Compound for inducing degradation of TEAD as well as preparation method and application of compound

Abstract

The invention provides a compound for inducing degradation of TEAD as well as a preparation method and application of the compound. Specifically, the invention provides a compound as shown in a formula I, pharmaceutically acceptable salts or stereoisomers thereof, and application of the compound in treatment of diseases such as tumors and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a new class of compounds capable of inducing the degradation of TEAD proteins, and their preparation methods and uses. Background Art

[0002] Research has found that the transcription factor TEADs are highly expressed in various tumor tissues such as lung cancer, gastric cancer, prostate cancer, and colorectal cancer, and are positively correlated with the malignancy of tumors and the poor prognosis of tumor patients. The transcriptional activity of TEADs themselves in cells is relatively low. They need to form complexes with transcriptional co-activators such as YAP / TAZ, SRC1, Vgll, etc. to act on specific DNA sequence sites to exert transcriptional activation functions. They can activate the expression of oncogenes such as CTGF, Cyr61, Axl, Myc, etc., and play roles in the processes of tumor cell proliferation, migration, and anti-apoptosis. Currently, the transcriptional co-activators that have been studied more and play important roles mainly include YAP, a key effector downstream of the Hippo signaling pathway, and its paralog TAZ. These two types of transcriptional co-activators are regulated by the Hippo pathway, and upstream kinases such as MST1 / 2 and LATS1 / 2 play important roles. MST1 / 2 can phosphorylate and activate LATS1 / 2, and the latter can phosphorylate YAP / TAZ. The phosphorylated YAP / TAZ proteins will be retained in the cytoplasm and will be further degraded through the ubiquitin-proteasome system. When the Hippo pathway is abnormal, the unphosphorylated YAP / TAZ proteins will enter the nucleus and bind to TEADs proteins to form a complex, thereby initiating the transcription process.

[0003] The TEAD family proteins have four different subtypes, namely TEAD1, TEAD2, TEAD3, and TEAD4. The protein structures of each member are highly conserved, and the expression of family members in different tissues also varies. Studies have found that the expression and functions of TEADs in different types of tumor tissues are also different. For example, TEAD1 is highly expressed in prostate cancer cells. After treating the tumor cells PC3 with siRNA, the cell proliferation ability can be significantly reduced. TEAD2 has been confirmed to have an important impact on the migration and invasion abilities of breast cancer cells. TEAD4 is found to be highly expressed in lung adenocarcinoma tissues. After treating H1299 and SPC-A1 cells with siRNA, it is found that there is no obvious effect on their proliferation, but the migration ability of tumor cells can be reduced. Some studies have found that TEAD2 and TEAD4 are highly expressed in colon cancer cells, but the expression levels of TEAD1 and TEAD3 have no obvious difference from those of normal cells. After treating colon cancer cells with shRNA to knockout TEAD4, it is found that there is no obvious effect on cell proliferation, but the metastasis ability of cells can be reduced. In summary, TEADs play an important role in tumor proliferation, metastasis, and anti-apoptosis processes and are considered potential targets for tumor treatment.

[0004] Therefore, there is a need in the art to develop more TEADs degrading agents with novel structures and excellent activities. Summary of the Invention

[0005] The object of the present invention is to provide a class of TEADs PROTAC-type degrading agents with novel structures and excellent activities.

[0006] In the first aspect of the present invention, a compound of formula I, its pharmaceutically acceptable salt or its stereoisomer is provided.

[0007]

[0008] Wherein, R 1 is one or more (such as 2, 3, 4, or 5) optionally substituents on the benzene ring to which it is attached, and each R 1 is independently selected from the group consisting of: H, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl;

[0009] Wherein, R 2 is one or more (such as 2, 3, 4, or 5) optionally substituents on the naphthalene ring to which it is attached, and each R 2 is independently selected from the group consisting of: H, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl;

[0010] R 3 is selected from the group consisting of: H, OH, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0011] A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from O, N, and S;

[0012] X is selected from the group consisting of: -NH-, -O-, -S-, -CH2-, a bond, or absent;

[0013] L is a linking group selected from the group consisting of:

[0014]

[0015] and

[0016] Y is a ligand moiety that links to an E3 ubiquitin ligase;

[0017] provided that when L is Y is not

[0018] In another preferred embodiment, each R 1 is independently -CF3, -CF2CF3, -CCl3, -CCl2CCl3, -CBr3, or -CBr2CBr3.

[0019] In another preferred embodiment, each R 2 is independently H, halogen, cyano, C1-C3 alkyl, and C1-C3 haloalkyl.

[0020] In another preferred embodiment, R 3 is methyl, ethyl, isopropyl, or cyclopropyl.

[0021] In another preferred embodiment, A is a 5- or 6-membered heteroaryl having 1 to 2 N atoms, preferably a 6-membered heteroaryl having 1 N atom.

[0022] In another preferred embodiment, A is In another preferred embodiment, Y is selected from the group consisting of:

[0023]

[0024] wherein R4 is -C1-C3 alkoxy, C1-C3 haloalkoxy, or halogen. In another preferred embodiment, Y is selected from the group consisting of:

[0025]

[0026] In another preferred embodiment, the compound has the structure of Formula II:

[0027]

[0028] wherein, R 1 、R 3 、X, L, and Y are as defined above.

