CN116425757A - Polycyclic compounds and uses thereof - Google Patents

Polycyclic compounds and uses thereof Download PDF

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Publication number
CN116425757A
CN116425757A CN202310034635.2A CN202310034635A CN116425757A CN 116425757 A CN116425757 A CN 116425757A CN 202310034635 A CN202310034635 A CN 202310034635A CN 116425757 A CN116425757 A CN 116425757A
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group
compound
yap
inhibitors
ring
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梁阿朋
李钧
吴豫生
刘广斌
董胜利
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Deuracor Therapeutic Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to polycyclic compounds and the use thereof. Specifically, the compound has a structure shown in a formula I, wherein the definition of each group and substituent is described in the specification; the invention also discloses a preparation method of the compound and application of the compound in regulating and treating related diseases caused by abnormal activity of YAP/TEAD.

Description

Polycyclic compounds and uses thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a polycyclic compound used for regulating a Hippo pathway, a preparation method and application thereof, which are mainly used for treating or preventing proliferative diseases (such as cancers), in particular to regulating and treating related diseases caused by abnormal activity of YAP/TEAD.
Background
The Hippo pathway consists essentially of a core kinase cascade comprising the Ste-20 family of protein kinases MST1-2, the scaffold protein Salvador and the large tumor suppressor kinase LATS1-2, and the suppressor coactivators YAP (Yes 1-related proteins) and TAZ (transcriptional coactivators with PDZ binding motifs). YAP and TAZ are major effectors of Hippo signaling pathways, which act as transcription factors together with tea (transcription enhanced association domain) within the nucleus, thereby increasing expression of target genes such as CTGF (connective tissue growth factor), CYR61, and the like. The Hippo pathway is an important regulator of cell growth, proliferation and migration. TEAD transcription factors are located at the core of the Hippo pathway and are critical for regulating organ growth and wound repair. Deregulation of TEAD and its regulatory cofactor Yes-related protein (YAP) has been implicated in many human cancers and hyperproliferative pathological processes in which deregulation of this pathway is often detected. As with TEAD proteins, YAP and TAZ activation have been identified in many human tumors and are critical for initiation, progression and metastasis of the tumor, as elevated YAP expression is present in breast, ovarian, colon, liver and pancreatic cancer patients and is associated with reduced survival. In agreement therewith, activation or overexpression of YAP or TAZ enhances TEAD-dependent gene expression (e.g., CCN1, CTGF, ITGB2, and Birc 5/survivin) and promotes cell proliferation and migration in many cell types. In contrast, blocking the YAP/TAZ-TEAD complex signaling or intervention prevents the expression of many mitogenic TEAD target genes, significantly reducing cell proliferation and oncogenic transforming activity. In addition, the Hippo pathway also cross-talk (cross-talk) with other signaling pathways such as Wnt, notch, hedgehog and MAPK, affecting a variety of biological functions, which may be involved in many human diseases in addition to cancer. The YAP-TEAD complex is a promising therapeutic target.
Disclosure of Invention
The invention aims to provide a compound shown in a formula I, a preparation method thereof and application thereof in regulating and treating related diseases caused by abnormal activity of YAP/TEAD.
In a first aspect of the present invention there is provided a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof,
Figure BDA0004048207300000021
wherein, the liquid crystal display device comprises a liquid crystal display device,
ring a is selected from the group consisting of:
Figure BDA0004048207300000022
ring B is a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein one C atom on the ring is bonded to R 1 And are linked, said substituents being substituted with 1 to 3 substituents R;
ring C is selected from the group consisting of: a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, said substitution being by 1-3 substituents R;
R 1 selected from the group consisting of:
Figure BDA0004048207300000023
R 2 、R 3 、R 4 and R is 5 Each independently selected from the group consisting of substituted or unsubstituted: H. halogen, CN, NH 2 An ester group, a urea group, a urethane group, an amide group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein said substitution means substitution with 1-3 substituents R;
or R is 4 、R 5 Forming a 4-6 membered heterocyclic group containing 1N with adjacent N;
R 6 and R is 7 Each independently selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein said substituents refer to substitution with 1-3 substituents R;
each R is independently selected from the group consisting of: halogen, CN, OH, NH 2 An ester group, urea group, urethane group, amide group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6-C10 aryl group, 6-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S;
m is selected from the group consisting of: 0.1, 2 and 3;
n is selected from the group consisting of: 0.1, 2 and 3.
