hz,1H),8.11(d,J＝8.8Hz,1H),8.01(s,1H),7.97(dd,J＝8.4,2.0Hz,1H),7.72(dd,J＝8.8,2.4Hz,1H),7.55(d,J＝2.4Hz,1H),7.38(d,J＝8.4Hz,1H),7.25(dd,J＝8.8,2.4Hz,1H),7.16(td,J＝8.8,2.4Hz,1H),7.10(dd,J＝8.8,4.4Hz,1H),3.89(t,J＝6.8Hz,2H),3.82(s,3H),3.51(t,J＝4.4Hz,4H),2.54(t,J＝6.4Hz,2H),2.48-2.37(m,4H).
Isomer B1H NMR(400MHz,DMSO-d6):δ8.13(d,J＝8.8Hz,1H),7.82(s,1H),7.62(d,J＝1.6Hz,1H),7.55(d,J＝2.8Hz,1H),7.49-7.38(m,3H),7.31(dd,J＝8.8,2.4Hz,1H),7.21(td,J＝8.8,2.4Hz,1H),7.15(dd,J＝8.8,4.4Hz,1H),3.89(t,J＝6.4Hz,2H),3.78(s,3H),3.53(t,J＝4.4Hz,4H),2.55(t,J＝6.4Hz,2H),2.39-2.49(m,4H).
MS(ESI):m/z 568[M+H]+.
Example 364- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-nitrobenzonitrile (LS 3-68)
2-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-5-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000382
The synthesis was as in example 1.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,DMSO-d6):δ8.76(d,J＝2.0Hz,1H),8.43(d,J＝2.0Hz,1H),8.02(s,1H),7.99(dd,J＝8.4,1.6Hz,1H),7.95(dd,J＝9.2,2.4Hz,1H),7.73(dd,J＝8.8,2.4Hz,1H),7.45(d,J＝8.4Hz,1H),7.16(td,J＝8.8,2.8Hz,1H),7.10(dd,J＝8.8,4.4Hz,1H),6.95(d,J＝8.8Hz,1H),3.90(t,J＝6.4Hz,2H),3.84(s,3H),3.52(t,J＝4.4Hz,4H),2.54(t,J＝6.4Hz,2H),2.45(s,4H).
Isomer B1H NMR(400MHz,DMSO-d6):δ8.42(d,J＝2.4Hz,1H),7.97(dd,J＝9.2,2.0Hz,1H),7.82(s,1H),7.64(d,J＝1.2Hz,1H),7.53-7.40(m,3H),7.22(td,J＝8.8,2.4Hz,1H),7.15(dd,J＝8.8,4.4Hz,1H),7.01(d,J＝8.8Hz,1H),3.89(t,J＝6.4Hz,2H),3.80(s,3H),3.53(t,J＝4.8Hz,4H),2.55(t,J＝6.4Hz,2H),2.48-2.38(m,4H).
MS(ESI):m/z 568[M+H]+.
Example 374- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-nitrobenzonitrile (LS 3-69)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-nitrobenzonitrile
Figure BDA0002209716250000391
The synthesis was as in example 1.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,DMSO-d6):δ8.75(d,J＝2.0Hz,1H),8.67(d,J＝2.4Hz,1H),8.04(dd,J＝8.8,2.0Hz,1H),8.01(s,1H),7.97(dd,J＝8.4,1.6Hz,1H),7.72(dd,J＝8.8,2.4Hz,1H),7.40(d,J＝8.4Hz,1H),7.19-7.12(m,1H),7.11-7.07(m,1H),7.06(d,J＝8.8Hz,1H),3.89(t,J＝6.4Hz,2H),3.82(s,3H),3.51(t,J＝4.4Hz,4H),2.54(t,J＝6.8Hz,2H),2.49-2.39(m,4H).
Isomer B1H NMR(400MHz,DMSO-d6):δ8.67(d,J＝2.0Hz,1H),8.07(dd,J＝8.8,2.0Hz,1H),7.80(s,1H),7.62(s,1H),7.48-7.41(m,3H),7.21(td,J＝8.8,2.4Hz,1H),7.17-7.10(m,2H),3.88(t,J＝6.4Hz,2H),3.78(s,3H),3.53(t,J＝4.8Hz,4H),2.55(t,J＝6.4Hz,2H),2.48-2.37(m,4H).
MS(ESI):m/z 545[M+H]+.