[0029] In another preferred embodiment, the compound has the structure of Formula III or Formula IV:

[0030]

[0031]

[0032] Wherein, R4 is C1-C3 alkoxy or C1-C3 haloalkoxy or halogen, and R 1 , R 3 and L are as defined above. In another preferred embodiment, R 4 is methoxy or ethoxy.

[0033] In another preferred embodiment, in Formula III, L is In another preferred embodiment, in Formula IV, L is In another preferred embodiment, the compound is selected from the group consisting of:

[0034]

[0035]

[0036] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising the compound as described in the first aspect of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0037] In a third aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a drug for preventing or treating a disease mediated by abnormal function of the transcriptional enhancer associated domain (TEAD) protein or the "Hippo pathway".

[0038] In another preferred embodiment, the transcriptional enhancer associated domain transcription factor is selected from one or more of TEAD1, TEAD2, TEAD3, and TEAD4.

[0039] In another preferred embodiment, the disease is a tumor. Preferably, the tumor is selected from the group consisting of: liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma, mesothelioma, esophageal cancer, hematological malignancies.

[0040] In a third aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a drug for preventing or treating a tumor disease.

[0041] In another preferred example, the disease is a tumor. Preferably, the tumor is selected from the group consisting of: liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing's sarcoma, head and neck cancer, prostate cancer, meningioma, mesothelioma, esophageal cancer, and hematological malignancies.

[0042] In a fifth aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer, or a transcription enhancer-associated domain (TEAD) transcription factor degrader of the pharmaceutical composition as described in the second aspect of the present invention.

[0043] In another preferred example, the transcription enhancer-associated domain transcription factor is selected from one or more of TEAD1, TEAD2, TEAD3, and TEAD4.

[0044] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 Shows the ability of the exemplary compound of the present invention to induce the degradation of TEADs protein in NCI-H226 cells. DETAILED DESCRIPTION OF THE INVENTION

[0046] Through extensive and in-depth research, and through a large number of screenings and tests, the present inventors have provided compounds capable of inducing TEAD degradation, their preparation methods and uses. More specifically, a class of TEADs PROTAC-type degraders with novel structures and excellent activities has been provided. The present invention has been completed on this basis.

[0047] TERMS

[0048] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains.

[0049] As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of..." or "consisting of...".

[0050] As used herein, the term "room temperature" or "ambient temperature" refers to a temperature of 4 - 40 °C, preferably 25 ± 5 °C.

[0051] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0052] As used herein, "halogen" or "halo atom" refers to F, Cl, Br, and I. More preferably, the halogen or halo atom is selected from F, Cl, and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0053] In the present invention, "alkyl", by itself or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms. For example, C1-8 represents 1-6 carbons. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pivalyl, or similar groups.

[0054] In the present invention, the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3-6 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0055] In the present invention, the term "heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms. For example, "5-6 membered heteroaryl" refers to an aromatic heterocycle containing 1-3 (such as 1, 2, or 3) heteroatoms selected from oxygen, sulfur, and nitrogen and 5-6 ring atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. The heteroaryl can be optionally substituted or unsubstituted.

[0056] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "plural" can be 2, 3, 4, 5, or 6

[0057] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described correspondingly above or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group can have a substituent selected from a specific group at any substitutable site of the group, and the substituents can be the same or different at each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Unless otherwise specified, the "substituted" means that H on the group is replaced by one or more groups selected from the following group (but not limited to): halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl.

[0058] Active ingredient

[0059] The present invention provides a class of compounds that can induce the degradation of TEAD, which can be used as active ingredients for the preparation of drugs for preventing or treating diseases such as cancer.

[0060] More specifically, a compound of formula I is provided,

[0061]

[0062] wherein each group is defined as above.

[0063] The salts that may be formed by the compounds in the present invention also fall within the scope of the present invention. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or a base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; 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 amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0064] Another preferred class of salts is the salts formed by the compounds of the present invention with bases, such as alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed by morpholine, piperazine, and lysine, respectively.

[0065] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and their mixtures are included in the present invention.

[0066] The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C,14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.

[0067] The crystal forms, hydrates and solvates of the compounds in the present invention are also within the scope of coverage.

[0068] Pharmaceutical compositions and their uses

[0069] The present invention provides a pharmaceutical composition, which comprises the compound of formula I above, its pharmaceutically acceptable salts, or its stereoisomers; and a pharmaceutically acceptable carrier.

[0070] The compounds of the present invention have the activity of inducing TEAD degradation, and thus can be used for preventing or treating diseases mediated by abnormal functions of transcriptional enhancer-associated domain (TEAD) proteins or "Hippo pathway", especially cancers. The cancers include but are not limited to fibrosarcoma, bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, etc.

[0071] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0072] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents can be used simultaneously, separately, or sequentially with the compound of the present invention for the prevention and / or treatment of diseases related to tumors. The other pharmaceutically acceptable therapeutic agents may comprise one or more anti-cancer agents. For example, the anti-cancer agents can be selected from (but are not limited to): PARP1 / 2 inhibitors, chemotherapeutic drugs that induce DNA damage in cancer cells, DNA alkylating drugs, DNA or RNA synthesis inhibitors, EGFR, ALK, or FGFR tyrosine receptor kinase inhibitors, KRAS, MEK, or ERK tumor signaling pathway inhibitors, tumor immunotherapy drugs (such as PD-1 antibodies, PD-L1 antibodies, etc.).

[0073] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range, and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, it contains 1 - 200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or a tablet.

[0074] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0075] The pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder, or a granule.