In another preferred embodiment, ring B is selected from the group consisting of:
Figure BDA0004048207300000031
Figure BDA0004048207300000032
ring C is selected from the group consisting of:
Figure BDA0004048207300000033
in another preferred embodiment, R 1 Selected from the group consisting of:
Figure BDA0004048207300000034
R 2 selected from the group consisting of: trifluoromethyl, fluoro, chloro, bromo, iodo, cyclopentyl, cyclohexyl.
In another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0004048207300000035
in a second aspect of the invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
In a third aspect of the invention there is provided the use of a pharmaceutical composition according to the second aspect of the invention for the manufacture of a medicament for the treatment of a disease associated with a disorder of the Hippo pathway.
In a fourth aspect of the invention there is provided the use of a pharmaceutical composition according to the second aspect of the invention for the manufacture of a medicament for the treatment of a disease associated with YAP or TAZ or YAP/TEAD or YAP/TAZ/TEAD disorders.
In a fifth aspect of the invention there is provided the use of a pharmaceutical composition according to the second aspect of the invention for the manufacture of a medicament for the treatment of a related disorder caused by YAP/TEAD or YAP/TAZ/TEAD disorders.
In another preferred embodiment, the disease is cancer.
In a sixth aspect of the invention there is provided the use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with a second active ingredient for the manufacture of a medicament for the treatment of cancer;
the second active ingredient is selected from the group consisting of: ERK inhibitors, MEK inhibitors, KRAS inhibitors, BRAF inhibitors, EGFR inhibitors, wnt inhibitors, PD-1 inhibitors.
In another preferred embodiment, the cancer is selected from the group consisting of: breast cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows the results of an activity test according to the invention, wherein TY-2400 corresponds to compound FA according to the invention T-1, TY-2401 corresponds to compound FA according to the invention, TY-2407b corresponds to compound T-2 according to the invention, TY-2410 corresponds to compound T-4 according to the invention, TY-2412 corresponds to compound T-8 according to the invention.
FIG. 2 is a structural formula of TY-2401 corresponding to Compound FA.
Detailed Description
The present inventors have made intensive studies for a long time, and have unexpectedly prepared a compound of formula I having excellent regulatory and therapeutic effects on diseases associated with abnormal activity of YAP/TEAD. On this basis, the inventors completed the present invention.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the term "halogen" refers to F, cl, br or I.
In the present invention, "C1-C6 alkyl" means a straight-chain or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.
In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, including without limitation ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms containing one triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like.
In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "C3-C6 cycloalkyl" has similar meaning.
In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably C1-C4 alkoxy.
In the present invention, the term "heterocyclyl" is a 4-8 membered heterocyclyl containing 1,2 or 3 heteroatoms selected from N, O, S, including, but not limited to, the following groups:
Figure BDA0004048207300000051
Figure BDA0004048207300000052
in the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring.
In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms. For example, "C3-C10 heteroaryl" refers to aromatic heterocycles containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
In the present invention, the term "halo" refers to substitution with halogen.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): halogen, hydroxy, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.
In the present invention, the term 1-6 means 1,2, 3, 4, 5 or 6. Other similar terms have similar meanings.
The term "ester group" has the structure-C (O) -O-R ' or R ' -C (O) -O-wherein R ' independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heteroaryl, heterocyclyl, as defined above.
The term "ureido" has
Figure BDA0004048207300000061
Structure wherein Ra, rb are each independently selected from H, C C6 alkyl, halogenated C1C 6 alkyl, C6C 10 aryl.