Example 384- (4- ((5-fluoro-1- (3-propylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 3-155)
4-(4-((5-fluoro-1-(3-morpholinopropyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000401
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.78(s,0.8H),7.98(d,J＝7.2Hz,1.8H),7.85(s,1H),7.78-7.57(m,2.6H),7.47(s,0.8H),7.44-7.13(m,6H),7.00(t,J＝8.4Hz,1.6H),6.94-6.73(m,3.4H),3.99-3.74(m,9H),3.70(d,J＝3.6Hz,7.2H),2.43(d,J＝6.0Hz,10.8H),1.91(t,J＝6.4Hz,3.6H).
MS(ESI):m/z 582[M+H]+.
Example 394- (4- ((5-fluoro-1- (4-butylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 4-1)
4-(4-((5-fluoro-1-(4-morpholinobutyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000402
The synthesis was as in example 1.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ8.76(s,1H),7.95(s,1H),7.65(d,J＝8.8Hz,1H),7.60(d,J＝8.0Hz,1H),7.45(s,1H),7.25-7.20(m,1H),7.16(d,J＝8.0Hz,1H),6.99(t,J＝6.8Hz,1H),6.89-6.70(m,2H),3.88(s,3H),3.79(t,J＝7.2Hz,2H),3.69(s,4H),2.53-2.29(m,6H),1.78-1.67(m,2H),1.65-1.50(m,2H).
MS(ESI):m/z 596[M+H]+.
Example 404- (4- ((5-fluoro-1- (4- (4-methylpiperazin-1-yl) butyl) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 4-3)
4-(4-((5-fluoro-1-(4-(4-methylpiperazin-1-yl)butyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000411
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.77(d,J＝2.0Hz,1H),7.98(d,J＝1.6Hz,0.7H),7.96(d,J＝2.0Hz,1H),7.84(s,0.7H),7.71(dd,J＝8.4,2.0Hz,0.7H),7.66(dd,J＝8.4,2.0Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.46(s,1H),7.38(dd,J＝8.8,2.4Hz,0.7H),7.32-7.22(m,3.4H),7.17(d,J＝8.0Hz,1H),7.03-6.96(m,1.7H),6.86-6.76(m,3.1H),3.89(s,3H),3.86-3.72(m,5.5H),2.85-2.30(m,17H),2.28(d,J＝2.4Hz,5.1H),1.80-1.68(m,3.4H),1.60-1.52(m,3.4H).
MS(ESI):m/z 609[M+H]+.
Example 413-bromo-4- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) benzonitrile (LS 4-35)
3-bromo-4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)benzonitrile
Figure BDA0002209716250000412
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.74(d,J＝2.0Hz,0.8H),7.91(d,J＝2.0Hz,1H),7.89(d,J＝2.0Hz,0.8H),7.82(s,1H),7.59(dd,J＝8.8,2.0Hz,0.8H),7.49(dd,J＝8.4,2.0Hz,1H),7.47-7.41(m,1.8H),7.38(dd,J＝8.8,2.4Hz,1H),7.30-7.26(m,0.8H),7.26-7.21(m,1.8H),7.16(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,0.8H),7.02-6.92(m,1.8H),6.82-6.76(m,1.8H),6.74(d,J＝8.4Hz,1H),6.72(d,J＝8.4Hz,0.8H),3.92-3.86(m,6H),3.79(s,3H),3.70-3.64(m,7.2H),2.65-2.58(m,3.6H),2.57-2.50(m,7.2H).
HRMS(ESI):m/z 578.1064[M+H]+.
Example 424- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -1-naphthacenitrile (LS 4-36)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-1-naphthonitrile
Figure BDA0002209716250000421
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.79(d,J＝1.2Hz,1H),8.50(t,J＝8.8Hz,2H),8.24(dd,J＝8.0,4.8Hz,2H),7.87(s,1H),7.85-7.72(m,4H),7.72-7.56(m,3H),7.55-7.39(m,2H),7.37-7.19(m,4H),7.14(d,J＝8.4Hz,1H),7.06-6.94(m,2H),6.82(td,J＝8.8,4.4Hz,2H),6.69(dd,J＝8.0,5.6Hz,2H),4.02-3.83(m,7H),3.80(s,3H),3.70(dd,J＝9.2,5.2Hz,8H),2.73-2.60(m,4H),2.57(s,8H).
HRMS(ESI):m/z 550.2114[M+H]+.