[0076] There is no particular limitation on the administration method of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0077] The prodrug compounds of the present invention can be conveniently formulated into pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. See Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa., Mack Publishing Co., 1995), which discloses typical carriers and common methods for preparing pharmaceutical compositions. The methods can be used as described or modified to prepare medicaments containing the compounds of the present invention. As previously mentioned, the compounds of the present invention can also be administered in the form of pharmaceutically acceptable salts, etc.

[0078] 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 calcium phosphate dibasic, or with the following components: (a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0079] 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 can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0080] 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 conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, e.g., ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0081] In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and fragrances.

[0082] In addition to the active compound, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc.

[0083] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0084] 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 that may be necessary.

[0085] Examples of subjects to which the pharmaceutical composition or therapeutic agent of the present invention is administered include mammals (such as, for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0086] The present invention also provides a treatment method which includes the steps of: administering to a subject in need of treatment a compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof described in the present invention, or administering the pharmaceutical composition described in the present invention, for inducing the degradation of the transcriptional enhancer-associated domain (TEAD), preventing or treating diseases mediated by abnormal functions of the transcriptional enhancer-associated domain (TEAD) protein or the "Hippo pathway", and / or preventing or treating cancer.

[0087] The main advantages of the present invention include:

[0088] 1. The present invention provides a class of TEADs degradants with novel structures.

[0089] 2. The compounds of the present invention have excellent TEADs degradation activity, thus providing a new solution for preventing or treating TEADs-mediated diseases.

[0090] 3. The compounds of the present invention have good pharmacokinetics (such as longer half-life and higher bioavailability) and pharmacodynamics properties, as well as excellent drug-likeness, and are very suitable for preparing drugs for preventing or treating TEADs-mediated diseases or disorders.

[0091] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0092] Example

[0093] Example 1

[0094] N-((1S)-1-(6-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (1)

[0095]

[0096] Synthesis method of Example 1

[0097]

[0098] 5-(4-(Trifluoromethyl)phenyl)-2-naphthoic acid (A3)

[0099]

[0100] At room temperature, PdCl2(dppf)·CH2Cl2 (0.5743 g, 0.71 mmol) was added to a mixture of 5-bromo-2-naphthoic acid (A1, 3.56 g, 14.18 mmol), 4-trifluoromethylphenylboronic acid (A2, 3.23 g, 17.01 mmol) and Na2CO3 (4.51 g, 42.54 mmol) in 1,4-dioxane (70 mL) and H2O (7 mL). The mixture was degassed and refilled with nitrogen three times, and then stirred at 90 °C for 16 hours. It was detected by thin layer chromatography that most of the raw materials had reacted. The mixture was concentrated under reduced pressure to remove the organic solvent, diluted with water (10 mL), the pH was adjusted to 1 with 1M NaOH, and extracted with ethyl acetate (15 mL × 2). The separated aqueous layer was adjusted to pH ~2 with 1M HCl and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to obtain only the crude product. Purification by silica gel column chromatography (methanol / dichloromethane = 10 / 1) gave 5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid as an off-white solid, namely compound A3 (3.1 g, 70% yield). 11H NMR (600 MHz, DMSO) δ 12.33 (s, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.9, 1.8 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.93–6.86 (m, 3H), 6.81 (dd, J = 7.0, 1.3 Hz, 1H). MS m / z (ESI): 317.3 [M+H] + 。

[0101] (S)-N-(1-(6-Bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A5)

[0102]

[0103] To a solution of compound A3 (800.0 mg, 2.53 mmol) in tetrahydrofuran was added (S)-1-(6-bromopyridin-2-yl)ethan-1-amine hydrochloride (A4, 508.6 mg, 2.58 mmol), 1-hydroxybenzotriazole (512.7 mg, 3.79 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (727.3 mg, 3.79 mmol) and N,N-diisopropylethylamine (1.32 mL, 7.59 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, ethyl acetate and water were added to the resulting mixture for extraction. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After concentration under reduced pressure, it was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain (S)-N-(1-(6-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A5, 1.01 g, 79.97% yield) as a white solid. 1 1H NMR (400 MHz, DMSO) δ 9.15 (d, J = 7.5 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.98 (dd, J = 8.9, 1.9 Hz, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.77–7.68 (m, 4H), 7.61 (dd, J = 7.1, 1.2 Hz, 1H), 7.58–7.47 (m, 2H), 5.19 (p, J = 7.1 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H). MS m / z (ESI): 499.3 [M+H] + 。

[0104] (S)-N-(1-(6-(Piperidin-4-ylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A7)

[0105]

[0106] Compound A5 (250.0 mg, 0.50 mmol) was added into a sealed tube and dissolved in dimethyl sulfoxide (5 mL). Then, 1-Boc-4-aminopiperidine (A6, 200.6 mg, 1.00 mmol), L-proline (23.1 mg, 0.20 mmol), potassium phosphate (21.25 mg, 0.10 mmol), and copper(I) iodide (28.61 mg, 0.15 mmol) were added successively. Nitrogen was displaced three times, and the reaction was carried out at 100 °C for 16 h. It was detected by thin-layer chromatography that most of the reaction had occurred, and there was still a small amount of reactant unreacted. Ethyl acetate and water were added for extraction, the organic phase was separated, washed twice with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound (S)-tert-butyl 4-((6-(1-(5-(4-(trifluoromethyl)phenyl)-2-naphthamido)ethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (151.1 mg, 48.78% yield). 1 H NMR (400 MHz, DMSO) δ 8.78 (d, J = 8.1 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.97 (dd, J = 9.0, 1.8 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.78–7.67 (m, 3H), 7.60 (dd, J = 7.2, 1.3 Hz, 1H), 7.37–7.30 (m, 1H), 6.53 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.32 (d, J = 7.9 Hz, 1H), 5.05 (t, J = 7.3 Hz, 1H), 3.96 - 3.65 (m, 4H), 2.79 (s, 2H), 1.88 (d, J = 12.6 Hz, 2H), 1.49 (dd, J = 7.1, 2.2 Hz, 3H), 1.39 (s, 1H), 1.38 (d, J = 3.5 Hz, 9H). MS m / z (ESI): 619.3 [M + H] + 。