The term "urethane group" has
Figure BDA0004048207300000062
Structure wherein Ra, rb are each independently selected from H, C C6 alkyl, halogenated C1C 6 alkyl, C6C 10 aryl.
The term "amide" refers to a group having the structure-CONRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
Compounds of formula (I)
The invention provides a compound shown as a formula I, or pharmaceutically acceptable salt, solvate or prodrug thereof,
Figure BDA0004048207300000063
wherein each group is as defined above.
In another preferred embodiment, of the compounds, ring A, ring B, ring C, R 1 、R 2 And m are each a group corresponding to a specific compound described herein.
In another preferred embodiment, the compound is preferably the compound prepared in the examples.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.
Another preferred class of salts are salts of the compounds of the invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, and triethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
The term "solvate" refers to a complex of a compound of the invention coordinated to a solvent molecule to form a specific ratio.
The term "prodrug" includes a class of compounds which may themselves be biologically active or inactive, and which upon administration by an appropriate method undergo a metabolic or chemical reaction in the human body to convert to a compound of formula I, or a salt or solution of a compound of formula a. The prodrugs include, but are not limited to, carboxylic acid esters, carbonic acid esters, phosphoric acid esters, nitric acid esters, sulfuric acid esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compound.
Preparation method
The following more particularly describes the preparation method of the compound of the formula I, but these specific methods do not limit the present invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Typically, the process for preparing the compounds of the present invention is as shown in example 1, wherein the starting materials and reagents used, unless otherwise specified, are commercially available.
Pharmaceutical compositions and methods of administration
Because the compound of the present invention has excellent antitumor activity, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the treatment, prevention and alleviation of diseases associated with tumors.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" means herein that the components of the composition are capable of interacting with the compounds of the inventionBlending without significantly reducing the potency of the compound. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.
Figure BDA0004048207300000081
) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
The mode of administration of the compounds or pharmaceutical compositions 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 topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with 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 compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used 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, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, 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 excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antineoplastic agents).
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
Compared with the prior art, the invention has the following main advantages:
(1) The compounds of the invention have very good inhibitory activity against YAP/TEAD.
(2) The compound has good pharmacological, pharmaceutical and pharmacodynamic effects.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
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 methods and materials described herein are presented for illustrative purposes only.
Example 1
The compound synthesized by the invention:
Figure BDA0004048207300000101
the synthetic route is as follows:
Figure BDA0004048207300000111
the experimental procedure was as follows:
(1) Synthesis of Compound 3
In a 250mL three-necked flask, compound 1 (10 g,64.4 mmol), compound 2 (20 g,74.1 mmol), acetic acid (100 mL) and 130℃were added and reacted for 16h. After the reaction, 200mL of water is added, the pH value is regulated to about 8 by adding sodium bicarbonate, ethyl acetate is used for extraction, a large amount of suspended solids are obtained, the product is extracted until the water phase is free of the product, the organic phase and the solids are dissolved by adding methanol, the mixture is dried and passed through a column, and 4.0g of pure product is separated.
(2) Synthesis of Compound 5
A500 mL single flask was charged with compound 3 (3.9 g,0.01 mol,1.0 eq), water/1, 4-dioxane (1/5) (240 mL), pd (dppf) Cl 2 (0.48 g, 0.015 mmol,0.11 eq), sodium carbonate (3.43 g,0.032mol,3.0 eq), compound 4 (2.69 g,0.013mol,1,2 eq), after three nitrogen substitutions, are placed in an oil bath, raised to 100 degrees for 18 hours, cooled to room temperature after the reaction, filtered, washed with ethyl acetate, and the filtrate is spun through the column to give 2.3g of product.
(3) Synthesis of Compound 6
Compound 5 (2.3 g,6.33mmol,1.0 eq) was dissolved in ethanol (50 mL), pd/C (0.07 g, 10%) was added and reacted under hydrogen for 1.5 days until the starting material disappeared, and then directly filtered and spun-dried to give 2.0g of crude product.