Example 433- (4- (4-bromo-2- (trifluoromethyl) phenoxy) -3-methoxybenzyl ylide) -5-fluoro-1- (2-ethylmorpholine) indol-2-one (LS 4-38)
3-(4-(4-bromo-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-5-fluoro-1-(2-morpholinoethyl)indolin-2-one
Figure BDA0002209716250000422
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.72(d,J＝2.0Hz,1H),7.83(s,1H),7.78(dd,J＝6.4,2.4Hz,2H),7.58(dd,J＝8.4,1.6Hz,1H),7.54(dd,J＝8.8,2.4Hz,1H),7.50(dd,J＝8.8,2.0Hz,1H),7.46-7.40(m,2H),7.28-7.26(m,1H),7.26-7.22(m,2H),7.11(d,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,1H),7.01-6.94(m,2H),6.80(td,J＝8.4,4.0Hz,2H),6.71(dd,J＝8.8,6.4Hz,2H),3.97-3.87(m,7H),3.82(s,3H),3.69(dd,J＝9.2,4.8Hz,8H),2.63(td,J＝6.8,3.6Hz,4H),2.60-2.46(m,8H).
HRMS(ESI):m/z 621.0985[M+H]+.
Example 444- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzoic acid methyl ester (LS 4-39)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzoate
Figure BDA0002209716250000431
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.73(d,J＝1.6Hz,1H),8.36(d,J＝2.0Hz,1H),8.35(d,J＝2.0Hz,1H),8.09(dd,J＝8.8,2.4Hz,1H),8.05(dd,J＝8.8,2.0Hz,1H),7.83(s,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.45(s,1H),7.42(dd,J＝8.8,2.4Hz,1H),7.31-7.27(m,1H),7.26-7.22(m,2H),7.20(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),7.01-6.94(m,2H),6.84-6.75(m,4H),3.94-3.87(m,13H),3.79(s,3H),3.68(dd,J＝9.6,5.6Hz,8H),2.66-2.60(m,4H),2.60-2.50(m,8H).
HRMS(ESI):m/z 601.1945[M+H]+.
Example 454- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -phenoxy) -3-trifluoromethylbenzonitrile (LS 4-46)
4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)phenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000432
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.45-8.35(m,2H),8.01(d,J＝2.0Hz,1H),7.99(d,J＝2.0Hz,1H),7.84(s,1H),7.78(dd,J＝8.8,2.0Hz,1H),7.74(dd,J＝8.4,2.0Hz,1H),7.72-7.65(m,2H),7.47(s,1H),7.33(dd,J＝8.8,2.4Hz,1H),7.27-7.22(m,1H),7.23-7.16(m,2H),7.16-7.11(m,2H),7.06(t,J＝8.8Hz,2H),6.99(td,J＝8.8,2.8Hz,2H),6.80(td,J＝8.4,4.0Hz,2H),3.96-3.86(m,4H),3.69(dd,J＝9.2,4.8Hz,8H),2.66-2.58(m,4H),2.59-2.49(m,8H).
HRMS(ESI):m/z 538.1742[M+H]+.
Example 463-difluoromethyl-4- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) benzonitrile (LS 4-52)
3-(difluoromethyl)-4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)benzonitrile
Figure BDA0002209716250000441
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.74(d,J＝1.6Hz,1H),7.96(d,J＝6.0Hz,2H),7.84(s,1H),7.67-7.56(m,3H),7.46(s,1H),7.40(dd,J＝8.8,2.4Hz,1H),7.32-7.26(m,2H),7.26-7.20(m,2.5H),7.16(d,J＝8.0Hz,1H),7.13(d,J＝4.4Hz,1H),7.04-6.96(m,2.5H),6.88-6.72(m,4H),3.92(t,J＝7.2Hz,4H),3.87(s,3H),3.78(s,3H),3.70(dd,J＝9.6,5.2Hz,8H),2.64(td,J＝6.8,4.8Hz,4H),2.56(s,8H).
HRMS(ESI):m/z 550.1935[M+H]+.
Example 473- (4- (2-chloro-5-methoxy-4-nitrophenoxy) -3-methoxybenzyl ylide) -5-fluoro-1- (2-ethylmorpholine) indol-2-one (LS 4-83)
3-(4-(2-chloro-5-methoxy-4-nitrophenoxy)-3-methoxybenzylidene)-5-fluoro-1-(2-morpholinoethyl)indolin-2-one
Figure BDA0002209716250000442
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.82(d,J＝2.0Hz,1H),8.14(d,J＝6.0Hz,2H),7.86(s,1H),7.63(dd,J＝8.4,1.6Hz,1H),7.46(s,1H),7.32(dd,J＝9.2,2.8Hz,1H),7.30-7.24(m,3H),7.18(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),7.04-6.95(m,2H),6.86-6.77(m,2H),6.42(s,2H),3.98-3.88(m,7H),3.85(s,3H),3.79(s,3H),3.76(s,3H),3.74-3.67(m,8H),2.65(t,J＝6.8Hz,4H),2.57(s,8H).