[0107] Under an ice-water bath, dissolve tert-butyl (S)-4-((6-(1-(5-(4-(trifluoromethyl)phenyl)-2-naphthamido)ethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (70 mg) in dichloromethane (4 mL), slowly add trifluoroacetic acid (1 mL), and stir at room temperature under a nitrogen atmosphere for 1 hour. Detect the completion of the reaction by thin-layer chromatography. Directly distill off trifluoroacetic acid under reduced pressure to obtain crude product A7, which is used directly in the next reaction without further purification. MS m / z (ESI): 519.3 [M+H] + 。

[0108] (S)-N-(1-(6-((1-(azetidin-3-ylmethyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A9)

[0109]

[0110] Dissolve compound A7 (124.6 mg, 0.24 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (A8, 53.4 mg, 0.29 mmol) in dichloromethane (4 mL), then add NaBH(OAc)3 (254.6 mg, 1.20 mmol) to the mixture, and stir at room temperature overnight. After the reaction is completed, add 10 mL of dichloromethane and 5 mL of water, extract and separate,

[0111] Collect the organic phase, dry it over anhydrous sodium sulfate, filter, evaporate the solvent, and separate by silica gel column chromatography to obtain the product tert-butyl (S)-3-(((4-((6-(1-(5-(4-(trifluoromethyl)phenyl)-2-naphthamido)ethyl)pyridin-2-yl)amino)piperidin-1-yl)methyl)azetidine-1-carboxylate (85.2 mg, 85.20% yield), which is a pale yellow solid. MS m / z (ESI): 688.5 [M+H] + 。

[0112] Dissolve the product obtained from the above reaction in dichloromethane (4 mL), then add trifluoroacetic acid (1 mL) to the mixture, stir at room temperature for 0.5 hour, and detect the completion of the reaction by thin-layer chromatography. Directly distill off trifluoroacetic acid under reduced pressure to obtain crude product A9, which is used directly in the next reaction without further purification.

[0113] N-((1S)-1-(6-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (1)

[0114]

[0115] Compound A9 (40 mg, 0.068 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (A10, 28.20 mg, 0.102 mmol), and DIPEA (0.1 mL, 0.574 mmol) were added to a dimethyl sulfoxide solution (3 mL), and the system was heated to 90 °C and reacted for 16 hours. The reaction was detected to be complete by thin-layer chromatography. Ethyl acetate and water were added for extraction, the organic phase was separated, washed twice with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 20 / 1). It was purified by preparative high-performance liquid chromatography and lyophilized to obtain Compound 1. LC-MS (ESI) m / z: [M+H] + 844.4。 1 HNMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.60 (s, 1H), 9.00 (s, 1H), 8.66 (d, J = 9.1 Hz, 1H), 8.21–8.12 (m, 1H), 8.02–7.88 (m, 3H), 7.84 (dd, J = 9.0, 5.8 Hz, 1H), 7.80–7.68 (m, 3H), 7.68–7.42 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.70 (s, 2H), 5.20–5.02 (m, 2H), 4.64–3.08 (m, 8H, covered by the water peak), 3.05–2.79 (m, 3H), 2.68–2.41 (m, 3H, covered by the solvent peak), 2.20 (d, J = 13.3 Hz, 2H), 2.08–1.93 (m, 2H), 1.78–1.47 (m, 5H).

[0116] Example 2

[0117] N-((1S)-1-(6-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (2)

[0118]

[0119] Using compound A9 and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione as reaction raw materials, compound 2 was synthesized by the same reaction operation as compound 1. 1 H NMR(400MHz,DMSO)δ11.08(s,1H),9.83–9.42(m,1H),8.99(s,1H),8.66(d,J=7.3Hz,1H),8.15(t,J=7.1Hz,1H),8.01–7.87(m,4H),7.84(dd,J=8.9,5.4Hz,1H),7.78–7.66(m,4H),7.64–7.41(m,2H),6.80(s,1H),6.73–6.44(m,3H),5.20–4.99(m,2H),4.29–3.16(m,9H,covered by the water peak),3.10–2.80(m,3H),2.65–2.52(m,2H),2.27–2.13(m,2H),2.10–1.93(m,2H),1.79–1.58(m,2H),1.55(d,J=7.3Hz,3H).LC-MS(ESI)m / z[M+H] + 844.4.

