CN108484640B - Anti-tumor apoptosis protein inhibitor - Google Patents
Anti-tumor apoptosis protein inhibitor Download PDFInfo
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- CN108484640B CN108484640B CN201810492800.8A CN201810492800A CN108484640B CN 108484640 B CN108484640 B CN 108484640B CN 201810492800 A CN201810492800 A CN 201810492800A CN 108484640 B CN108484640 B CN 108484640B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, isomer or prodrug thereof, wherein R1、R2、R3、R4The definition of (A) is shown in the specification. Such compounds are useful for inhibiting IAPs and thus are useful for treating diseases associated with the overexpression of IAP proteins, such as cancer. The invention also relates to pharmaceutical compositions containing such compounds, and to processes for preparing such compounds. The compound of the invention has good activity, potential medicinal value and wide market prospect.
Description
Technical Field
Belongs to the field of medicinal chemistry, and particularly relates to an (apoptosis protein) IAP inhibitor for treating cancer and a preparation method thereof.
Background
Apoptosis or programmed cell death is a regulated mechanism in gene and biochemistry that plays an important role in invertebrate and vertebrate development and homeostasis. Apoptotic abnormalities that lead to premature cell death have been associated with a variety of developmental disorders. Defects in apoptosis leading to a lack of cell death have been associated with cancer and chronic viral infections.
Current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, indirectly induce apoptosis in cancer cells. Thus, the inability of cancer cells to perform apoptotic programs due to defects in normal apoptotic mechanisms is often associated with increased resistance to chemotherapy, radiation, or immunotherapy-induced apoptosis. Such primary or acquired resistance of cancer to current therapies due to apoptosis defects is a major problem in current cancer therapies. One class of central negative regulators of apoptosis are Inhibitors of Apoptosis Proteins (IAPs). This class includes proteins such as XIAP, cIAP1, cIAP2, ML-IAP, HIAP, KIAP, TSIAP, NAIP, survivin, livin, ILP-2, apollon and BRUCE. IAP proteins, which are effective in inhibiting apoptosis in cancer cells induced by a wide variety of apoptotic stimuli, including chemotherapeutic agents, radiation, and immunotherapy, are novel targets for the apoptotic pathway.
Patent applications for inventions relating to IAP inhibitors are WO2011018474a1, WO2008016893a1, WO2014047024a1, CN101484151A, etc.
Among the IAP inhibitors currently under development are LCL161, birinapag, BV6, GDC-0152, AZD5582, AT406, etc., wherein AT-406 is a potent, orally available Smac mimetic that is an antagonist of IAPs and inhibits XIAP, cIAP1 and cIAP2 proteins having the structural formulae shown below:
IAP inhibitors have a very good market value and the development of this variety still presents major challenges. In order to meet the clinical requirement of the apoptosis protein inhibitor at present and achieve better treatment effect of tumor diseases, the study and development of drug design and the like of a series of high-efficiency and low-toxicity IAP inhibitors are dedicated, and the method has great significance for the field of medicine.
Disclosure of Invention
It is an object of the present invention to provide novel IAP protein inhibitors or pharmaceutically acceptable salts, isomers or prodrugs thereof, said compounds having the general formula (I):
wherein the content of the first and second substances,
Wherein X is halogen;
In one embodiment, X is F;
The present invention also provides a method for preparing the compound of the general formula (I) and a salt, isomer or prodrug thereof, but is not limited to the method described below. All starting materials are prepared or purchased directly according to the general rules of the target molecule and by protocols in these routes, methods well known to those of ordinary skill in the art of organic chemistry. The compounds of the invention can be synthesized by combining the methods described below with synthetic methods known in the art of synthetic organic chemistry or variations thereon as recognized by those skilled in the art. The reaction scheme is as follows:
preparation of the Compounds of formula (I)
In the above preparation of formula (I), R1、R2、R3、R4And the X group is as defined above in the specification.