HRMS(ESI):m/z 584.1573[M+H]+.
Example 483- (4- (2, 6-dichloro-4-nitrophenoxy) -3-methoxybenzyl ylide) -5-fluoro-1- (2-ethylmorpholine) indol-2-one (LS 4-90)
3-(4-(2,6-dichloro-4-nitrophenoxy)-3-methoxybenzylidene)-5-fluoro-1-(2-morpholinoethyl)indolin-2-one
Figure BDA0002209716250000451
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3):δ8.83(d,J＝1.6Hz,1H),8.31(d,J＝7.2Hz,4H),7.80(s,1H),7.50-7.38(m,3H),7.27(d,J＝2.0Hz,1H),7.23(dd,J＝8.4,2.4Hz,1H),7.15(dd,J＝8.4,1.2Hz,1H),7.02-6.92(m,2H),6.80(td,J＝9.2,4.0Hz,2H),6.60(d,J＝8.4Hz,1H),6.52(d,J＝8.4Hz,1H),4.05(s,3H),3.95(s,3H),3.91(td,J＝7.2,2.4Hz,4H),3.69(dd,J＝7.6,3.6Hz,8H),2.63(td,J＝6.8,2.0Hz,4H),2.60-2.46(m,8H).
HRMS(ESI):m/z 588.1072[M+H]+.
Example 494- (4- ((5-fluoro-1- (2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) ethyl) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 4-70)
4-(4-((5-fluoro-1-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000452
The synthesis was as in example 1.
HRMS(ESI):m/z 664.2887[M+H]+.
Example 504- (4- ((5-fluoro-2-carbonyl-1- (2- (4- (pyrrol-1-yl) piperidin-1-yl) ethyl) indole-3-ylide) methyl) -2-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 4-77)
4-(4-((5-fluoro-2-oxo-1-(2-(4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)indolin-3-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000453
The synthesis was as in example 1.
HRMS(ESI):m/z 635.2609[M+H]+.
Example 514- ((2- (2-ethylmorpholine) -1-carbonyl-1, 2-dihydrobenzo [6,7] oxepino [4,3,2-cd ] indol-8-yl) oxy) -3-trifluoromethylbenzonitrile (LS 1-132)
4-((2-(2-morpholinoethyl)-1-oxo-1,2-dihydrobenzo[6,7]oxepino[4,3,2-cd]indol-8-yl)oxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000461
4- (4- ((4-bromo-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -3-hydroxyphenoxy) -3-trifluoromethylbenzonitrile (LS 1-125,24mg,0.04mmol), cesium carbonate (32mg,0.1mmol), cuprous iodide (1mg,0.004mmol), tetramethylethylenediamine (1drop) were dissolved in 5 ml of N, N-dimethylformamide, protected with argon, and heated to 100 ℃ for reaction overnight. The reaction system was cooled, filtered through celite, the filtrate was extracted three times with dichloromethane, the organic phases were combined, washed with saturated brine, spin dried, and separated by column chromatography to give a white solid (7mg, 32%).
1H NMR(400MHz,CDCl3):δ8.00(d,J＝1.6Hz,1H),7.79(dd,J＝8.4,2.0Hz,1H),7.16-7.01(m,3H),6.88(s,1H),6.67(dd,J＝8.4,2.4Hz,1H),6.56(d,J＝2.4Hz,1H),6.43(d,J＝7.6Hz,1H),6.31(d,J＝8.4Hz,1H),3.81(t,J＝6.4Hz,2H),3.77-3.66(m,4H),2.68-2.45(m,6H).
MS(ESI):m/z 534[M+H]+.
Example 524- (2- ((5-fluoro-2-indolone-3-ylide) methyl) -6-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS3-80)
4-(2-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-6-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000462
The synthesis was as in example 1, step 2.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ10.61(s,1H),8.28(d,J＝2.0Hz,1H),7.94(dd,J＝8.8,2.0Hz,1H),7.68-7.49(m,1H),7.47-7.31(m,3H),7.14-7.01(m,2H),6.89-6.72(m,2H),3.79(s,3H).
MS(ESI):m/z 455[M+H]+.
Example 534- (2- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -6-methoxyphenoxy) -3-trifluoromethylbenzonitrile (LS 3-82)
4-(2-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-6-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile
Figure BDA0002209716250000471
The synthesis was as in example 1.