[0120] Example 3

[0121] (S)-N-(1-(6-((1-(azetidine-3-carbonyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A12)

[0122]

[0123] Compound A7 (165.2 mg, 0.32 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (A11, 64.1 mg, 0.32 mmol), HATU (181.7 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.59 mmol) were successively added to 3 mL of N,N-dimethylformamide solution, stirred at room temperature for 16 hours, then extracted and separated with ethyl acetate to obtain the organic phase, dried with anhydrous sodium sulfate, and separated by silica gel column chromatography after rotary evaporation to obtain compound (S)-tert-butyl 3-(4-((6-(1-(5-(4-(trifluoromethyl)phenyl)-2-naphthamido)ethyl)pyridin-2-yl)amino)piperidine-1-carbonyl)azetidine-1-carboxylate (120.9 mg, 54.08% yield). 11H NMR (600 MHz, DMSO) δ 8.81–8.78 (m, 1H), 8.64 (dd, J = 4.3, 2.0 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.00–7.94 (m, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.85–7.80 (m, 1H), 7.76–7.67 (m, 3H), 7.59 (dd, J = 7.0, 1.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 6.45–6.39 (m, 1H), 6.33 (d, J = 8.5 Hz, 1H), 5.05 (p, J = 6.9 Hz, 1H), 4.23–4.07 (m, 2H), 3.92 (s, 4H), 3.64–3.45 (m, 2H), 3.17 (d, J = 4.7 Hz, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 1.91 (d, J = 11.1 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.37 (t, J = 2.5 Hz, 10H). MS m / z (ESI): 702.3 [M+H] + 。

[0124] Dissolve the product obtained from the above reaction in dichloromethane (4 mL), then add trifluoroacetic acid (1 mL) to the mixed system, stir at room temperature for 0.5 h, and detect the completion of the reaction by thin layer chromatography. Directly distill off trifluoroacetic acid under reduced pressure to obtain crude product A12, which is used directly in the next reaction without further purification.

[0125] N-((1S)-1-(6-((1-(1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidine-3-carbonyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (3)

[0126]

[0127] Using (S)-N-(1-(6-((1-(azetidine-3-carbonyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A12) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (A10) as raw materials, compound 3 was synthesized by a reaction operation similar to that of compound 1. LC-MS (ESI) m / z: [M+H] + 858.3。 11H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.14 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.9 Hz, 1H), 7.79–7.68 (m, 4H), 7.59 (dd, J = 14.9, 7.3 Hz, 2H), 7.14 (d, J = 7.0 Hz, 1H), 6.94–6.62 (m, 3H), 5.19 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.91–3.27 (m, 8H, covered by the water peak), 3.12 (q, J = 11.8, 11.4 Hz, 1H), 2.87 (ddd, J = 17.7, 13.9, 5.4 Hz, 2H), 2.63–2.42 (m, 2H, covered by the solvent peak), 2.07–1.88 (m, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.37 (s, 2H).

[0128] Example 4

[0129] N-((1S)-1-(6-((1-(1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (4)

[0130]

[0131] Using compound A12 and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione as raw materials, compound 4 was synthesized by a reaction operation similar to that of compound 1. LC-MS (ESI) m / z: [M+H] + 858.3。 11H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.14 (s, 1H), 8.68 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.81–7.70 (m, 4H), 7.64 (dd, J = 15.3, 7.7 Hz, 2H), 6.82 (d, J = 10.6 Hz, 3H), 6.69 (d, J = 8.4 Hz, 1H), 5.20 (t, J = 7.3 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.92–3.75 (7H, covered by the water peak), 3.63 (t, J = 18.0 Hz, 1H), 3.21–3.04 (m, 1H), 2.88 (ddt, J = 22.3, 14.3, 6.9 Hz, 2H), 2.63–2.44 (m, 2H, covered by the solvent peak), 2.08–1.89 (m, 3H), 1.58 (d, J = 6.9 Hz, 3H), 1.50–1.16 (m, 2H).

[0132] Example 5

[0133] N-((1S)-1-(6-((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (5)

[0134]

[0135] Using compound A9 and 4-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as reaction raw materials, compound 5 was synthesized by a reaction operation similar to that of compound 1. LC-MS (ESI) m / z [M+H] + 858.4. 11H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 8.96 (s, 1H), 8.65 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.05–7.86 (m, 6H), 7.83 (d, J = 8.9 Hz, 1H), 7.77–7.69 (m, 3H), 7.61 (dd, J = 7.1, 1.3 Hz, 1H), 7.48 (s, 1H), 6.65 (s, 1H), 6.47 (s, 1H), 5.19 (dd, J = 12.8, 5.4 Hz, 1H), 5.08 (s, 1H), 4.86 (s, 2H), 4.68–2.99 (m, 13H, covered by the water peak), 2.98–2.84 (m, 1H), 2.68–2.52 (m, 2H), 2.18 (s, 1H), 2.10–1.95 (m, 2H), 1.63 (s, 1H), 1.55–1.47 (d, J = 7.1 Hz, 3H).

[0136] Example 6

[0137] N-((1S)-1-(6-((1-((1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (6)

[0138]

[0139] Compound 6 was synthesized by using compound A9 and 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as reaction raw materials and adopting a reaction operation similar to that of compound 1. LC-MS (ESI) m / z [M+H] + 858.4. 11H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.12–7.89 (m, 6H), 7.83 (d, J = 8.9 Hz, 1H), 7.72 (dd, J = 15.9, 8.6 Hz, 3H), 7.60 (dd, J = 7.1, 1.3 Hz, 1H), 7.41 (s, 1H), 6.68–6.34 (m, 2H), 5.18 (dd, J = 12.8, 5.4 Hz, 1H), 5.13–5.00 (m, 1H), 4.59 (s, 2H), 4.25–2.83 (m, 14H, covered by the water peak), 2.69–2.53 (m, 2H), 2.24–1.95 (m, 3H), 1.78–1.59 (m, 1H), 1.51 (d, J = 7.1 Hz, 3H).