(4) Synthesis of Compound 7
Compound 6 (1.6 g,4.38 mol) was added to ethanol, and then 9.6g of hydrazine hydrate was added, refluxed for 3 hours at 95℃and directly dried after cooling to give 1.5g of crude product.
(5) Synthesis of Compound 9
Compound 7 (1.5 g,4.27mmol,1.0 eq) was dissolved in DCM/DMF (30 mL/30 mL), triethylamine (863 mg,8.54mmol,2.0 eq) was added, the reaction solution was cooled to 0℃and Compound 8 (1.04 mg,8.54mmol,2.0 eq) was added dropwise, and then the reaction mixture was allowed to react at room temperature for 4h, after which the reaction mixture was directly dried by spinning through a column to give 2.145g.
(6) Synthesis of Compound 10
Compound 9 (2.145 g,4.91mmol,1.0 eq) was dissolved in DCM/DMF (40 mL/40 mL), then p-toluenesulfonyl chloride (2.79 g,14.6mmol,3.0 eq) was added, triethylamine (1.49 g,14.7mmol,3.0 eq) was reacted at room temperature for 5h, after completion of the reaction, water was added, after EA extraction, dried, filtered and spun dry, and purified by column to yield 488mg of yellow solid.
(7) Synthesis of Compound T-1
Compound 10 (35 mL,0.083mmol,1.0 eq) was added with ammonia (3 mL), stirred at room temperature for 3h, and the solid was directly filtered to give 9mg of product. LC-MS [ M+1]:405.1.
referring to the synthetic method of example 1, the following compounds were synthesized:
Figure BDA0004048207300000121
Figure BDA0004048207300000131
the biological activity test experiment process is as follows:
(1) Transfection
a) Cell culture: 2 x 10≡6 293T cells were seeded into 10cm dishes for culture the day before transfection, the next day the cell density was about 70%.
b) Prior to transfection, the dishes with cells cultured were replaced with 10mL fresh DMEM medium (10% serum, without diabodies).
c) Two sterile centrifuge tubes were taken, 750. Mu.L of DMEM without antibiotics and serum were added, and then 10. Mu.g of 3 XSYAP-luci and 3. Mu.g of Renilla plasmid were added to one tube and gently mixed by pipetting; another tube was filled with 30. Mu.L Lipo6000 transfection reagent and gently mixed by pipetting. Standing at room temperature for 5 min, adding the culture solution containing DNA into the culture solution containing Lipo6000 transfection reagent by a pipette, mixing by gently reversing a centrifuge tube, and standing at room temperature for 5 min.
d) The mixed Lipo6000 transfection reagent-DNA mixture was added dropwise to the dish and gently mixed.
e) After 6 hours of incubation, the culture was replaced with fresh complete broth.
f) After further incubation for 24 hours, the cells were treated with trypsin and counted and 96 well plates were added per well 6000 cells.
(2) Drug treatment
Drug concentration:
Figure BDA0004048207300000141
blanc DMEM Medium
DMSO: DMEM medium containing 1% DMSO
Detection of fluorescent signals after 48 hours of treatment
(3) Detection of fluorescent signals
a) Preparation of detection reagents
i. The Dual-Lumi II firefly luciferase detection reagent and the Dual-Lumi II Renilla luciferase detection buffer were thawed and brought to room temperature.
A suitable amount of Dual-Lumi II Renilla luciferase assay reagent was prepared in an amount of 50. Mu.L of Dual-Lumi II Renilla luciferase assay reagent per sample. And mixing a proper amount of the Dual-Lumi II Renilla luciferase detection substrate and a proper amount of the Dual-Lumi II Renilla luciferase detection buffer solution according to a ratio of 1:100 to prepare the Dual-Lumi II Renilla luciferase detection reagent.
b) Detection of luciferase
Detection of firefly luciferase
i. The cell culture plates were removed and equilibrated at room temperature for 10 minutes.
