CN114105977B - Estrogen receptor modulator compounds and uses thereof - Google Patents

Estrogen receptor modulator compounds and uses thereof Download PDF

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Publication number
CN114105977B
CN114105977B CN202110997502.6A CN202110997502A CN114105977B CN 114105977 B CN114105977 B CN 114105977B CN 202110997502 A CN202110997502 A CN 202110997502A CN 114105977 B CN114105977 B CN 114105977B
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compound
compounds
pharmaceutically acceptable
estrogen receptor
methyl
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CN114105977A (en
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张雁
杨圣伟
庞司林
唐锋
王峰
彭少平
任晋生
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Hainan Xiansheng Zaiming Pharmaceutical Co ltd
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Xiansheng Zaiming Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The present application describes compounds having estrogen receptor modulating activity or function, and pharmaceutically acceptable salts thereof, having the structure of formula (I) and having the substituents and structural features described herein. The application also describes a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of estrogen receptor related diseases.

Description

Estrogen receptor modulator compounds and uses thereof
The application claims priority from a prior application filed by 8.28.2020 to the national intellectual property agency under the patent application number 202010886642.1 and entitled "estrogen receptor modulator compound and use thereof". The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The present application relates to estrogen receptor modulator compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds, and their use in the prevention or treatment of estrogen receptor related diseases.
Background
Estrogen (E2) and estrogen alpha receptor (erα) are important drivers of the development and progression of breast cancer. In breast cancer patients, more than 2/3 of the patients express ER transcription factors, and in most ER-positive patients, ER is a key driver even in tumors that progress after early endocrine treatment, and therefore ER is a major target for breast cancer treatment (Pharmacology & Therapeutics 186 (2018) 1-24). Endocrine therapy aims at reducing ER activity, and there are three main classes, including selective estrogen receptor modulators (selective estrogen receptor modulators, SERMs), such as tamoxifen (tamoxifen), which are allosteric modulators of ER and inhibit their transcriptional activity when bound to ER; aromatase inhibitors (aromatase inhibitors, AIs) reduce in vivo estrogen levels by inhibiting the conversion of androgens to estrogens; and selective estrogen receptor down-regulators such as fulvestrant (fulvestrant), which not only inhibit the activity of ER antagonists, but also have the effect of inducing ER protein degradation. Although endocrine therapy is the first choice for estrogen receptor positive breast cancer patients, about 30% of patients relapse after treatment and almost all metastatic breast cancer patients develop drug resistance and progress. The mechanisms of endocrine therapy for drug resistance mainly include two types, namely, the mechanism is concentrated on the estrogen receptor signaling pathway, and the mechanism comprises activation mutation, amplification, fusion with other genes, estrogen receptor co-regulation factors, downstream control cell cycle factors and the like of an ESR1 gene for encoding an estrogen receptor; another class of mechanisms includes activation of signaling pathways that cross-react with estrogen receptor signaling pathways, such as the growth factor receptor pathway, etc. (Oncol Ther,2017, 5:17-29).
Fulvestrant is the first and only drug of the class of selective estrogen receptor downregulators (selective estrogen receptor downregulators, SERDs) clinically approved for use in post-menopausal patients for ER-positive, metastatic breast cancer following progression of tamoxifen or aromatase inhibitors. In addition, a series of SERDs compounds with novel structures and corresponding medical applications are also disclosed by the aslicon (see patent application WO2018077630A 1) and the gene Talck company (see patent application WO2019245974A 1). The data from several studies show that fulvestrant-treated patients do not fully achieve ER degradation, but that fulvestrant doses (up to only 500mg, mainly the highest doses that can be administered to patients limited by their pharmacodynamic characteristics and intramuscular route of administration) may also limit their efficacy. Thus, SERDs that have higher bioavailability, higher antagonistic activity against ER, and are able to degrade ER to a greater extent, and that can be used in pre-menopausal patients with higher estrogen levels, for convenient oral administration, are highly desirable in the clinic.
Disclosure of Invention
The present invention relates to compounds of formula (I):
Wherein, the liquid crystal display device comprises a liquid crystal display device,
X 1 、X 2 、X 3 、X 4 independently selected from CR 7 Or N;
R 7 selected from H, F, cl, br, I, OH, CN, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyloxy or 3-6 membered heterocycloalkyloxy;
het is selected from
R 1 、R 2 Independently selected from hydrogen, OH, F, cl, br, I, C 1 -C 6 Alkyl or C 2 -C 8 Alkenyl groups;
alternatively, R 1 、R 2 Together with the carbon atoms to which they are attached form C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by R a Substitution;
w is selected from C in straight or branched chain form 1 -C 3 An alkylene group;
R 5 selected from C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 ；
R 6 Selected from H, C 1 -C 6 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1 -C 6 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 ；
R 3 Selected from H, CN, COOH, C (O) OR b 、OC(O)R b 、CONH 2 、C(O)NR b R c 、SO 2 R b 、SO 2 NR b R c 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl, C 6 -C 10 Aryl or C 5 -C 10 Heteroaryl, said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocycloalkyl, C 6 -C 10 Aryl or C 5 -C 10 Heteroaryl is optionally substituted with 1 or more R d Substitution;
R 4 selected from H, F, cl, br, I, OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or C 3 -C 6 Heterocycloalkyl, said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or C 3 -C 6 The heterocycloalkyl group is optionally substituted with one or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 ；
Ring Q is selected from C 6 -C 10 Aryl or 5-10 membered heteroaryl, said C 6 -C 10 Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more R 8 Substitution;
R 8 selected from F, cl, br, I, OH, CN, COOH, C (O) OR b 、OC(O)R b 、CONH 2 、C(O)NR b R c 、NR c C(O)R b 、SO 2 R b 、SO 2 NR b 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl, said C 3 -C 6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more groups selected from: F. cl, br, I, OH, CN, C 1 -C 6 Alkyl and C 1 -C 6 An alkoxy group;
R a selected from halogen, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with halogen;
R b independently selected from C 1 -C 6 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl;
R c independently selected from H, C 1 -C 6 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl;
R d independently selected from F, cl, br, I, OH, CN, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1 or more groups selected from F, cl, br, I or OH;
n is 0, 1 or 2.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (Ia):
in some embodiments, the R 1 、R 2 Together with the carbon atoms to which they are attached form C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by R a And (3) substitution.