The preparation scheme of the compound of the general formula (I) comprises the following steps:
step 1: carrying out amidation condensation reaction on the compound 1' and the compound 2' under the action of a condensing agent, and then carrying out Fmoc protecting group removing reaction under the catalysis of alkali to obtain a compound 3 ';
step 2: carrying out amidation reaction on the compound 3' and the compound 4' (Fmoc-proline) under the action of a condensing agent to obtain a compound 5 ';
and step 3: carrying out amidation reaction on the compound 5' and the compound 6' under the action of a condensing agent to obtain a compound 7 ';
and 4, step 4: carrying out amidation reaction on the compound 7' and the compound 8' under the action of a condensing agent to obtain a compound 9 ';
and 5: carrying out amidation reaction on the compound 9' and the compound 10' under the action of a condensing agent to obtain a compound 11 ';
step 6: carrying out a ring-closing reaction on the compound 11 'under the catalytic action of elemental iodine to obtain an intermediate compound 12';
and 7: the Boc protecting group of the compound of the general formula 12' is removed by reaction with an acid such as trifluoroacetic acid, hydrochloric acid, etc., and then reacted with a compound containing R2Carboxylic acid compounds of the group or with compounds containing R2Reacting acyl chloride compounds of the groups to obtain a compound 13';
and 8: removing Fmoc protecting group from compound 13' under the action of base such as piperidine, and reacting with compound containing R3Carboxylic acid compounds of the group or with compounds containing R3Reacting acyl chloride compounds of the groups to obtain a target molecular compound (I);
further, R2Group and R3The order of introduction of the groups may be dependent on the nature of the reactionThe situation is selected, i.e. the compound 12' can also be firstly subjected to Fmoc protecting group removal, and R is introduced by reaction3Removing Boc protecting group, and introducing R2A group is formed, and a target molecule is finally obtained;
the condensing agent for the amidation reaction in the above reaction is optionally selected from 1, 3-Dicyclohexylcarbodiimide (DCC), N, N ' -Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and hydrochloride thereof, 1- (3-dimethylaminopropyl) -3-ethylcarbonyldiamine methyl iodide (EDC), N, N-Diisopropylethylamine (DIEA), 1-hydroxybenzotriazole (HoBt), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HCTU), 2- (1H-benzotriazol L-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU), 2-succinimidyl-1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TSTU), 5-norbornene-2, 3-dicarbonyl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TNTU).
In the above preparation method, when group protection is required for stability of the preparation process of each intermediate, the corresponding intermediate needs to be subjected to deprotection reaction to finally obtain the target molecular compound. Methods for preparing compounds such as those involving protecting and deprotecting various chemical groups, the need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art.
The features mentioned above, or those mentioned in the examples, may be combined in any combination in accordance with the principles of medicine, and each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Unless specifically stated otherwise, the disclosed features are merely generic examples of similar or analogous features.
Specific compounds of the invention include, but are not limited to, compounds having the structures listed below or pharmaceutically acceptable salts, isomers, or prodrugs thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer or prodrug thereof as an active ingredient, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition preferably contains 1-80% by weight of the pharmaceutically acceptable salt, isomer or prodrug of formula (I) as an active ingredient, more preferably 10-70% by weight of the active ingredient.
Unless otherwise indicated, the following terms used in the claims and the specification have the following meanings or characteristics:
the term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Is a salt comprising a compound of formula (I) with an organic or inorganic acid. Such salts include: salts with acids are formed by reaction of the free base of the parent compound with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, and perchloric acids or organic acids such as, but not limited to, acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, citric, lactic, maleic, hydroxybenzoic, gamma-hydroxybutyric, methoxybenzoic, phthalic, tartaric, methanesulfonic, ethanesulfonic, naphthalene-1-sulfonic, p-toluenesulfonic, salicylic, naphthalene-2-sulfonic, mandelic, malonic, or succinic acids, and the like.
"isomers" refer to substances which, when optically rotated, exhibit physical and mirror image relationships with the molecular structure of formula (I) in the compounds according to the invention which are characterized by the general formula (I). The present invention includes both racemic compounds and optical isomers. When the compound of formula (I) is desired as a single enantiomer, it may be obtained by resolution of the final product or by stereospecific synthesis from isomerically pure starting materials or using chiral auxiliaries.
"pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts, isomers, prodrugs, etc. with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
By "pharmaceutically acceptable carrier" is meant a carrier or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered.
"excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Examples of excipients include, without limitation, microcrystalline cellulose, lactose, glucose, sucrose, potassium sorbitol, polyvinylpyrrolidone, methylcellulose, and the like.
The pharmaceutical composition may further comprise: pharmaceutically acceptable lubricants such as talc, magnesium stearate, and the like; a humectant; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweetening agents and flavoring agents. The compositions of the present invention may be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
The "prodrug" of the present invention refers to a pharmaceutically inactive derivative of the parent "drug" molecule that requires a biological transformation (e.g., spontaneous or enzymatic) within the target physiological system to release or convert (e.g., by enzymatic, physiological, mechanical, electromagnetic means) the prodrug into the active drug. Prodrugs are designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability. Exemplary prodrugs comprise the active drug molecule itself and a chemical masking group (e.g., a group that reversibly inhibits the activity of the drug). Some preferred prodrugs are variants or derivatives of the compounds having a group that is cleavable under metabolic conditions. Exemplary prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis or enzymatic degradation or other biochemical transformations (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation) under physiological conditions. Commonly used prodrugs include acid derivatives such as esters prepared by reacting the parent acid with a suitable alcohol (e.g., a lower alkanol), amides prepared by reacting the parent acid compound with an amine, or basic groups (e.g., lower alkyl amides) that are reacted to form an acylated base derivative.