And ii.96-well plates, the culture solution is sucked off, 50 mu L of Dual-Lumi II firefly luciferase detection reagent is added to each well, and the mixture is uniformly mixed.
incubation at room temperature for 10 min stabilizes the luminescent signal.
Chemiluminescent detection was performed using a microplate reader with a detection time of 1 second per well.
Detection of Renilla luciferase
50. Mu.L of Dual-Lumi II Renilla luciferase assay reagent was added to each well of the 96-well plate and mixed well.
incubation at room temperature for 10 min stabilizes the luminescence data.
Chemiluminescent detection was performed using a microplate reader with a detection time per well of 1 second
c) Data computation
The relative fluorescence signal intensity of each well is divided by the RLU value obtained by firefly luciferase assay by taking Renilla luciferase as an internal reference. The average signal intensity of the DMSO group was regarded as 100%, and the percentage of the signal intensity at each concentration was calculated, respectively.
(4) The experimental results are shown in fig. 1: wherein the concentration of the compound was 2.5. Mu.M and the treatment time of the compound was 72 hours.
Luciferase activity of DMSO vs drug treatment
*,ρ<0.05
**,ρ<0.01
***,ρ<0.001
The biological activity test experiment process is as follows:
test example 1 cell anti-proliferation assay
Proliferation inhibition assay of human pleural mesothelioma cells NCI-H226 by YAP-TEAD inhibitor compounds
Experimental materials and apparatus: human pleural mesothelioma cells NCI-H226 were purchased from Nanjac, bai Biotechnology Co. RPMI-1640 medium (Bio-Channel), DMSO (dimethyl sulfoxide), CCK8 (WST-8) cell assay kit (Biyun day), 0.25% EDTA-Tripsin (pancreatin digest), 1xPBS (phosphate buffer, pH 7.2), 96 well plates (Corning), fetal Bovine Serum (FBS), 10,000U/mL penicillin-G/streptomycin, high-speed cryocentrifuge (EPPENDORF 5810R), enzyme-linked immunosorbent assay (Tecan Spark).
Experiment preparation:
1. cell plating
A) Tumor cells were cultured to 80-90% intensity in RPMI-1640 (containing 10% FBS and 100U/mL penicillin-G/streptomycin) at 37℃under 5% CO2 and saturated humidity.
B) Removing the culture medium in the 10cm dish;
c) The cells were rinsed once with 10ml of 1 xPBS;
d) Adding 4ml of 0.25% EDTA-Tripsin, placing into a 37 ℃ and 5% CO2 incubator, performing pancreatin digestion for 5 minutes, transferring into a 15ml centrifuge tube, centrifuging for 5 minutes with 200g, and discarding the supernatant to obtain cell sediment;
e) Resuspended in 4ml DMEM medium, counted and adjusted to 10,000 cells/ml.
F) The cell suspension was added to a 96-well plate at 100. Mu.L per well volume and incubated overnight at 37℃in a 5% CO2 incubator.
2. Treatment with a compound
Dilution of the Compounds
A) Preparing a test compound gradient dilution solution: test compounds were formulated as 1mM stock solutions. Then 1.5. Mu.l stock solution was dissolved in 1.5ml of DMSO-free medium, and 3-fold serial gradient dilutions were made in 0.1% DMSO medium for a total of 9 concentrations, with the following compound concentrations after dilution:
333.33nM，111.11nM，37.03nM，12.35nM，4.15nM，1.37nM，0.46nM，0.15nM
b) After fully and uniformly mixing, respectively taking 100 mu L of culture compound solution to replace culture solution in a cell culture plate, wherein each concentration is 4 compound holes;
c) Cells were transferred to an incubator for 3 days.
3. CCK8 (WST-8) cell assay
A) The cell culture plate was removed and 10 microliters of CCK-8 (WST-8) solution was added to each well in the biosafety cabinet;
b) Placing the cell culture plate back into the incubator for further incubation for 3 hours;
c) The absorbance was measured on a TECAN enzyme-linked immunosorbent assay instrument at a wavelength of 450 nm.