In some embodiments, the R 1 、R 2 Together with the carbon atoms to which they are attached form C 3 -C 4 Cycloalkyl or 3-4 membered heterocycloalkyl, said C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by R a And (3) substitution.
In some embodiments, the R 1 、R 2 Together with the carbon atoms to which they are attached form cyclopropane.
In some embodiments, the R 1 、R 2 Independently selected from hydrogen, OH, F, cl, br, I, C 1 -C 6 Alkyl or C 2 -C 8 Alkenyl groups.
In some embodiments, the R 1 、R 2 Independently selected from hydrogen, OH, F, cl, br or I.
In some embodiments, the R 1 、R 2 Selected from hydrogen.
In some embodiments, n is selected from 0 or 1.
In some embodiments, n is selected from 0.
In some embodiments, the R 3 Selected from C 1 -C 6 Alkyl, CN, COOH, C (O) OR b 、OC(O)R b 、CONH 2 、C(O)NR b R c Or C 6 -C 10 Aryl, said C 1 -C 6 Alkyl or C 6 -C 10 Aryl is optionally substituted with one or more R d Substituted, R d Independently selected from F, cl, br, I, OH, CN or C optionally substituted with 1 or more groups selected from F, cl, br, I or OH 1 -C 6 An alkyl group.
In some embodiments, the R 3 Selected from C 1 -C 6 Alkyl or C 6 -C 10 Aryl, said C 1 -C 6 Alkyl or C 6 -C 10 Aryl is optionally substituted with one or more R d Substituted, R d Independently selected from F, cl, br, OH or C optionally substituted with 1 or more groups selected from F, cl, br or OH 1 -C 6 An alkyl group.
In some embodiments, the R 3 Selected from C 1 -C 3 Alkyl, said C 1 -C 3 Alkyl is optionally substituted with one or more R d Substituted, R d Independently selected from F or OH.
In some embodiments, the R 3 Selected from-CH 2 CF 3 Or (b)
In some embodiments, the R 3 Selected from the group consisting of
In some embodiments, the R 4 Selected from the group consisting of optionally a primer F, cl,Br or I substituted C 1 -C 6 An alkyl group.
In some embodiments, the R 4 Selected from methyl optionally substituted with F, cl, br or I.
In some embodiments, the R 4 Is methyl.
In some embodiments, the W is selected from C in a linear form 1 -C 3 An alkylene group.
In some embodiments, the W is selected from the group consisting of-CH 2 -or-CH 2 CH 2 -。
In some embodiments, the W is selected from the group consisting of-CH 2 -。
In some embodiments, the R 5 Is C 3 -C 6 Cycloalkyl group, the C 3 -C 6 Cycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 。
In some embodiments, the R 5 Is C 3 -C 5 Cycloalkyl group, the C 3 -C 5 Cycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 。
In some embodiments, the R 5 Is cyclopropyl or cyclobutyl, optionally substituted with 1 or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 。
In some embodiments, the R 5 Is cyclopropyl or cyclobutyl, optionally substituted with 1 or more groups selected from: F. cl, br, I and CN.
In some embodiments, the R 5 Is cyclopropyl or cyclobutyl, optionally substituted with 1 or more groups selected from: F. cl, br and I.
In some embodiments, the R 5 Is that
In some embodiments, the X 1 、X 4 Selected from CR 7 Or N, X 2 、X 3 Is CR (CR) 7 。
In some embodiments, the R 7 Selected from H, F, cl, br or I.
In some embodiments, the X 1 、X 4 Selected from CH, CF or N, X 2 、X 3 CH.
In some embodiments, the X 1 、X 4 Is CF, X 2 、X 3 CH.
In some embodiments, the X 1 Is N, X 2 、X 3 、X 4 CH.
In some embodiments, the R 6 Selected from H or C 1 -C 6 An alkyl group.
In some embodiments, the R 6 Selected from H.
In some embodiments, when Het and NR 6 When the attached atom is chiral carbon, its configuration is the (S) -configuration.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (II):
wherein X is 1 、X 2 、X 3 、X 4 、Het、R 3 、R 4 And R is 6 As defined in formula (I);
R 10 selected from H, C 1 -C 6 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl, said C 1 -C 6 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, br, I, CN, OH, OCH 3 And SO 2 CH 3 。
In some embodiments, R 10 Selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl.
In some embodiments, R 10 H.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIa):
wherein X is 1 、X 2 、X 3 、X 4 、Het、R 3 、R 4 、R 6 And R is 10 As defined by formula (II).
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (III):
wherein X is 1 、X 2 、X 3 、X 4 、Het、R 3 、R 4 And R is 6 As defined by formula (I).
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIIa):
wherein X is 1 、X 2 、X 3 、X 4 、Het、R 3 、R 4 And R is 6 As defined by formula (I).