The invention also provides the use of said compounds of formula (I) and pharmaceutically acceptable salts, isomers or prodrugs thereof:
preparing a medicament for a disease associated with the overexpression of an IAP protein in a mammal;
furthermore, the compound of the invention can be used for preparing medicaments for treating tumor diseases.
The practicability is as follows:
the compounds of the invention are useful for inducing apoptosis in a cell, or sensitizing a cell, particularly a cancer cell, to apoptotic signals.
The compounds of the invention are useful for inducing apoptosis in cells that overexpress IAP proteins (e.g., c-IAP1, c-IAP2, X-IAP, or ML-IAP). Alternatively, the compounds of the invention may be used to induce apoptosis in cells in which the mitochondrial apoptotic pathway is disrupted such that release of Smac ML-IAP proteins is inhibited, for example, by upregulation of Bcl-2 or downregulation of Bax/Bak. More broadly, the compounds are useful for the treatment of cancer. It is particularly useful in the treatment of all cancer types that fail to undergo apoptosis. Examples of such cancer types include neuroblastoma, intestinal cancers such as rectal, colon, familial adenomatous polyposis and hereditary nonpolyposis colorectal, esophageal, lip, larynx, hypopharynx, tongue, salivary gland, stomach, adenocarcinoma, medullary thyroid, papillary thyroid, kidney, renal parenchymal, ovarian, cervix, corpus, endometrium, choriocarcinoma, pancreas, prostate, testicular, breast, urinary, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, Acute Lymphatic Leukemia (ALL), Chronic Lymphatic Leukemia (CLL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), colon carcinoma of the larynx, and the body, Adult T-cell leukemia lymphoma, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small-cell lung carcinoma, non-small-cell lung carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngeal tumor, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, and plasmacytoma.
The compounds of the invention are useful for sensitizing cells to apoptotic signals. Thus, the compounds may be administered prior to, concurrently with, or subsequent to radiation therapy or cell proliferation inhibiting chemotherapy or anti-tumor chemotherapy.
Detailed Description
The following examples further illustrate the invention, but are intended to be illustrative only and not limiting as to the scope of the invention.
Example 1
Step 1: 12.73g of benzhydrylamine was dissolved in 200ml of DMF, 40.69g of Fmoc-Cys (Trt) -OH, 39.49g of HBTU and 13.47g of DIEA were added in this order, and the mixture was stirred at room temperature for 2 hours and subjected to TLC detection (PE: EA: 2:1) until the starting material was reacted completely. Is turned to the reverse direction20ml piperidine was added to the reaction solution, the reaction was stirred at room temperature, and TLC detection (PE: EA: 2:1) was carried out until the starting material was reacted completely. The reaction was poured into 1L of water, extracted 2 times with ethyl acetate (500ml x2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-1-1(30.02g yellow oily liquid, [ M + H ]]+=529.7);
Step 2: 30.00g of compound I-1-1 was dissolved in 150ml of DMF, followed by addition of 19.15g of Fmoc-proline, 32.26g of HBTU and 11.00g of DIEA, followed by stirring at room temperature for 3 hours and detection by TLC (PE: EA: 2:1) until the starting material was reacted completely. 20ml of piperidine was added to the reaction mixture, the reaction was stirred at room temperature for 0.5h, and the starting material was completely reacted by TLC (PE: EA: 2: 1). The reaction was poured into 1L of water, extracted 2 times with ethyl acetate (500ml x2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-1-2(29.48g, yellow solid, [ M + H ] + ═ 626.3);
and step 3: 29.40g of the compound I-1-2 was dissolved in 150ml of DMF, and 17.87g of Fmoc-cyclohexylglycine, 26.77g of HBTU and 9.13g of DIEA were added in this order and reacted at room temperature for 2 hours, followed by completion of the reaction of the starting material by TLC detection (PE: EA: 1), 20ml of piperidine was added to the reaction mixture and the reaction was stirred at room temperature for half an hour, followed by completion of the reaction of the starting material by TLC detection (developing reagent PE: EA, 1: 1). The reaction was poured into 1L of water, extracted 2 times with ethyl acetate (500ml x2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (eluent DCM: MeOH) to give compound I-1-3(29.19g, yellow solid, [ M + H ]]+=766.1);