Further column chromatography separation to obtain:
isomer A1H NMR(400MHz,CDCl3):δ7.91(d,J＝2.0Hz,1H),7.69(s,1H),7.58(dd,J＝8.8,2.0Hz,1H),7.39(t,J＝8.0Hz,1H),7.36-7.30(m,1H),7.19(dd,J＝8.8,2.8Hz,1H),7.16-7.10(m,1H),6.98(td,J＝8.8,2.4Hz,1H),6.76(dd,J＝8.8,4.4Hz,1H),6.65(d,J＝8.8Hz,1H),3.84(t,J＝6.8Hz,2H),3.80(s,3H),3.65(t,J＝4.4Hz,4H),2.59(t,J＝6.8Hz,2H),2.51(t,J＝4.4Hz,4H).
Isomer B1H NMR(400MHz,CDCl3):δ8.28(dd,J＝8.0,0.8Hz,1H),7.97(d,J＝2.0Hz,1H),7.67-7.60(m,2H),7.39(t,J＝8.0Hz,1H),7.14(dd,J＝8.4,1.2Hz,1H),7.10(dd,J＝8.0,2.4Hz,1H),6.98(td,J＝8.4,2.4Hz,1H),6.76(t,J＝4.0Hz,1H),6.72(d,J＝8.8Hz,1H),3.85(t,J＝7.2Hz,2H),3.80(s,3H),3.69(t,J＝4.8Hz,4H),2.60(t,J＝7.2Hz,2H),2.54(t,J＝4.4Hz,4H).
MS(ESI):m/z 568[M+H]+.
Example 543-amino-4- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) benzonitrile (LS 4-93)
3-amino-4-(4-((5-fluoro-1-(2-morpholinoethyl)-2-oxoindolin-3-ylidene)methyl)-2-methoxyphenoxy)benzonitrile
Figure BDA0002209716250000481
4- (4- ((5-fluoro-1- (2-ethylmorpholine) -2-indolone-3-ylide) methyl) -2-methoxyphenoxy) -3-nitrobenzonitrile (LS 3-69,55mg,0.1mmol), reduced iron powder (17mg,0.3mmol), and ammonium chloride (77mg,1mmol) were dissolved in a mixed solvent of 8 ml of ethanol and 4 ml of water, and heated to reflux until the reaction was completed. After suction filtration through celite, the filtrate was spin-dried and isolated by column chromatography to give a yellow solid (37mg, 73%).
1H NMR(400MHz,CDCl3):δ8.77(d,J＝1.6Hz,1H),7.84(s,1H),7.55(dd,J＝8.8,2.0Hz,1H),7.48-7.41(m,2H),7.27-7.22(m,3H),7.15-7.03(m,3H),7.04-6.93(m,5H),6.81(td,J＝8.4,4.4Hz,2H),6.72(d,J＝5.2Hz,1H),6.70(d,J＝5.2Hz,1H),4.15(d,J＝10.0Hz,4H),3.99-3.88(m,7H),3.85(s,3H),3.70(dd,J＝9.2,4.8Hz,8H),2.64(td,J＝7.2,3.2Hz,4H),2.56(s,8H).
MS(ESI):m/z 515[M+H]+.
Example 55 time resolution-fluorescence resonance energy transfer assay (TR-FRET test)
The effect of the compounds described in examples 1-54 on the interaction of the estrogen-related receptor ERR α with the coactivator protein PGC-1 α was examined using a time-resolved fluorescence resonance energy transfer assay (TR-FRET test).
Using a commercial screening kit (LanthaScreen)TMEstrogen Related Receptor alpha TR-FRET Coactivator assay, Invitrogen PV4663), which adopts the principle of fluorescence resonance energy transfer, and comprises the following specific steps: the compounds were mixed in 5 concentration gradients (2X) using Buffer (the 2-indolone compounds in this example were present in cis-trans tautomeric mixtures in the activity assay solutions), and 10. mu.L of each solution was applied to a 384-well blackboard (Thermo, #267461), and then 5. mu.L of ERR alpha-LBD (20nM, 4X) solution was added to each well, followed by 5. mu.L of a mixed solution containing fluoro-resein-PGC 1. alpha. (2. mu.M, 4X) and Tb anti-GST antibody (20nM, 4X); the reaction mixture was left at room temperature for 1 hour with exclusion of light, and the emission intensities at 520nm and 495nm were measured and the ratio thereof was calculated. The ratio (emission coefficient) is positively correlated with the concentration of the compound, and the IC is calculated by making a curve of the relationship between the ratio and the concentration50The value is obtained.