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:
in one aspect, the compounds of the application are present in racemic mixtures or in enantiomerically enriched or enantiomerically pure form. In certain embodiments, the compounds of the present application are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomer. In some embodiments, resolution of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation/resolution techniques based on solubility differences. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by enzymatic resolution. In some embodiments, resolution of individual stereoisomers is performed using a lipase or an esterase. In some embodiments, resolution of individual stereoisomers is performed by lipase or esterase catalyzed asymmetric deacylation. In other embodiments, separation of stereoisomers is performed by chromatography, or by forming a salt of a diastereomer and separating by recrystallization or chromatography, or any combination thereof. In some embodiments, stereoisomers are obtained by stereoselective synthesis.
The invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient.
In some embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.
In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.
Further, the invention relates to application of a compound shown in the formula (I) or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for preventing or treating estrogen receptor related diseases.
Further, the present invention relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for preventing or treating an estrogen receptor related disease.
Further, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for preventing or treating an estrogen receptor related disease.
Further, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating an estrogen receptor-related disease.
The invention also relates to a method of treating an estrogen receptor related disorder comprising administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention.
The present invention also relates to a method of treating an estrogen receptor related disorder in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Preferred embodiments of the present invention wherein the estrogen receptor related disorder includes, but is not limited to, cancer, autoimmune diseases, and the like.
In some embodiments of the invention, the estrogen receptor-related disorder is preferably a tumor.
In some embodiments of the invention, the estrogen receptor related disorder includes, but is not limited to, breast cancer.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present invention, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
Herein, a method of manufacturing a semiconductor deviceRepresenting the ligation site.
The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.
The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the invention. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the definition of compounds of the invention. The asymmetric atom-containing compounds of the present invention may be isolated in optically pure form or in racemic form, which may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, wedge-shaped keys and dotted keys are usedAnd->) Representing the absolute configuration of a stereogenic center. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the invention.
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (e.g. CH 2 CH 2 F) Polysubstituted (e.g. CHFCH 2 F、CH 2 CHF 2 Etc.) or fully substituted (CF) 2 CF 3 ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
C herein m -C n Refers to having an integer number of carbon atoms in the m-n range. For example "C 1 -C 10 By "is meant that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "alkyl" refers to a compound of the formula C n H 2n+1 The alkyl group may be linear or branched. The term "C 1 -C 6 Alkyl "is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5, 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, etc.
The term "alkoxy" refers to a monovalent group derived from a straight or branched chain alcohol by the loss of a hydrogen atom from a hydroxyl groupIt is understood that "-O-alkyl". According to the invention, suitable alkoxy groups are C 1-6 Alkoxy radicals, e.g. C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy groups including methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, sec-butoxy and the like.
The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, straight or branched chain, and having at least one double bond. The term "C 2 -C 8 Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. The term "C 2 -C 4 Alkynyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3 or 4 carbon atoms.
The term "cycloalkyl" refers to a fully saturated carbocycle in the form of a single ring, a parallel ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C 3 -C 6 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C 3 -C 5 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 5 carbon atoms, such as cyclopropyl, cyclobutyl or cyclopentyl.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. The term "3-6 membered heterocycloalkyl" refers to a heterocycloalkyl having 3, 4, 5, 6 ring atoms, respectively. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, ethylene oxide, ethylene nitride, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxalkyl, 1, 4-dioxane, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and the like.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. The term "C 6 -C 10 Aryl "is understood to mean preferably a mono-or bicyclic hydrocarbon ring with monovalent aromaticity of 6 to 10 carbon atoms. In particular having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C " 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being aromatic ring groups of C. The term "5-10 membered heteroaryl" is understood to include such monovalent monocyclic or bicyclic aromatic ring systems: having 5 to 10 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S. The term "5-10 membered heteroaryl" is understood to include such monovalent monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9, 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, furthermore, can be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiadiazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The term "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for use in the above formulations are: saccharides, starches, cellulose and derivatives thereof, and the like.
The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
The words "comprise", "comprising" or "includes" and variations thereof such as include or comprise are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to".
The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is from 0.01mg/kg to 200mg/kg body weight, preferably from 0.05mg/kg to 50mg/kg body weight, more preferably from 0.1mg/kg to 30mg/kg body weight, either alone or in divided doses.
The invention also includes isotopically-labeled compounds of the invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labeled compounds of the invention (e.g., with 3 H is H 14 C-tag) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled books can generally be prepared by substituting an isotopically-labeled reagent for an unlabeled reagent by the following procedures similar to those disclosed in the schemes and/or examples below The compound of the application.
The term "IC 50 "half maximal inhibitory concentration" means the concentration of a particular compound required to obtain 50% inhibition of an in vitro biological process. IC (integrated circuit) 50 The values can be converted logarithmically into pIC 50 Value (-log IC) 50 ) Where higher values represent exponentially greater efficacy.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
The application is further illustrated by examples, which are not intended to limit the scope of the application, for clarity. All reagents used in the present application are commercially available and can be used without further purification.
Detailed Description
The following examples illustrate the technical aspects of the invention in detail, but the scope of the invention is not limited thereto. The present invention has been described in detail herein, and embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the invention without departing from the spirit and scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).
Example 1:3- (((1 r,3 r) -1- (2, 6-difluoro-4- ((1- ((((1 r,2 r) -2-fluorocyclopropyl) methyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
Step 1: synthesis of 5-bromo-2- (diethoxymethyl) -1, 3-difluorobenzene
4-bromo-2, 6-difluorobenzaldehyde (2.19 g,10.0 mmol) was added to 50mL of ethanol, triethyl orthoformate (1.48 g,10.0 mmol) was added dropwise, and after 1 drop of concentrated sulfuric acid was added, the mixture was heated to 60℃and stirred, after 4 hours, the reaction solution was dried by spinning to give the title compound.