And 4, step 4: dissolving 29.10g of compound I-1-3 in 200ml of DMF, adding 16.27g N2-Fmoc-N3-Boc-D-2.3-diaminopropionic acid, 21.70g of HBTU and 7.40g of DIEA in sequence, stirring at room temperature for 2h, detecting by TLC (PE: EA ═ 1:1) until the raw materials react completely, adding 30ml of piperidine to the reaction solution, stirring at room temperature for 0.5h, detecting by TLC (PE: EA ═ 1:1) until the raw materials react completely, pouring the reaction solution into 1L of water, extracting 2 times (500ml × 2) with ethyl acetate, combining organic phases, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-1-4(33.62g of yellow oily liquid, ([ M + H ] + ═ 952.4);
and 5: 30.00g of compound I-1-4 was dissolved in 300ml of DMF, followed by addition of 18.48g of Fmoc-S-trityl-L-cysteine, 17.94g of HBTU and 6.12g of DIEA, followed by stirring at room temperature for 2 hours and detection by TLC (PE: EA ═ 2:1) until the starting material was reacted completely. The reaction mixture was added with 40ml of piperidine, stirred at room temperature for 0.5h, checked by TLC (PE: EA ═ 1:1) until the starting material reacted completely, poured into 1.5L of water, extracted 2 times with ethyl acetate (500ml × 2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-1-5(37.87g white solid, [ M + H ]]+=1520.1);
Step 6: dissolving 3.40g of compound I-1-5 in 200ml of DCM, dropwise adding a mixed solvent of 5.69g of elemental iodine and 1L (DCM: MeOH ═ 10:1) at room temperature, continuing the reaction for 0.5h after the dropwise addition is finished, and detecting by TLC (PE: EA ═ 1:1) until the raw materials are completely reacted. Dropwise adding saturated sodium sulfite aqueous solution into the reaction solution for quenching, adding 500ml of water into the reaction solution, separating, back-extracting the water phase once, combining the organic phases, washing the organic phase once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-1-6(1.92g white solid, [ M + H ]]+=1033.6);
And 7: dissolving 1.0g of compound I-1-6 in 20ml of DMF, adding 4ml of piperidine to the reaction solution, stirring at room temperature for reaction for 0.5h, after the reaction is finished, pouring the reaction solution into 150ml of water, extracting 2 times (50 ml. times.2) with ethyl acetate, combining organic phases, washing once with saturated sodium chloride, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-1-7(0.61g white solid, [ M + H ]]+=810.0);
And 8: dissolving 0.61g of compound I-1-7 in 40ml of DCM, adding 8ml of trifluoroacetic acid, reacting for 1.5h at room temperature, adjusting the pH value to 7-8 by using saturated aqueous sodium bicarbonate solution after the reaction is finished, separating liquid, back extracting the aqueous phase once by using 40ml of DCM, combining the organic phases, and washing the organic phase by using saturated sodium chlorideOnce, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-1(52mg white solid, [ M + H ]]+=710.31)
Example 2
Step 1: 1.40g of compound I-1-6 was dissolved in 40ml of DCM, 8ml of trifluoroacetic acid was added, the reaction was carried out at room temperature for 2.5h, after the reaction was completed, the pH was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate, liquid separation was carried out, the aqueous phase was back-extracted once with 40ml of DCM, the organic phases were combined, the organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Adding 30ml methyl tert-ether, pulping at room temperature for 0.5h, and filtering to obtain compound I-2-1(2.41g, white solid);
step 2: 1.0g of Compound I-2-1 was dissolved in 40ml of DMF, followed by addition of 0.44g of N-Boc-2-methylalanine, 1.22g of HBTU and 0.55g of DIEA, reaction at room temperature for 1.0h, and TLC detection (DCM: MeOH ═ 15:1) until the starting material was reacted completely. To the reaction was added 8ml piperidine, reacted at rt for 0.5h and checked by TLC (DCM: MeOH ═ 15:1) until the starting material was reacted completely. The reaction solution was poured into 400ml of water, 80ml of 2 was extracted with ethyl acetate, the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-2-2(0.81g, white solid);
and step 3: 0.5g of Compound I-2-2 was dissolved in 40ml of DMF, and 0.13g of Compound 2, 0.32g of HBTU and 0.12g of DIEA were added in this order to react at room temperature for 1.0 hour, after completion of the reaction. The reaction solution was poured into 400ml of water, a small amount of white solid was precipitated, 80ml of x2 was extracted with ethyl acetate, the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. To obtain compound I-2-3(0.63g, white solid), and directly feeding into the next step;