[0140] Example 7

[0141] N-((1S)-1-(6-((1-((1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (7)

[0142]

[0143] Compound 7 was obtained by using the corresponding starting materials and a synthetic method similar to that of compound 1. LC-MS (ESI) m / z: [M+H] + 872.4. 11H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.66 (dd, J = 9.3, 1.8 Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 8.01–7.88 (m, 3H), 7.84 (dd, J = 8.9, 5.6 Hz, 1H), 7.77–7.65 (m, 4H), 7.61 (dd, J = 7.1, 1.2 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.27 (dt, J = 8.7, 2.4 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.52 (s, 1H), 5.09 (dq, J = 13.1, 6.3, 5.6 Hz, 2H), 4.55–3.14 (m, 4H, covered by the water peak), 3.07–2.81 (m, 7H), 2.68–2.52 (m, 2H), 2.23–1.93 (m, 5H), 1.88–1.61 (m, 4H), 1.53 (dd, J = 7.0, 5.0 Hz, 3H), 1.35–1.13 (m, 2H).

[0144] Example 8

[0145] N-((1S)-1-(6-((1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (8)

[0146]

[0147] Compound 8 was obtained by using the corresponding starting materials and adopting a synthetic method similar to that of compound 1. LC-MS (ESI) m / z: [M+H] + 941.6。 11H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.96 (d, J = 133.1 Hz, 2H), 8.96 (s, 1H), 8.65 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.95 (dd, J = 17.5, 8.5 Hz, 3H), 7.83 (d, J = 8.9 Hz, 1H), 7.72 (dq, J = 16.1, 8.2, 7.5 Hz, 4H), 7.61 (d, J = 7.1 Hz, 1H), 7.49 (s, 1H), 7.35 (dd, J = 7.7, 4.1 Hz, 2H), 6.58 (d, J = 64.4 Hz, 2H), 5.09 (dd, J = 12.7, 5.6 Hz, 2H), 4.54–2.98 (m, 15H, covered by the water peak), 2.95–2.78 (m, 3H), 2.67–2.53 (m, 2H), 2.21 (d, J = 13.0 Hz, 2H), 2.10–1.95 (m, 2H), 1.84–1.33 (m, 10H).

[0148] Example 9

[0149] N-((1S)-1-(6-((1-((1-((1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (9)

[0150]

[0151] Compound 9 was obtained by a synthetic method similar to that of Compound 1 using the corresponding starting materials. LC-MS (ESI) m / z: [M+H] + 941.6. 11H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 10.18–9.57 (m, 2H), 8.94 (s, 1H), 8.65 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.95 (dd, J = 17.0, 8.5 Hz, 3H), 7.83 (d, J = 8.9 Hz, 1H), 7.80–7.65 (m, 4H), 7.61 (d, J = 7.1 Hz, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.45 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 2H), 4.33 (s, 2H), 4.20–4.03 (m, 4H), 3.96 (d, J = 13.8 Hz, 3H), 3.73–2.82 (m, 9H, covered by the water peak), 2.67–2.52 (m, 2H), 2.21 (d, J = 13.2 Hz, 2H), 2.02 (dd, J = 12.7, 6.5 Hz, 2H), 1.93–1.78 (m, 1H), 1.78–1.43 (m, 7H), 1.24 (d, J = 11.8 Hz, 2H).

[0152] Example 10

[0153] N-((1S)-1-(6-((1-((1-(1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbonyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (10)

[0154]

[0155] (S)-N-(1-(6-((1-(azetidin-3-ylmethyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A9, 55.10 mg), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxylic acid (36.13 mg), HATU (53.47 mg), and DIPEA (0.09 mL) were successively added to 3 mL of N,N-dimethylformamide solution, and the reaction was stirred at room temperature for 16 hours. The reaction was detected to be complete by thin layer chromatography. Ethyl acetate and water were added for extraction, the organic phase was separated, washed twice with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 20 / 1). The compound 10 was obtained after purification by preparative high performance liquid chromatography and freeze drying. LC-MS (ESI) m / z [M+H] + 955.3 1 HNMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.36 (s, 1H), 9.01 (d, J = 20.0 Hz, 1H), 8.65 (d, J = 5.7 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.95 (dd, J = 17.1, 8.5 Hz, 3H), 7.88–7.80 (m, 1H), 7.78–7.50 (m, 6H), 7.34 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 38.6 Hz, 2H), 5.10 (dt, J = 12.9, 6.9 Hz, 2H), 4.83–3.57 (m, 8H, covered by the water peak), 3.53–3.13 (m, 5H), 3.11–2.75 (m, 6H), 2.66–2.53 (m, 1H), 2.39 (q, J = 7.7 Hz, 1H), 2.20 (d, J = 12.2 Hz, 1H), 2.07–1.91 (m, 2H), 1.83–1.60 (d, J = 8.9 Hz, 5H), 1.55 (d, J = 6.8 Hz, 3H).