Step 2: synthesis of tert-butyl 3- (((4- (diethoxymethyl) -3, 5-difluorophenyl) amino) azetidine-1-carboxylate
5-bromo-2- (diethoxymethyl) -1, 3-difluorobenzene (2.94 g,10.0 mmol), 1-t-butoxycarbonyl-3-aminocyclobutylamine (2.06 g,12.0 mmol), tris (dibenzylideneacetone) dipalladium (458 mg,0.5 mmol) 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (579 mg,1.00 mmol) and cesium carbonate (9.75 g,30.0 mmol) were added to 40mL of 1, 4-dioxane, and after stirring under argon gas at 80℃for 6 hours, the reaction mixture was concentrated, 100mL of ethyl acetate was added, suction filtration and the filtrate was concentrated to give a crude product.
Step 3: synthesis of tert-butyl 3- ((3, 5-difluoro-4-formylphenyl) amino) azetidine-1-carboxylate
Adding the crude product obtained in the last step into 50mL of tetrahydrofuran, adding 20mL of 2N dilute hydrochloric acid solution, stirring at room temperature, after 2 hours, adjusting the pH of the reaction solution to 8-9 by using saturated sodium bicarbonate aqueous solution, adding 50mL of water, extracting by using ethyl acetate, combining organic layers, concentrating and performing column chromatography to obtain the title compound.
Step 4: synthesis of tert-butyl 3- ((4- ((1R, 3R) -2- (2, 2-difluoro-3-hydroxypropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridinyl [3,4-b ] indol-1-yl) -3, 5-difluorophenyl) amino) azetidine-1-carboxylic acid ester
Tert-butyl 3- ((3, 5-difluoro-4-formylphenyl) amino) azetidine-1-carboxylate (2.50 g,8.00 mmol), (R) -3- (((1- (1H-indol-3-yl) prop-2-yl) amino) -2, 2-difluoropropan-1-ol (2.18 g,8.00 mmol) was added to 40mL toluene, 4mL acetic acid was added and heated to 80 ℃ C. And stirred for 20 hours after completion of the reaction, the reaction was concentrated, 100mL water was added, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, ethyl acetate extraction, the organic layers were combined and column chromatography after concentration gave the title compound.
Step 5: synthesis of 3- ((1R, 3R) -1- (4- (azetidin-3-ylamino) -2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyridinyl [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
3- ((1R, 3R) -1- (4- (azetidin-3-ylamino) -2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyridinyl [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol (2.88 g,5.12 mmol) is dissolved in 30mL of tetrahydrofuran, cooled to 0 ℃, concentrated sulfuric acid (2.78 mL,52.0 mmol) is slowly added dropwise, after the dropwise addition is completed, the reaction is completed after stirring for 2 hours at room temperature, the reaction solution is cooled to 0 ℃, saturated aqueous sodium bicarbonate is slowly added dropwise, the pH is adjusted to 8-9, 50mL of water is added, ethyl acetate is used for extraction, the organic layers are combined, anhydrous sodium sulfate is dried, and the title compound is obtained after suction filtration and concentration.
Step 6: synthesis of (3- ((4- ((1R, 3R) -2- (2, 2-difluoro-3-hydroxypropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridinyl [3,4-b ] indol-1-yl) -3, 5-difluorophenyl) amino) azetidin-1-yl) ((1R, 2R) -2-fluorocyclopropyl) methanone
3- ((1R, 3R) -1- (4- (azetidin-3-ylamino) -2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyridinyl [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol (2.34 g,5.06 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.30 g,6.07 mmol), (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid (526 mg,5.06 mmol) was dissolved in 30mL of N, N-dimethylformamide, after addition of N, N-diisopropylethylamine (1.96 g,15.2 mmol) and stirring at room temperature for 1 hour, the reaction was added to 100mL of water, the ethyl acetate extracts, the combined organic layers were dried over anhydrous sodium sulfate and the organic layers were concentrated to give the title compound.
Step 7: synthesis of 3- (((1R, 3R) -1- (2, 6-difluoro-4- ((1- ((((1R, 2R) -2-fluorocyclopropyl) methyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
(3- ((4- ((1R, 3R) -2- (2, 2-difluoro-3-hydroxypropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridinyl [3,4-b ] indol-1-yl) -3, 5-difluorophenyl) amino) azetidin-1-yl) ((1R, 2R) -2-fluorocyclopropyl) methanone (0.60 g,1.09 mmol) was added to 10mL of anhydrous tetrahydrofuran, cooled to 0 ℃, a solution of lithium aluminum hydride in tetrahydrofuran (2.00 mL,1.00 mol/L) was slowly added dropwise, the mixture was stirred at room temperature for 2 hours after the dropwise addition was completed, the reaction solution was cooled to 0 ℃, and 10mL of ethyl acetate solution was slowly added dropwise, and methanol was slowly added dropwise after the dropwise addition was completed: 2mL of water=10:1 solution, followed by dropwise addition of the reaction solution to ice water, extraction with ethyl acetate, combination of organic layers, drying over anhydrous sodium sulfate, concentration and column chromatography gave the title compound.