and 4, step 4: 0.63g of Compound I-2-3 was dissolved in 20ml of DCM, and 4ml of trifluoroacetic acid was added thereto to react at 30 ℃ for 1.0h, after the reaction was completed. Pouring the reaction solution into 200ml of water, adjusting the pH value to 7-8 by using saturated sodium bicarbonate aqueous solution, separating the solution, and adding waterThe phases were back-extracted with DCM 40ml x2, the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (eluent DCM: MeOH) to give compound I-2(0.44g, white solid, [ M + H ])]+=1018.8)。
Example 3
Step 1: 0.21g of Compound I-2-2 was dissolved in 10ml of DMF, and 0.2g of Compound 2 was added thereto and reacted at room temperature for 1.5 hours, after the reaction was completed. Pouring the reaction solution into 100ml water, extracting 40ml x2 with ethyl acetate, combining organic phases, washing the organic phase once with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (eluent DCM: MeOH) to obtain compound I-3(0.15g, white solid, [ M + H ] purifying]+=1021.7)。
Example 4
Step 1: 0.5g of the compound I-2-2 was dissolved in 20ml of methanol, 0.14g of the compound 4 and 0.85g of triethylamine were sequentially added thereto, and the mixture was heated to 50 ℃ to react overnight, after which the reaction was completed. The solvent was removed by rotary removal under reduced pressure, ethyl acetate and water were added, the layers were separated, the aqueous phase was back-extracted once with 40ml ethyl acetate, the organic phases were combined, the organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give compound I-4-1(0.63g, white solid).
Step 2: 0.63g of Compound I-4-1 was dissolved in 20ml of DCM, and 3.5ml of trifluoroacetic acid was added thereto to react at 30 ℃ for 1.0h, after the reaction was completed. Adjusting pH to 7-8 with saturated sodium bicarbonate water solution, separating, back-extracting the water phase with DCM to 20ml 2, mixing the organic phases, washing the organic phase with saturated sodium chloride once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (eluent DCM: MeOH) to obtain compound I-4(0.22g, white solid, [ M + H ])]+=987.4)。
Example 5
Step 1: dissolving 100mg of compound I-4 in 10ml of DCM, adding 200mg of triethylamine, cooling to-10 ℃, dropwise adding 132mg/2ml of dichloromethane solution of DCM acryloyl chloride, dropwise adding into the reaction solution, reacting for 0.5h after the dropwise adding is finished, and finishing the reaction. To the reaction solution was added 20ml of water, and the solution was separated, the aqueous phase was back-extracted with 20ml of 2 with DCM, the organic phases were combined, the organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (eluent DCM: MeOH) to give Compound I-5(25mg, white solid).
Example 6
Step 1: 150mg of compound I-2-2 was dissolved in 10ml of DMF, and 58mg of compound 5, 95mg of HBTU and 32mg of DIEA were added in this order to react at room temperature for 1.0 hour, after completion of the reaction. Pouring the reaction solution into 100ml of water, extracting with ethyl acetate (40ml x2), combining organic phases, washing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain a compound I-6-1(200mg, yellow oily substance), and directly putting into the next step;
step 2: 200mg of compound I-6-1 was dissolved in 20ml of DCM, 4ml of trifluoroacetic acid was added, and the reaction was carried out at 30 ℃ for 1.0 h. Adjusting pH to 7-8 with saturated sodium bicarbonate water solution, separating, back-extracting the water phase with DCM (20ml 2), mixing the organic phases, washing the organic phase with saturated sodium chloride once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (DCM: MeOH) to obtain compound I-6(80mg, white solid, [ M + H ], [ M ] as solid]+=1009.7)。
Example 7
Step 1:500 mg of Compound I-2-2 was dissolved in 15ml of DMF, and 330mg of Compound 6, 320mg of HBTU and 110mg of DIEA were added in this order to react at room temperature for 2.0 hours, after completion of the reaction. Pouring the reaction solution into 150ml of water, extracting with ethyl acetate (50 ml. times.2), combining organic phases, washing the organic phases once with saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and purifying by column chromatography (eluent DCM: MeOH) to obtain compound I-7-1(210mg, off-white solid);
step 2: 210mg of compound I-7-1 are dissolved in 20ml of DCM, 4ml of trifluoroacetic acid are added and the reaction is carried out at 30 ℃ for 1.0h, after the reaction is finished. Adjusting pH to 7-8 with saturated sodium bicarbonate water solution, separating, back-extracting the water phase with DCM (20ml X2), mixing the organic phases, washing the organic phase with saturated sodium chloride once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying with column chromatography (DCM: MeOH) to obtain compound I-7(60mg, white solid, [ M + H ])]+=933.6)。