Table 1 lists the numbers of the compounds of the examples and the results of the activity corresponding to TR-FRET.
TABLE 1
Figure BDA0002209716250000482
Figure BDA0002209716250000491
Figure BDA0002209716250000501
Wherein, the positive molecule C29 is obtained from J.Med.chem.2011,54, 788-.
As can be seen from the data in Table 1, the indolone molecules of the invention have stronger binding capacity with ERR alpha, thereby influencing the interaction between ERR alpha and coactivator PGC-1 alpha, and the activity of partial compounds is better than that of the positive molecule C29.
EXAMPLE 56 Effect of Compounds on tumor cell proliferation inhibitory Activity
Tumor cells were stored in the corresponding growth medium and passaged at least two passages before resuscitative use. The appropriate number of cells in logarithmic growth phase were seeded in 96-well plates in a volume of 100. mu.L per well in a medium containing 5% CO2Was cultured overnight in a 37 ℃ incubator. After 2. mu.L of compound solutions with different concentrations (the 2-indolone compounds in this example all exist in a mixed form of cis-trans isomer interconversion in the activity test solution) and 998. mu.L of culture solution were mixed uniformly, 100. mu.L of the culture solution was added to the corresponding 96-well plate, and 2. mu.L of DMSO was used as a blank. After 72 hours of co-incubation, 20. mu.L of MTT (5mg/mL) reagent was added, shaken for 10 minutes, and run with SynergyTMHT (Bio Tek)/OD570 stained cell number was read. Data were processed with Graph Pad Prism version 4.0 and fitted to a non-linear regression curve to obtain IC50The value is obtained.
The tumor cell strain adopts SKBr3(HER2+), BT-474(HER2+), MDA-MB-231(TNBC), HS578T, A549, H460 and the like.
Table 2 lists the numbers of the compounds of the examples and the corresponding results of cell proliferation inhibitory activity.
TABLE 2
Figure BDA0002209716250000511
Note: -is not detected.
As can be seen from the data in Table 2, the indolone compounds of the invention have good proliferation inhibition activity on tumor cells, which is superior to the positive molecule C29. Wherein the compound LS 1-86 has cell proliferation inhibition activity IC on breast cancer cells SKBr3 and BT-47450The values were 5.3. mu.M and 6.8. mu.M, respectively.
EXAMPLE 57 Effect of Compounds on the oral maximum glucose tolerance test in BKS-DB (DB/DB) mice
DB/DB mice (leptin receptor gene knockout mice, animal source: Nanjing model animal research institute) of 6 weeks old were selected and bred for one week after purchase to eliminate stress and adapt to the environment. 32 male mice were randomly divided into 4 groups of 8 mice each, as LS 1-86 groups (15mg/kg i.p.), LS 1-149 groups (15mg/kg i.p.), rosiglitazone groups (10mg/kg i.p.), and negative controls. The administration is once daily for 28 days. Mice were monitored daily for body weight, feed intake. Oral maximum glucose tolerance test (OGTT) was performed on day 28, fasting was performed overnight before the test, glucose (2g/kg) was gavaged, and blood glucose concentrations of mice at 0, 30, 60, 90, 120, 150min were measured by tail vein blood sampling and plotted.
The test results are shown in fig. 1. As can be seen from the curve in FIG. 1, the indolone compounds of the invention have a large effect on the down-regulation of blood sugar, which indicates that the tolerance of mice to glucose is improved after the indolone compounds of the invention are injected.