[0156] Example 11

[0157] N-((1S)-1-(6-((1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)azacyclohexane-3-yl)methyl)pyridin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (11)

[0158]

[0159] Compound 11 was obtained using the corresponding starting materials and a synthetic method similar to that of compound 10. LC-MS (ESI) m / z [M+H] + 955.3 1 H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.48 (s, 1H), 8.98 (s, 1H), 8.65 (d, J = 6.9 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.02–7.89 (m, 3H), 7.83 (dd, J = 9.1, 4.2 Hz, 1H), 7.78–7.44 (m, 6H), 7.33 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.8, 2.3 Hz, 1H), 6.62 (d, J = 50.7 Hz, 2H), 5.18–5.03 (m, 2H), 4.86–3.13 (m, 11H, covered by the water peak), 3.11–2.80 (m, 6H), 2.68–2.53 (m, 2H), 2.19 (d, J = 13.2 Hz, 2H), 2.10–1.92 (m, 2H), 1.79–1.43 (m, 9H).

[0160] Example 12

[0161] (S)-N-(1-(6-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5(4-(trifluoromethyl)phenyl)-2-naphthamide (12)

[0162]

[0163] Compound 12 was obtained using compound A7 and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid as reaction starting materials and a synthetic method similar to that of compound 10. LC-MS (ESI) m / z [M+H] + 765.3 1HNMR(400MHz,DMSO)δ10.34(s,1H),9.15(s,1H),8.68–8.64(m,1H),8.18–8.10(m,1H),8.00–7.89(m,3H),7.84(d,J=8.9Hz,1H),7.77–7.68(m,4H),7.61(dd,J=7.2,1.3Hz,1H),7.42–7.33(m,2H),7.17(d,J=8.7Hz,1H),6.81(s,2H),5.19(s,1H),4.81 - 3.71(s,6H,covered by the water peak),3.60(t,J=6.7Hz,2H),3.22–2.97(m,2H),2.68(t,J=6.7Hz,2H),2.08–1.89(m,2H),1.62–1.38(m,5H).

[0164] Example 13

[0165] (S)-N-(1-(6-((1-((1-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (13)

[0166]

[0167] Using (S)-N-(1-(6-((1-(azetidin-3-ylmethyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A9) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid as reaction raw materials, compound 13 was obtained by a synthetic method similar to that of compound 10. LC-MS(ESI) m / z [M + H] + 834.4. 11H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 9.53 (s, 1H), 9.02 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 8.3, 4.2 Hz, 1H), 8.01–7.88 (m, 3H), 7.87–7.81 (m, 1H), 7.73 (dd, J = 7.7, 5.6 Hz, 3H), 7.66–7.44 (m, 4H), 7.17 (d, J = 8.8 Hz, 1H), 6.71 (s, 2H), 5.12 (s, 1H), 4.62–2.89 (m, 16H, covered by the water peak), 2.69 (t, J = 6.7 Hz, 2H), 2.18 (d, J = 12.1 Hz, 2H), 2.07–1.89 (m, 1H), 1.78–1.42 (m, 5H).

[0168] Example 14

[0169] (S)-N-(1-(6-((1-((1-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (14)

[0170]

[0171] Using (S)-N-(1-(6-((1-(piperidin-4-ylmethyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid as reaction raw materials, compound 14 was obtained by a synthetic method similar to that of compound 10. LC-MS (ESI) m / z [M+H] + 862.4. 11H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 9.05 (d, J = 63.0 Hz, 2H), 8.65 (dd, J = 8.2, 2.0 Hz, 1H), 8.15 (t, J = 7.3 Hz, 1H), 8.01–7.89 (m, 4H), 7.83 (dd, J = 9.0, 4.8 Hz, 1H), 7.79–7.67 (m, 4H), 7.65–7.44 (m, 2H), 7.42–7.29 (m, 2H), 7.17 (d, J = 8.6 Hz, 1H), 6.79 - 6.37 (m, 2H), 5.10 (s, 1H), 4.78–2.77 (m, 15H, covered by the water peak), 2.68 (t, J = 6.6 Hz, 2H), 2.23–1.94 (m, 5H), 1.74 (d, J = 8.2 Hz, 4H), 1.53 (t, J = 6.5 Hz, 3H), 1.27–1.08 (m, 3H).

[0172] Example 15

[0173] (S)-N-(1-(6-((1-((1-((1-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)azetidin-3-yl)methyl)pyridin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (15)

[0174]

[0175] Using (S)-N-(1-(6-((1-((1-(piperidin-4-ylmethyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid as reaction raw materials, compound 15 was obtained by a synthetic method similar to that of compound 10. LC-MS (ESI) m / z [M + H] + 931.4

[0176] Example 16

[0177] (S)-N-(1-(6-((1-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)azetidin-3-yl)methyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (16)

[0178]

[0179] Using (S)-N-(1-(6-((1-(azetidine-3-carbonyl)piperidin-4-yl)amino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (A12) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid as reaction raw materials, compound 16 was obtained by a synthesis method similar to that of compound 10. LC-MS (ESI) m / z [M+H] + 848.3. 1 H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 9.16 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.00–7.86 (m, 3H), 7.84 (d, J = 8.9 Hz, 1H), 7.72 (dd, J = 12.9, 8.0 Hz, 4H), 7.66–7.53 (m, 3H), 7.16 (d, J = 8.7 Hz, 1H), 6.79 (s, 2H), 5.18 (s, 1H), 5.01–3.73 (m, 10H, covered by the water peak), 3.59 (t, J = 6.7 Hz, 3H), 3.10 (d, J = 9.7 Hz, 1H), 2.83 (s, 1H), 2.69 (t, J = 6.7 Hz, 2H), 2.03–1.88 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H), 1.48–1.22 (m, 2H).