Example 8
Step 1: 1.29g of Compound I-2-1 was dissolved in 45ml of DMF, and 240mg of Compound 7, 840mg of HBTU and 286mg of DIEA were added in this order to react at room temperature for 2.5 hours, after completion of the reaction. 9ml of piperidine was added to the reaction solution, and the reaction was carried out at room temperature for 0.5 h. Pouring the reaction solution into 500ml of water, extracting with ethyl acetate (50 ml. times.2), combining organic phases, washing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound I-8-1(680mg, off-white solid);
step 2: 680mg of the compound I-8-1 was dissolved in 15ml of DMF, and 330mg of Boc-N-methyl-DL-alanine, 403mg of HBTU and 136mg of DIEA were added in this order to react at room temperature for 2.0 hours, after completion of the reaction. Pouring the reaction solution into 150ml of water, extracting with ethyl acetate (50ml x2), combining organic phases, washing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a compound I-8-2(800mg, off-white solid), and directly putting the compound I-8-2 into the next step;
and step 3: 800mg of compound I-8-2 are dissolved in 30ml of DCM, 6ml of trifluoroacetic acid are added, and the reaction is carried out at 30 ℃ for 1.0h, after the reaction is finished. Adjusting pH to 7-8 with saturated aqueous sodium bicarbonate solution, separating, back-extracting the aqueous phase with DCM (20mlX2), combining the organic phases, and adding the organic phaseWashing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (DCM: MeOH) to obtain compound I-8(30mg, white solid, [ M + H ]]+=923.3)。
Example 9
Step 1: 1.29g of Compound I-2-1 was dissolved in 45ml of DMF, and 605mg of Compound 8, 840mg of HBTU and 286mg of DIEA were added in this order to react at room temperature for 2.5 hours, after completion of the reaction. 9ml of piperidine was added to the reaction solution, and the reaction was carried out at room temperature for 0.5 h. Pouring the reaction solution into 500ml of water, extracting with ethyl acetate (50 ml. times.2), combining organic phases, washing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound I-9-1(1.6g, off-white solid);
step 2: 1.6g of the compound I-9-1 was dissolved in 25ml of DMF, and 330mg of Boc-N-methyl-DL-alanine, 403mg of HBTU and 136mg of DIEA were added in this order to react at room temperature for 2.0 hours, after completion of the reaction. Pouring the reaction solution into 250ml of water, extracting with ethyl acetate (80 ml. times.2), combining organic phases, washing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain a compound I-9-2(750mg, off-white solid), and directly putting into the next step;
and step 3: 750mg of compound I-9-2 are dissolved in 30ml of DCM, 6ml of trifluoroacetic acid are added, and the reaction is carried out for 1.0h at 30 ℃ after the reaction is finished. Adjusting pH to 7-8 with saturated sodium bicarbonate water solution, separating, back-extracting the water phase with DCM (20ml X2), mixing the organic phases, washing the organic phase with saturated sodium chloride once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying with column chromatography (DCM: MeOH) to obtain compound I-9(45mg, white solid, [ M + H ])]+=1116.5)。
Example 10
Step 1: 2.55g of benzhydrylamine was dissolved in 25ml of DMF, 10.20g of Fmoc-Cys (Trt) -OH, 9.65g of HBTU and 3.38g of DIEA were added in this order, and the mixture was stirred at room temperature for 2 hours and checked by TLC (PE: EA. RTM. 2:1) until the starting material was reacted completely. To the reaction mixture was added 5ml of piperidine, the reaction was stirred at room temperature, and checked by TLC (PE: EA ═ 2:1) until the starting material was reacted completely. The reaction was poured into 250ml of water, extracted 2 times with ethyl acetate (50 ml. times.2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-10-1(7.76g, pale yellow solid);
step 2: 7.75g of the compound I-10-1 was dissolved in 25ml of DMF, and 5.32g of Fmoc-proline, 8.13g of HBTU and 2.75g of DIEA were added in this order, and the mixture was stirred at room temperature for 3 hours and subjected to TLC detection (PE: EA: 2:1) until the starting material was reacted completely. 5ml piperidine was added to the reaction mixture, the reaction was stirred at room temperature for 0.5h, and the starting material was completely reacted by TLC (PE: EA: 2: 1). The reaction was poured into 250ml of water, extracted 2 times with ethyl acetate (50 ml. times.2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-10-2(7.4g, pale yellow solid);