DMSO-d6δ H 10.52(s,1H),7.38-7.37(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.72-6.71(m,1H),6.12-6.09(m,2H),5.26-5.23(m,1H),5.05(s,1H),4.83-4.79(m,0.5H),4.66-4.63(m,0.5H),3.96-3.93(m,1H),3.69-3.60(m,3H),3.47-3.37(m,2H),3.14-3.03(m,1H),2.85-2.80(m,3H),2.64-2.50(m,3H),2.47-2.42(m,1H),1.07-1.06(m,3H),0.89-0.85(m,1H),0.79-0.73(m,1H),0.60-0.50(m,1H).
LC/MS(m/z,MH + ):535.2
Example 2:3- (((1 r,3 r) -1- (2, 6-difluoro-4- ((1- ((((1 s,2 s) -2-fluorocyclopropyl) methyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The procedure was analogous to example 1, except that (1 r,2 r) -2-fluorocyclopropane-1-carboxylic acid in step 6 of example 1 was replaced with (1 s,2 s) -2-fluorocyclopropane-1-carboxylic acid, the last two steps of reaction of example 1 was carried out in the same manner to obtain the title compound.
DMSO-d6δ H 10.50(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.70-6.68(m,1H),6.11-6.08(m,2H),5.25-5.20(m,1H),5.05(s,1H),4.82-4.78(m,0.5H),4.65-4.62(m,0.5H),3.95-3.92(m,1H),3.69-3.60(m,3H),3.47-3.37(m,2H),3.14-3.03(m,1H),2.85-2.80(m,3H),2.64-2.50(m,3H),2.47-2.42(m,1H),1.07-1.05(m,3H),0.91-0.85(m,1H),0.79-0.71(m,1H),0.59-0.49(m,1H).
LC/MS(m/z,MH + ):535.2
Example 3:3- (((1 r,3 r) -1- (2, 6-difluoro-4- ((1- ((((1 s,2 r) -2-fluorocyclopropyl) methyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The procedure was analogous to example 1, except that (1 r,2 r) -2-fluorocyclopropane-1-carboxylic acid in step 6 of example 1 was replaced with (1 s,2 r) -2-fluorocyclopropane-1-carboxylic acid, the last two steps of reaction of example 1 was carried out in the same manner to obtain the title compound.
DMSO-d6δ H 10.51(s,1H),7.38-7.35(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.70-6.68(m,1H),6.11-6.08(m,2H),5.25-5.20(m,1H),5.05(s,1H),4.82-4.78(m,0.5H),4.65-4.62(m,0.5H),3.95-3.92(m,1H),3.69-3.60(m,3H),3.47-3.37(m,2H),3.14-3.03(m,1H),2.85-2.80(m,3H),2.64-2.49(m,3H),2.47-2.42(m,1H),1.07-1.05(m,3H),0.91-0.85(m,1H),0.79-0.71(m,1H),0.59-0.49(m,1H).
LC/MS(m/z,MH+):535.2
Example 4:3- ((1 r,3 r) -1- (4- ((1- ((2, 2-difluorocyclopropyl) methyl) azetidin-3-yl) amino) -2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The procedure was analogous to example 1, except that (1 r,2 r) -2-fluorocyclopropane-1-carboxylic acid in step 6 of example 1 was replaced with 2, 2-difluorocyclopropane-1-carboxylic acid, the last two steps of reaction of example 1 was carried out in the same manner to obtain the title compound.
DMSO-d6δ H 10.51(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.71-6.70(m,1H),6.12-6.09(m,2H),5.25-5.22(m,1H),5.05(s,1H),3.98-3.90(m,1H),3.71-3.60(m,3H),3.47-3.38(m,2H),3.14-3.03(m,1H),2.83-2.80(m,3H),2.68-2.55(m,3H),2.43-2.38(m,1H),1.75-1.62(m,1H),1.57-1.48(m,1H),1.20-1.12(m,1H),1.07-1.06(m,3H).
LC/MS(m/z,MH + ):553.2
Example 5:3- ((1 r,3 r) -1- (4- ((1- ((3, 3-difluorocyclobutyl) methyl) azetidin-3-yl) amino) -2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyridinyl [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The procedure was analogous to example 1, except that (1 r,2 r) -2-fluorocyclopropane-1-carboxylic acid in step 6 of example 1 was replaced with 3, 3-difluorocyclobutane-1-carboxylic acid, the last two steps of reaction of example 1 being carried out in the same manner to obtain the title compound.
DMSO-d6δ H 10.51(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.08-6.91(m,2H),6.69-6.68(m,1H),6.12-6.08(m,2H),5.24-5.21(m,1H),5.05(s,1H),3.97-3.90(m,1H),3.72-3.62(m,3H),3.49-3.36(m,3H),3.13-3.03(m,1H),2.84-2.77(m,3H),2.68-2.55(m,4H),2.27-2.15(m,3H),2.08-2.06(m,1H),1.07-1.06(m,3H).
LC/MS(m/z,MH + ):567.2
Example 6:3- ((1 r,3 r) -1- (2, 6-difluoro-4- ((1- ((3-fluorocyclobutyl) methyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The procedure was analogous to example 1, except that (1 r,2 r) -2-fluorocyclopropane-1-carboxylic acid in step 6 of example 1 was replaced with 3-fluorocyclobutane carboxylic acid, the last two steps of reaction of example 1 was carried out in the same manner to obtain the title compound.
DMSO-d6δ H 10.51(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.69-6.67(m,1H),6.11-6.08(m,2H),5.24-5.21(m,1H),5.05(s,1H),3.95-3.90(m,1H),3.72-3.62(m,4H),3.43-3.36(m,3H),3.13-3.03(m,1H),2.84-2.77(m,3H),2.68-2.55(m,4H),2.27-2.15(m,3H),2.08-2.06(m,1H),1.07-1.05(m,3H).