4. Data analysis
Cell Viability (% Cell Viability) was calculated using the following formula:
cell viability (%) = [ a (dosing) -a (blank) ]/[ a (0 dosing) -a (blank) ]100
A (dosing): absorbance of wells with cells, CCK8 solution and drug solution
A (blank): absorbance of wells with medium and CCK8 solution without cells
A (0 dosing): absorbance of wells with cells, CCK8 solution without drug solution
Cell viability: cell proliferation viability or cytotoxicity viability IC50 values were obtained by curve fitting using GraphPad Prism 8 software.
Test example 2, nano Luciferase method for detecting YAP-TEAD inhibitor Activity
(1) Experimental materials and apparatus: 293T cells were purchased from Nanjac, bai Biotechnology Co. DMEM medium (high sugar, phenol red free, bio-Channel), DMSO (dimethyl sulfoxide), lipo6000 (TM) transfection reagent (Biyun), pGL3B-8 xGTiC-nLuc-CMV-fLuc plasmid, 0.25% EDTA-Tripsin (pancreatin digest), 1xPBS (phosphate buffer, pH 7.2), 96 well white cell culture plate (Perkinelmer), fetal Bovine Serum (FBS), 10,000U/mL penicillin-G/streptomycin, high speed cryocentrifuge (EPPENDORF 5810R), CO2 incubator at 37 ℃,
Figure BDA0004048207300000161
cell counter, envision microplate reader (PerkinElmer).
Reagent(s)
Figure BDA0004048207300000162
(2) Transient transfection of 293T cells
Resuscitated 293T cells were seeded into 10cm dishes, incubated in a 5% CO2 incubator at 37℃and cells in the log phase (cell density approximately 50% -70%) should be used to ensure transfection efficiency.
The day before transfection, the logarithmic phase cells were digested with Trypsin-EDTA, the reaction was stopped by adding medium, and the mixture was stirred with a pipette to prepare a cell suspension.
Cell concentration was determined using Vi-cells, diluted to a suspension of 5X 10≡5 cells per ml. After preparation of the cell suspension, it was gently mixed and 10ml of liquid was added to a 10cm dish. Thus, the number of cells in each 10cm dish is 5 x 10≡6. The cells were incubated at 37℃for 1 day in a 5% CO2 incubator.
Taking two clean sterile centrifuge tubes, adding 750 mu L of opti-MEM Medium without antibiotics and serum respectively, then adding 15 mu g of plasmid (pGL 3B-8 xGTiC-nLuc-CMV-fLuc) into one tube, and gently beating and mixing by a pipette; the other tube was filled with Lipo6000 transfection reagent and gently mixed by pipetting. After 5 minutes of standing at room temperature, the culture solution containing DNA was gently added to the culture solution containing Lipo6000 transfection reagent, and the mixture was gently mixed with a reversed centrifuge tube and left standing at room temperature for 5 minutes.
The mixture was added dropwise to a 10cm dish and after 6 hours of incubation replaced with fresh complete medium.
(3) 96-well plate paving
After 1 day of transfection, the cells were digested with Trypsin EDTA, the reaction was stopped by adding medium, and the mixture was stirred with a pipette to prepare a cell suspension.
Cell concentration was determined using Vi-cell, diluted to 20000 cells per ml.
After preparation of the cell suspension, the mixture was gently mixed, and 100. Mu.L of the mixture was added to each well of a 96-well plate, so that the density of cells to be measured was 2000 per well.
(4) Adding the compounds
The inoculated cell culture plates were placed in an incubator for cultivation, and after about 24 hours, a concentration gradient of the compound was added.
10mM stock solution of compound was diluted to 50. Mu.M with medium, and 50. Mu.M solution of compound was added sequentially to the third column of the deep well plate, and 216. Mu.L of medium containing 0.5% DMSO was added to the fourth to eleventh columns.