and step 3: 6.9g of compound I-10-2 was dissolved in 25ml of DMF, and 4.47g of Fmoc-cyclohexylglycine, 6.73g of HBTU and 2.27g of DIEA were added in this order to react at room temperature for 2 hours, followed by completion of the starting material reaction by TLC detection (PE: EA: 1), and then 5ml of piperidine was added to the reaction mixture to react at room temperature for 0.5 hours and TLC detection (developing reagent PE: EA: 1) followed by completion of the starting material reaction. The reaction solution was poured into 500ml of water, extracted 2 times with ethyl acetate (100 ml. times.2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (eluent DCM: MeOH) to give compound I-10-3(6.85g, yellow solid);
and 4, step 4: 6.85g of compound I-10-3 was dissolved in 20ml of DMF, and 4.10g N2-Fmoc-N3-Boc-D-2.3-diaminopropionic acid, 5.4g of HBTU and 1.85g of DIEA were added in this order, reacted at room temperature for 2 hours, detected by TLC (PE: EA ═ 1:1) until the starting material was reacted completely, 4ml of piperidine was added to the reaction solution, reacted at room temperature for 0.5 hours with stirring, detected by TLC (PE: EA ═ 1:1) until the starting material was reacted completely, the reaction solution was poured into 200ml of water, extracted with ethyl acetate 2 times (50ml × 2), the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-10-4(7.21g, off-white solid);
and 5: 7.21g of the compound I-10-4 was dissolved in 30ml of DMF, followed by addition of 4.62g of Fmoc-S-trityl-L-cysteine, 4.48g of HBTU and 1.53g of DIEA, followed by stirring at room temperature for 2 hours and detection by TLC (PE: EA ═ 2:1) until the starting material was reacted completely. The reaction solution was poured into 300ml of water, extracted 2 times with ethyl acetate (50 ml. times.2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-10-5(8.46g white solid);
step 6: dissolving 2.8g of compound I-10-5 in 200ml of DCM, dropwise adding a mixed solvent of 4.80g of elemental iodine and 1L (DCM: MeOH ═ 10:1) at room temperature, continuing the reaction for 0.5h after the dropwise addition is finished, and detecting by TLC (PE: EA ═ 1:1) until the raw materials are completely reacted. Dropwise adding saturated sodium sulfite aqueous solution into the reaction solution for quenching, adding 500ml of water into the reaction solution, separating, back-extracting the water phase once, combining the organic phases, washing the organic phase once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-10-6(1.52g, white solid);
and 7: dissolving 1.0g of compound I-10-6 in 40ml of DCM, adding 8ml of trifluoroacetic acid, reacting for 1.5h at room temperature, after the reaction is finished, adjusting the pH value to 7-8 by using a saturated sodium bicarbonate aqueous solution, separating liquid, back-extracting an aqueous phase once by using 40ml of DCM, combining organic phases, washing the organic phase once by using saturated sodium chloride, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain a compound I-10-7(800mg of white solid), and directly putting the compound I-10-7 into the next step;
and 8: dissolving 800mg of compound I-10-7 in 20ml of DMF, sequentially adding 588mg of compound 8, 507mg of HBTU and 172mg of DIEA, stirring at room temperature for reaction for 2 hours, adding 4ml of piperidine into the reaction solution after the reaction is finished, stirring at room temperature for reaction for 0.5 hour, pouring the reaction solution into 150ml of water after the reaction is finished, extracting with ethyl acetate (50ml of 2), combining organic phases, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-10-8(778mg white solid);
and 8: 778mg of compound I-10-8 was dissolved in 20ml of DMF, 173mg of Boc-N-methyl-DL-alanine, 403mg of HBTU and 137mg of DIEA were added in this order, and the mixture was stirred at room temperature for 2 hours, after completion of the reaction, the reaction mixture was poured into 200ml of water, extracted with ethyl acetate (50 ml. times.2), and the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-10-9(726mg, white solid);
and step 9: 726mg of compound I-10-9 was dissolved in 40ml of DCM, 8ml of trifluoroacetic acid was added, reaction was carried out at room temperature for 1.5h, after completion of the reaction, pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate, liquid separation was carried out, the aqueous phase was back-extracted once with 40ml of DCM, the organic phases were combined, the organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain compound I-10(28mg of white solid).