LC/MS(m/z,MH + ):549.2
Example 7:3- (((1 r,3 r) -1- (2, 6-difluoro-4- (((S) -1- ((((1S, 2S) -2-fluorocyclopropyl) methyl) pyrrolidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyridin [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The procedure was carried out in analogy to example 1, except for replacing 1-tert-butoxycarbonyl-3-aminocyclobutylamine in step 2 of example 1 with tert-butyl (S) -3-aminopyrrolidine-1-carboxylate and the following six steps of reaction of example 1 were carried out to obtain the title compound.
DMSO-d6δ H 10.51(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.22-6.19(m,3H),5.25-5.22(m,1H),5.03(s,1H),4.85-4.81(m,0.5H),4.68-4.64(m,0.5H),3.76-3.62(m,2H),3.46-3.36(m,2H),3.12-3.02(m,2H),2.83-2.78(m,1H),2.70-2.60(m,3H),2.46-2.38(m,4H),1.07-1.05(m,3H),0.82-0.57(m,5H).
LC/MS(m/z,MH + ):549.2
Example 8:3- ((1 r,3 r) -1- (2, 6-difluoro-4- (((S) -5- ((((1 r,2 r) -2-fluorocyclopropyl) methyl) -5-azaspiro ] [2.4] heptan-7-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol
The title compound was obtained in analogy to example 1, except that 1-tert-butoxycarbonyl-3-aminocyclobutylamine in step 2 of example 1 was replaced with tert-butyl (S) -7-amino-5-azaspiro [2.4] heptane-5-carboxylate and the following six steps of reaction were performed in the same manner as in example 1.
DMSO-d6δ H 10.51(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.22-6.19(m,3H),5.25-5.22(m,1H),5.03(s,1H),4.85-4.81(m,0.5H),4.68-4.64(m,0.5H),3.76-3.62(m,2H),3.46-3.36(m,2H),3.12-3.02(m,2H),2.83-2.78(m,1H),2.70-2.54(m,4H),2.46-2.38(m,3H),1.07-1.05(m,3H),1.00-0.94(m,1H),0.81-0.71(m,2H),0.65-0.41(m,4H).
LC/MS(m/z,MH + ):575.2
Example 9: n- (1- ((((1R, 2R) -2-fluorocyclopropyl) methyl) azetidin-3-yl) -6- ((6S, 8R) -8-methyl-7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinolin-6-yl) pyridin-3-amine
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Step 1: synthesis of tert-butyl 3- ((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinolin-6-yl) pyridin-3-yl) amino) azetidine-1-carboxylic acid ester
The intermediate (6S, 8R) -6- (5-bromopyridin-2-yl) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinoline was prepared according to the procedure of example 17 of WO2018077630A 1.
(6S, 8R) -6- (5-bromopyridin-2-yl) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinoline (5.08 g,10.0 mmol), 1-t-butoxycarbonyl-3-aminocyclobutylamine (2.06 g,12.0 mmol), tris (dibenzylideneacetone) dipalladium (458 mg,0.5 mmol) 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (579 mg,1.00 mmol), cesium carbonate (9.75 g,30.0 mmol) were added to 40mL of 1, 4-dioxane, the reaction was heated to 80℃under argon and stirred for 6 hours, 100mL ethyl acetate was added, and the filtrate was concentrated to give a crude product.
Step 2: synthesis of N- (azetidin-3-yl) -6- (((6S, 8R) -8-methyl-7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4],3-f ] isoquinolin-6-yl) pyridin-3-amine
Tert-butyl 3- ((6S, 8R) -8-methyl-3- (tetrahydro-2H-pyran-2-yl) -7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinolin-6-yl) pyridin-3-yl) amino) azetidine-1-carboxylate (600 mg,1.00 mmol) was dissolved in 30mL of methanol, cooled to 0 ℃, 4M/L of dioxane solution of hydrogen chloride (2.50 mL,10.0 mmol) was slowly added dropwise, after the dropwise addition was completed, the reaction was stirred at room temperature for 2 hours, after the completion of the reaction, the reaction solution was cooled to 0 ℃, saturated aqueous sodium bicarbonate was slowly added dropwise, the pH was adjusted to 8-9, ethyl acetate was added for extraction, the organic layer was combined, dried over anhydrous sodium sulfate, and concentrated after suction filtration to give the title compound.
Step 3: synthesis of((1R, 2R) -2-fluorocyclopropyl) (3- ((6S, 8R) -8-methyl-7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinolin-6-yl) pyridin-3-yl) amino) azetidin-1-yl) methanone
N- (azetidin-3-yl) -6- (((6S, 8R) -8-methyl-7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4],3-f ] isoquinolin-6-yl) pyridin-3-amine (416 mg,1.00 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (380 mg,1.00 mmol), and (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid (104 mg,1.00 mmol) were dissolved in 30mL of N, N-dimethylformamide, N, N-diisopropylethylamine (254 mg,2.00 mmol) was added and stirred at room temperature for 1 hour after completion of reaction, the title reaction solution was added to 100mL of water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the organic layer was concentrated and then column chromatographed to give the title compound.