The technical features of the above-mentioned embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the following embodiments are not described, however, as long as there is no contradiction between the combinations of the technical features, the combinations should be considered as the scope of the present description.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (18)

1. An indolone compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003596616940000011
wherein the content of the first and second substances,
m is selected from: 0.1 and 2;
ring (C)
Figure FDA0003596616940000012
Selected from: s number of R0Substituted or unsubstituted C6-C10Aryl, s R0Substituted or unsubstituted C5-C10A heteroaryl group;
R1、R2、R3、R4、R5、R6、R7、R8、R0each independently selected from: hydrogen, halogen, cyano, nitro, amino, hydroxy, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C3-C6Cycloalkyl radical, RfSubstituted or unsubstituted C1-C6Alkoxy radical, RfSubstituted or unsubstituted C3-C6Cycloalkoxy, RfSubstituted or unsubstituted C2-C6Alkenyl radical, RfSubstituted or unsubstituted C2-C6Alkynyl, RfSubstituted or unsubstituted phenyl, - (CH)2)pNRaRb-C (═ O) OR, -CONHR, OR R3And R5Are linked together by a chemical bond to form-O-, -NH-, or- (CH)2)n；
R9Selected from: hydrogen, - (CH)2)qNRdRe、-(CH2)qORd、-(CH2)qOCRcRdRe、-(CH2)qCRcRdRe；
s is selected from: an integer of 0 to 5;
n is selected from: 1 or 2;
p is selected from; an integer of 0 to 6;
q is selected from: 1 to 6;
Ra、Rbeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl, RfSubstituted or unsubstituted C1-C6Heteroalkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted heteroatom-containing monocyclic, fused, spiro or bridged ring;
r is selected from: hydrogen, C1-C6An alkyl group;
Rcselected from: hydrogen, C1-C3An alkyl group;
Rd、Reeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl radical, RfSubstituted or unsubstituted C1-C6Heteroalkyl, or Rd、ReTogether with the N or C atom to which they are attached to form RfA substituted or unsubstituted heteroatom-containing monocyclic, fused, spiro or bridged ring;
each RfEach independently selected from: halogen, hydroxy, amino, C1-C3Alkyl, hydroxy substituted C1-C3Alkyl radical, C1-C3Alkoxy, -NH (C)1-C3Alkyl), -N (C)1-C3Alkyl) (C1-C3Alkyl), -C (═ O) (C)1-C3Alkyl), R is a substituted or unsubstituted 5-to 7-membered heterocyclic group.
2. The indolone compound or pharmaceutically acceptable salt thereof of claim 1, wherein the ring is
Figure FDA0003596616940000021
Selected from the group consisting of: a benzene ring, a pyridine ring, a naphthalene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a pyrazine ring, a pyridazine ring, an imidazole ring or a pyrimidine ring.
3. The indolone compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is1、R2、R3、R4、R5、R6、R7、R8、R0Each independently selected from: hydrogen, halogen, cyano, nitro, amino, hydroxy, C1-C6Alkyl, halo C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C3-C6Cycloalkoxy, C2-C6Alkenyl radical, C2-C6Alkynyl, phenyl, - (CH)2)pNRaRb-C (═ O) OR, -CONHR, OR R3And R5Are linked together by a chemical bond to form-O-;
Raand RbEach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C3Alkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 3-8 membered monocyclic ring containing 1,2 or 3 heteroatoms, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 8-12 membered fused, spiro or bridged ring containing 1,2 or 3 heteroatoms; the heteroatom is selected from: o, N, S is added.
4. The indolone compound or pharmaceutically acceptable salt thereof of claim 3, wherein R is1、R2、R3、R4、R5、R6、R7、R8、R0Each independently selected from: hydrogen, halogen, cyano, nitro, hydroxy, C1-C3Alkyl, halo C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, phenyl, -C (═ O) OR, -CONHR, OR R3And R5Are linked together by a chemical bond to form-O-; wherein R is selected from: hydrogen、C1-C3An alkyl group.
5. The indolone compound or pharmaceutically acceptable salt thereof of claim 3, wherein R is1、R2、R3、R4、R5、R6、R7、R8、R0Each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, methyl, ethyl, isopropyl, propyl, cyclopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, cyclopropyloxy, vinyl, ethynyl, phenyl, - (CH)2)p-NH2、
Figure FDA0003596616940000022
Figure FDA0003596616940000023
Figure FDA0003596616940000024
-C(＝O)OH、-C(＝O)OCH3、-C(＝O)OCH2CH3、-C(＝O)OCH2(CH3)CH3、-CONH2、-CONHCH3Or R is3And R5Are linked together by a chemical bond to form-O-; wherein p is an integer of 0 to 3.
6. The indolone compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is9Selected from: hydrogen, - (CH)2)qNRdRe(ii) a Wherein the content of the first and second substances,
q is selected from: 1.2, 3 or 4;
Rd、Reeach independently selected from: hydrogen, RfSubstituted or unsubstituted C1-C6Alkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 3-8 membered monocyclic ring containing 1,2 or 3 heteroatoms, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 8-12 membered fused, spiro or bridged ring containing 1,2 or 3 heteroatoms; the heteroatom is selected from: o, N, S are provided.