[0180] Example 17

[0181] Compound anti-NCI-H226 tumor cell proliferation activity

[0182] The tumor cells NCI-H226 (human lung squamous carcinoma cells) in the logarithmic growth phase for the experiment were inoculated into a 96-well cell culture plate (NEST, 713011) at 100 μl per well (1000 cells), and a series of concentration gradients of the compound were added. The cells were cultured for 5 days at 37 °C and 5% CO2. Then, 20 μl of CellTiter-Meiluncell reagent (meilunbio, PWL111) was added to each well. After mixing, 80 μl was taken and transferred to an OptiPlate-96 white plate. The plate was read in Luminescence mode on a TECAN Spark multi-functional microplate reader. By calculating the inhibition rate = (1 - (compound well value - blank value) / (DMSO well value - blank value)) * 100, the inhibition rates of the compound at different concentrations were obtained. The logarithm of the compound concentration was taken in Graphpad Prism, and analysis was performed by the four-parameter fitting algorithm in non-linear regression. The IC 50 curve of the compound inhibition rate with respect to the logarithm of the concentration was fitted and the IC 50 value was obtained.

[0183]

[0184] Example 18

[0185] Compound degradation of TEADs activity

[0186] The supernatant of the cell culture medium of NCI-H226 (human lung squamous carcinoma cells) intervened with the compound was discarded, washed twice with pre-cooled PBS, and the cells were lysed by adding an appropriate amount of RIPA lysis buffer (medium) (added with protease inhibitor and phosphatase inhibitor). The cell lysate was collected into an EP tube with a cell scraper, sonicated 3 - 5 times (150 W, on for 5 s, off for 10 s), and then centrifuged at 4 °C (12000 r / min, 15 min). The supernatant was taken, which was the total cell protein. The protein concentration was quantitatively detected by the BCA method, and the protein was diluted with 5× protein loading buffer and PBS and denatured at 100 °C for 5 min. The total cell protein was electrophoretically separated in 10% SDS-PAGE (upper gel 70 V, 30 min; lower gel 120 V, 60 min), transferred (250 mA, 60 min), blocked with 5% milk for 1 h, incubated with primary antibodies (Pan-TEAD (CST, D3F7L), GAPDH (CST, D4C6R)) overnight at 4 °C, washed three times with TBST, incubated with secondary antibodies (Anti-Rabbit (Promega, W4018), Anti-Mouse (Promega, W4021)) at room temperature for 1.5 h, washed three times with TBST, incubated with ECL luminescent solution and developed, and the relative gray values of each band were quantified by imageJ (taking the DMSO group as 100%) to obtain the degradation rate of the compound on TEADs protein at different concentrations.

[0187]

[0188] Conclusion: The compounds involved in this application have excellent degradation activity against TEAD protein, inhibit the proliferation of tumor cells, and the activity of the compounds is affected by the structure of the linking chain in the molecule.

[0189] All documents mentioned in this invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound of formula I, its pharmaceutically acceptable salt or its stereoisomer, Among them, R 1 is one or more optional substituents on the benzene ring to which it is attached, and each R 1 is independently selected from the group consisting of: H, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl; wherein R 2 is optionally one or more substituents on the naphthalene ring to which it is attached, and each R 2 is independently selected from the group consisting of: H, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 selected from the group consisting of: H, OH, C1-C6 alkyl, and C3-C6 cycloalkyl; A is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from O, N, and S; X is selected from the group consisting of: -NH-, -O-, -S-, -CH2-, a bond or absent; L is a linking group selected from the group consisting of: and Y is a ligand moiety that binds to the E3 ubiquitin ligase; Provided that when L is , Y is not 2. The compound according to claim 1, wherein Each R 1 is independently -CF3, -CF2CF3, -CCl3, -CCl2CCl3, -CBr3, or -CBr2CBr3.

3. The compound according to claim 1, characterized in that, A is a 5- or 6-membered heteroaryl having 1 to 2 N atoms, preferably a 6-membered heteroaryl having 1 N atom. Preferably, A is 4. The compound according to claim 1, wherein Y is selected from the group consisting of: wherein R4 is -C1-C3 alkoxy, C1-C3 haloalkoxy or halogen, preferably, Y is selected from the group consisting of:

5. The compound according to claim 1, characterized in that, The compound has the structure of formula II: wherein, R 1 , R 3 , X, L and Y are as defined in claim 1.

6. The compound according to claim 1, wherein The compound has the structure of formula III or formula IV: wherein R4 is C1-C3 alkoxy or C1-C3 haloalkoxy or halogen, and R 1 , R 3 and L are as defined in claim 1.

7. The compound according to claim 1, characterized in that, The compound is selected from the group consisting of:

8. A pharmaceutical composition comprising the compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, and a pharmaceutically acceptable carrier.

9. Use of the compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a drug for preventing or treating diseases mediated by abnormal functions of transcriptional enhancer-associated domain (TEAD) proteins or the "Hippo pathway", preferably, the disease is a tumor, more preferably the tumor is selected from the group consisting of: liver cancer, breast cancer, lung cancer, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer and meningioma, mesothelioma, esophageal cancer, hematological malignancies.

10. Use of the compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a transcriptional enhancer-associated domain (TEAD) transcription factor degrader.

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