Step 4: synthesis of N- (1- ((((1R, 2R) -2-fluorocyclopropyl) methyl) azetidin-3-yl) -6- ((6S, 8R) -8-methyl-7- (2, 2-trifluoroethyl) -6,7,8, 9-tetrahydro-3H-pyrazolo [4,3-f ] isoquinolin-6-yl) pyridin-3-amine
(3- ((4- ((1R, 3R) -2- (2, 2-difluoro-3-hydroxypropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridinyl [3,4-b ] indol-1-yl) -3, 5-difluorophenyl) amino) azetidin-1-yl) ((1R, 2R) -2-fluorocyclopropyl) methanone (250 mg,0.50 mmol) was added to 10mL anhydrous tetrahydrofuran, cooled to 0 ℃, a solution of borane in tetrahydrofuran (1.00 mL, 1.00M/L) was slowly added dropwise, after the dropwise addition was completed, the mixture was heated to 70℃and stirred for 2 hours, after the completion of the reaction, the reaction was cooled to 0 ℃, 20mL methanol was added, and column chromatography was performed after concentration to obtain the title compound.
DMSO-d6δ H 13.02(s,1H),8.06(s,1H),7.79-7.78(m,1H),7.24-7.22(m,1H),7.06-7.04(m,1H),6.98-6.96(m,1H),6.80-6.78(m,1H),6.58-6.56(m,1H),4.96(s,1H),4.52-4.51(m,0.5H),4.35-4.34(m,0.5H),3.95(m,1H),3.64-3.60(m,2H),3.55-3.45(m,2H),3.09-3.04(m,1H),3.00-2.94(m,1H),2.87-2.81(m,1H),2.74-2.71(m,2H),2.47-2.41(m,2H),1.07-1.06(m,3H),0.98-0.82(m,3H).
LC/MS(m/z,MH + ):489.2。
Biological Activity and related Property test cases
Experimental example 1: detection of degradation effect of compound of the invention on estrogen receptor in MCF7 cells
Test principle: determination of the degradation Activity of the Compounds of the invention on the endogenous expression of the estrogen receptor in MCF7 cells, according to IC 50 And evaluating the activity of the compound to be tested by maximum degradation efficiency.
The test method comprises the following steps:
MCF7 cells (purchased from ATCC, HTB-22) were cultured in complete medium with DMEM (purchased from Gibco, 11995-065) containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded at 3000 per well in 384 well plates using complete medium, 37 ℃,5% co 2 And (5) culturing the cells in a cell culture box. Test compounds were dissolved in DMSO, stored at a concentration of 10mM, diluted with Echo 550 (available from Labcyte Inc.) and added to cell culture plates, each compound was treated at an initial concentration of 100nM, 3-fold gradient dilution, 9 concentration points, a blank containing 0.5% DMSO was set, and each concentration point was set at doubleAnd (3) duplicate hole control. 37 ℃,5% CO 2 The cells were cultured in an incubator for 24 hours. Adding paraformaldehyde into each cell culture well to fix cells with a final concentration of about 3.7%, allowing the cells to act for 30 minutes, discarding the supernatant, and adding 50 mu L of PBS for washing once per well; cells were treated with PBS (0.5% v/v Tween-20) for 30 min and washed once with PBS; blocking solution (self-made, PBS containing 5% BSA and 0.05% v/v Tween-20) was added and incubated for 1 hour at room temperature; adding primary antibody mixture (anti-ER monoclonal antibody, estrogen Receptor alpha (D8H 8) Rabbit mAb, purchased from GST, # 864S, 1:1000 dilution; anti-GAPDH monoclonal antibody, GAPDH (D4C 6R) Mouse mAb, purchased from GST, #97166S,1:2000 dilution) into the deblocking solution, and incubating for 3 hours at room temperature; wash 3 times with PBST (homemade, PBS containing 0.05% v/v Tween-20); adding detection secondary antibody (800 CW-goat anti-rabbit IgG, purchased from LI-COR, P/N:926-32211,1:1000 dilution; 680 RD-goat anti-mouse IgG, purchased from LI-COR, #925-68070,1:1000 dilution), and incubating at room temperature in the absence of light for 45 min; PBST was washed 3 times and each well fluorescent signal was read using Odyssey CLx. XLfit for data processing, and inhibitory activity IC of each compound was calculated from the concentration of the compound and the fluorescence signal value 50 Maximum degradation efficiency.
Test results:
under the present experimental conditions, the test compounds have good inhibitory activity against ER levels at the cellular level. The results of the corresponding ER level activity test for the test compounds are shown in Table 1.
TABLE 1 test results of ER level Activity test of Compounds on cellular level in vitro
Test compounds ER level DC 50 (nM) Maximum ER downregulation (%)
Example 1 0.07 103.36
Example 2 0.14 95.76
Example 3 0.45 79.50
Example 4 0.12 95.84
Example 5 0.36 90.21
Example 6 0.23 84.93
Example 7 0.22 90.95
Example 8 0.31 95.37
Example 9 0.22 107.81
Experimental example 2: detection of inhibition effect of the inventive Compounds on T47D cell proliferation
Test principle: determining the inhibitory effect of the compounds of the invention on T47D cell proliferation in vitro, according to IC 50 The activity of the compounds was evaluated.