Gradient dilution: sucking 100 mu L of solution from the third column, adding the solution into the fourth column, and uniformly mixing; then 100. Mu.L of the solution was aspirated from the fourth column and added to the fifth column, and the operation was repeated until the eleventh column.
Using a multichannel pipettor, 25. Mu.L of compound solution was pipetted from the deep well plate into a 96 well culture plate and each compound was repeated four times on a 96 well plate. Finally, a concentration gradient of 10000nM,1:3.16 was established in 96-well plates.
(5) Adding Nano-luciferase detection reagent, reading
The 96-well plate was incubated in a 5% CO2 incubator at 37℃for 48 hours, and then taken out and equilibrated at room temperature for 10 minutes.
100 mu L of detection reagent is added into each hole, and the mixture is placed on a horizontal shaking table to shake for 10 minutes at a low speed, so that cells are fully lysed. Fluorescence values were measured for each well using a PerkinElmer Envision microplate reader.
(6) Result calculation
Values for each well were converted to percent using 0nM as control using [ Inhibitor ] in GrahpPad prism software]vs. response (thread parameters) non-linear fitting calculation IC 50 。
As shown in Table 1, wherein A.ltoreq.1. Mu.M; 1 μm < B <5 μm; c is greater than or equal to 5 mu M
TABLE 1
Figure BDA0004048207300000171
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Figure BDA0004048207300000181
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Figure BDA0004048207300000191
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Figure BDA0004048207300000201
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Figure BDA0004048207300000211
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Figure BDA0004048207300000221
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Figure BDA0004048207300000231
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof,
Figure FDA0004048207290000011
wherein, the liquid crystal display device comprises a liquid crystal display device,
ring a is selected from the group consisting of:
Figure FDA0004048207290000012
ring B is a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein one C atom on the ring is bonded to R 1 And are linked, said substituents being substituted with 1 to 3 substituents R;
ring C is selected from the group consisting of: a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, said substitution being by 1-3 substituents R;
R 1 selected from the group consisting of:
Figure FDA0004048207290000013
R 2 、R 3 、R 4 and R is 5 Each independently selected from the group consisting of substituted or unsubstituted: H. halogen, CN, NH 2 Ester, urea, carbamate, amide, C1-C6 alkylA group, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein said substitution means substitution with 1-3 substituents R;
or R is 4 、R 5 Forming a 4-6 membered heterocyclic group containing 1N with adjacent N;
R 6 and R is 7 Each independently selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein said substituents refer to substitution with 1-3 substituents R;
each R is independently selected from the group consisting of: halogen, CN, OH, NH 2 An ester group, urea group, urethane group, amide group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6-C10 aryl group, 6-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S;
m is selected from the group consisting of: 0.1, 2 and 3;
n is selected from the group consisting of: 0.1, 2 and 3.
2. The compound of claim 1, wherein ring B is selected from the group consisting of:
Figure FDA0004048207290000021
Figure FDA0004048207290000022
ring C is selected from the group consisting of:
Figure FDA0004048207290000023
3. the compound of claim 1, wherein R 1 Selected from the group consisting of:
Figure FDA0004048207290000024
Figure FDA0004048207290000025
R 2 selected from the group consisting of: trifluoromethyl, fluoro, chloro, bromo, iodo, cyclopentyl, cyclohexyl.
4. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0004048207290000026
5. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6. Use of a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of a related disease caused by a disorder of the Hippo pathway.
7. Use of a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of a related disease caused by YAP or TAZ or YAP/TEAD or YAP/TAZ/TEAD disorders.
8. Use of a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of a related disease caused by YAP/TEAD or YAP/TAZ/TEAD disorders.
9. The use according to any one of claims 6 to 8, wherein the disease is cancer.
10. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with a second active ingredient for the preparation of a medicament for the treatment of cancer;
the second active ingredient is selected from the group consisting of: ERK inhibitors, MEK inhibitors, KRAS inhibitors, BRAF inhibitors, EGFR inhibitors, wnt inhibitors, PD-1 inhibitors.
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