7. The indolone compound or pharmaceutically acceptable salt thereof of claim 6, wherein R isd、ReEach independently selected from: hydrogen, C1-C3Alkyl, or Ra、RbTogether with the N atom to which they are attached form RfA substituted or unsubstituted 5-7 membered monocyclic ring containing 1,2 or 3 heteroatoms; the heteroatom is selected from: o, N, respectively; rfSelected from the group consisting of: H. c1-C3Alkyl, -NH (C)1-C3Alkyl), -N (C)1-C3Alkyl) (C1-C3Alkyl), 5-to 7-membered heterocyclic group, C1-C3An alkyl-substituted 5-to 7-membered heterocyclic group.
8. The indolone compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is9Selected from the group consisting of: hydrogen, - (CH)2)q-NH2、
Figure FDA0003596616940000031
Figure FDA0003596616940000032
Figure FDA0003596616940000041
-(CH2)q-OH、-(CH2)q-OCH3、-(CH2)q-OCH2CH3(ii) a Wherein q is selected from: 1.2, 3 or 4.
9. The indolone compound or pharmaceutically acceptable salt thereof of claim 1, wherein the ring is
Figure FDA0003596616940000042
Selected from: benzene ring, naphthalene ring;
R1、R2、R3、R4、R5、R6、R7、R8each independently selected from: hydrogen, methoxy, hydroxy, fluoro, chloro, bromo, methyl, cyclopropyl, phenyl, or R3And R5Are linked together by a chemical bond to form-O-;
R0selected from: hydrogen, cyano, trifluoromethyl, nitro, fluoro, chloro, bromo, carboxamido, formyl, methyl formate, difluoromethyl, methoxy;
R9selected from: hydrogen, - (CH)2)q-NH2、
Figure FDA0003596616940000043
Figure FDA0003596616940000044
Figure FDA0003596616940000045
Figure FDA0003596616940000046
Wherein q is selected from: 1.2, 3 or 4.
10. The indolone compound or pharmaceutically acceptable salt thereof of claim 9 wherein the ring is
Figure FDA0003596616940000047
Selected from: benzene ring, naphthalene ring;
R1、R2、R3、R4、R5、R6、R7、R8each independently selected from: hydrogen, methoxy, hydroxy, fluoro, chloro, bromo, methyl, cyclopropyl, phenyl, or R3And R5Are connected together by a chemical bond to form-O-;
R0selected from: hydrogen, cyano, trifluoromethyl, nitro, fluoro, chloro, bromo, methyl formate, difluoromethyl, methoxy;
R9selected from: hydrogen, hydrogen,
Figure FDA0003596616940000048
Figure FDA0003596616940000049
Wherein q is selected from 1,2, 3 or 4.
11. The indolone compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 10, having a structure represented by formula (II) or formula (III):
Figure FDA0003596616940000051
wherein s is selected from: an integer of 0 to 4.
12. The indolone compound or pharmaceutically acceptable salt thereof of claim 11, wherein R is1、R2、R3、R4、R6、R7、R8Each independently selected from: hydrogen, methoxy, hydroxy, fluoro, chloro, bromo, methyl, cyclopropyl, phenyl;
R5selected from: hydrogen, phenyl; and when R is5When it is hydrogen, R2And R3Are not hydroxyl;
R0selected from: hydrogen, cyano, trifluoromethyl, nitro, fluoro, chloro, bromo, methyl formate, difluoromethyl, methoxy;
R9selected from: hydrogen, hydrogen,
Figure FDA0003596616940000052
Figure FDA0003596616940000053
q is selected from: 1.2, 3 or 4.
13. The indolone compound or pharmaceutically acceptable salt thereof of claim 1, wherein the indolone compound is selected from the group consisting of:
Figure FDA0003596616940000061
Figure FDA0003596616940000071
14. use of an indolone compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof in the preparation of an ERR α inverse agonist.
15. Use of the indolone compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of a disease associated with aberrant expression of ERR α protein activity.
16. The use of claim 15, wherein the disease associated with aberrant expression of ERR α protein activity is: tumors, metabolic diseases.
17. The use of claim 16, wherein the tumor is: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, endometrial cancer, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma, malignant melanoma, renal cancer, bladder cancer, ovarian cancer, cervical cancer, laryngeal cancer, or multiple myeloma, B lymphoma, leukemia;
the metabolic disease is: hyperglycemia, diabetes, obesity, atherosclerosis, metabolic syndrome, liver fibrosis, non-alcoholic fatty liver disease, gallstone, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, hypertension, hyperinsulinemia, hyperuricemia, Parkinson's disease, and Alzheimer's disease.
18. A pharmaceutical composition for preventing and/or treating diseases associated with abnormal expression of ERR α protein activity, which is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the indolone compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.
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