The test method comprises the following steps:
T47D (T-47D) cells (purchased from ATCC, HTB-133) were cultured with RPMI-1640 (purchased from Gibco, A10491-01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, T47D cells were seeded at 500/well in 384-well plates using complete medium, 37 ℃,5% co 2 The cell culture was incubated overnight in an incubator. The following day, test compounds were added for drug treatment, compound solutions with storage concentrations of 10mM were diluted with Echo550 (purchased from labyte inc.) and transferred into each cell culture well, each compound was diluted at 100nm in 3-fold gradient in the initial intracellular treatment concentration, 10 concentration points were set up as blank controls containing 0.3% dmso, and each concentration point was set up as double-well controls. 37 ℃,5% CO 2 The cell culture medium was cultured for 7 days, and the cell culture plate was removed from the incubator for the eighth day. Adding inLuminescent Cell Viability Assay (from Promega, G7573), after 10 minutes of standing at room temperature, luminescence signal values were read using a multi-label microplate reader EnVision (from Perkinelmer), and inhibitory activity IC of each compound was calculated from the concentration of the compound and the luminescence signal values using XLfit 50 。
Test results:
under the experimental conditions, the test compound shows good inhibition activity on T47D breast cancer cells. The results of the test compounds for their inhibitory activity on T47D cell proliferation are shown in Table 2.
Inhibitory Activity of the Compounds of Table 2 against T47D cell proliferation
Test compounds T47D IC 50 (nM)
Example 1 0.17
Experimental example 3: detection of the inhibitory Effect of the Compounds of the invention on proliferation of MCF7 cells
Test principle: determining the inhibitory effect of the compounds of the invention on the proliferation of MCF7 cells in vitro, according to IC 50 And maximum inhibition efficiency to evaluate the activity of the compounds.
The test method comprises the following steps:
MCF7 cells (ATCC, HTB-22) were cultured in complete medium of DMEM (Gibco, 11995-065) containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded at 500 per well in 384 well plates using complete medium, 37 ℃,5% co 2 The cell culture was incubated overnight in an incubator. The following day, test compounds were added for drug treatment, 10mM stock concentration of compound solution was diluted with Echo550 (Labcyte Inc.) and transferred into each cell culture well, each compound was diluted at 100nM in the initial concentration of treatment in the cell, 3-fold gradient, 9 concentration points, a blank control containing 0.3% DMSO was set, and a double well control was set at each concentration point. 37 ℃,5% CO 2 The cell culture medium was cultured for 7 days, and the cell culture plate was removed from the incubator for the eighth day. Adding inLuminescent Cell Viability Assay (Promega, G7573), after leaving at room temperature for 10 minutes, luminescence signal values were read using a multi-label microplate reader EnVision (PerkinElmer), and inhibitory activity IC of each compound was calculated from the concentration of the compound and the luminescence signal values using XLfit 50 。
Test results:
under the experimental conditions, the test compound has better inhibition activity on MCF-7 cell proliferation. The results are shown in Table 3.
Table 3 Compounds have inhibitory Activity against proliferation of MCF-7 cells
Numbering of compounds MCF-7 cell proliferation inhibition IC 50 (nM)
Example 1 0.07
Experimental example 4: pharmacokinetic property detection of the inventive Compounds
Test principle: the LC/MS method was used to determine the drug concentration in plasma at various times after intragastric and intravenous administration of the compounds of the invention in mice as test animals. The pharmacokinetic behavior of the compound of the invention in mice is studied and its pharmacokinetic profile is evaluated.
The test method comprises the following steps:
4.1 test animals
Healthy adult BALB/c mice, 24 female, equally divided into 4 groups of 6, 3 intragastric, 3 intravenous, were purchased from beijing velariwa laboratory animal technologies, inc, animal production license number: SCXK (Zhe) 2019-0001.
4.2 pharmaceutical formulation
A certain amount of the medicine is weighed and dissolved in DMSO 5% + PG 20% + absolute ethanol 5% + solvent 10% + water 60% to prepare 10mg/ml for gastric lavage. A certain amount of the medicine is weighed and dissolved in DMSO 1% + PG 4% + absolute ethanol 1% + solvent 2% + water 92% to prepare 1mg/ml for intravenous injection.
4.3 administration of drugs
Gastric lavage group: BALB/c mice were fed by gastric lavage after overnight fast, at a dose of 10mg/kg and a volume of 1mL/kg.
Vein group: BALB/c mice were dosed intravenously after overnight fast at a dose of 1mg/kg and a dosing volume of 1mL/kg.
4.4 operation
After the mice were subjected to gastric lavage or intravenous administration, 40. Mu.L of the blood was collected from the eyebox 5min, 15min, 30min, 1h, 2h, 4h, 24h, 5. Mu.L of EDTA-K2 was anticoagulated, and plasma was centrifuged at 12000rpm at 4℃for 5 minutes and stored at-20 ℃.
Determination of the content of test compounds in plasma of mice after gastric lavage or intravenous administration of different concentrations of drug: melting the sample at room temperature, and swirling for 1min; quantitatively transferring 15 μl to 2ml 96-well plate, adding 150 μl of internal standard precipitant, and shaking (1200 rpm for 3 min); centrifugation (4000 rpm. Times.15 min), transfer supernatant 100. Mu.L to 1ml 96 well plate; blow-dry with nitrogen, add 100 μl of complex solution (acetonitrile water 1:9), shake well (900 rpm 3 min), and analyze with 20 μl of sample. LC/MS conditions: mobile phase a:0.1% formic acid in water, mobile phase B:0.1% acetonitrile formate, column: ACE C18 μm (3.0 mm. Times.50 mm), column temperature: the flow rate was 0.5ml/min at 35 ℃.
Test results:
under the experimental conditions, the test compounds showed better pharmacokinetic properties, and the results are shown in table 4.
Table 4 pharmacokinetic parameters following single intragastric administration of compounds in mice
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included in the scope of the present invention.

Claims (4)

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:
2. a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
3. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of an estrogen receptor related disorder, wherein the estrogen receptor related disorder is a neoplasm.
4. The use of claim 3, wherein the tumor is breast cancer.
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