Example 11
Step 1: 1.2g of compound I-1-2 was dissolved in 25ml of DMF, and 1.0g of Fmoc-valine, 1.10g of HBTU and 0.38g of DIEA were added in this order to react at room temperature for 2 hours, followed by completion of TLC detection (PE: EA: 1) starting material reaction, and then 5ml of piperidine was added to the reaction mixture to react at room temperature for 0.5 hours, followed by completion of TLC detection (developing agent PE: EA: 1). The reaction solution was poured into 500ml of water, extracted 2 times with ethyl acetate (100 ml. times.2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (eluent DCM: MeOH) to give compound I-11-1(1.15g, white solid);
step 2: dissolving 1.15g of compound I-11-1 in 20ml of DMF, sequentially adding 1.0g N2-Fmoc-N3-Boc-D-2.3-diaminopropionic acid, 0.9g of HBTU and 0.3g of DIEA, reacting at room temperature for 2h, detecting by TLC (PE: EA ═ 1:1) until the raw materials react completely, adding 4ml of piperidine to the reaction solution, stirring at room temperature for 0.5h, detecting by TLC (PE: EA ═ 1:1) until the raw materials react completely, pouring the reaction solution into 200ml of water, extracting 2 times (50ml × 2) with ethyl acetate, combining organic phases, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-11-2(1.15g, off-white solid);
and step 3: 1.15g of compound I-11-2 was dissolved in 30ml of DMF, followed by addition of 1.1g of Fmoc-S-trityl-L-cysteine, 0.72g of HBTU and 0.24g of DIEA, followed by stirring at room temperature for 2 hours and detection by TLC (PE: EA ═ 2:1) until the starting material was reacted completely. The reaction solution was poured into 300ml of water, extracted 2 times with ethyl acetate (50 ml. times.2), the organic phases were combined and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-11-3(1.56g white solid);
and 4, step 4: dissolving 1.56g of the compound I-11-3 in 200ml of DCM, dropwise adding a mixed solvent of 2.70g of elemental iodine and 500ml of DCM (DCM: MeOH ═ 10:1) at room temperature, continuing the reaction for 0.5h after the dropwise addition is finished, and detecting by TLC (PE: EA ═ 1:1) until the raw materials are completely reacted. Dropwise adding saturated sodium sulfite aqueous solution into the reaction solution for quenching, adding 500ml of water into the reaction solution, separating, back-extracting the water phase once, combining the organic phases, washing the organic phase once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. Purifying the residue by column chromatography (eluent PE: EA) to obtain compound I-11-4(0.52g, white solid);
and 5: dissolving 520mg of compound I-11-4 in 20ml of DCM, adding 4ml of trifluoroacetic acid, reacting at room temperature for 1.5h, after the reaction is finished, adjusting the pH value to 7-8 by using a saturated sodium bicarbonate aqueous solution, separating liquid, back-extracting an aqueous phase once by using 40ml of DCM, combining organic phases, washing the organic phase once by using saturated sodium chloride, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I-11-5(420mg of a white solid);
step 6: the reaction mixture was dissolved in 10ml of DMF and 420mg of Compound I-11-5, followed by addition of 143mg of N-Boc-2-methylalanine, 267mg of HBTU and 91mg of DIEA at room temperature for 1.0h, and TLC detection (DCM: MeOH ═ 15:1) until the starting material was reacted completely. Adding 2ml piperidine into the reaction solution, stirring the reaction solution at room temperature for 0.5h, detecting by TLC (PE: EA is 1:1) until the raw materials completely react, pouring the reaction solution into 400ml water, extracting 80ml 2 by using ethyl acetate, combining organic phases, washing the organic phases once by using saturated sodium chloride, drying the organic phases by using anhydrous sodium sulfate, and concentrating the organic phases under reduced pressure. Purifying the residue by column chromatography (eluent DCM: MeOH) to obtain compound I-11-6(322mg, white solid);
and 7: dissolving 322mg of compound I-11-6 in 10ml of DCM, adding 100mg of triethylamine, cooling to-10 ℃, dropwise adding 70mg/2ml of dichloromethane solution of DCM acryloyl chloride into the reaction solution, reacting for 0.5h after the dropwise adding is finished, and finishing the reaction. Adding 20ml water into the reaction solution, separating, back-extracting the water phase with 20ml x2 with DCM, combining the organic phases, washing the organic phase once with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and purifying by column chromatography (eluent DCM: MeOH) to obtain compound I-11-7(250mg, white solid);
and 8: dissolving 250mg of compound I-11-7 in 10ml of DCM, adding 2ml of trifluoroacetic acid, reacting at room temperature for 1.5h, after the reaction is finished, adjusting the pH value to 7-8 by using a saturated sodium bicarbonate aqueous solution, separating liquid, back-extracting an aqueous phase once by using 20ml of DCM, combining organic phases, washing the organic phase once by using saturated sodium chloride, drying the organic phase by using anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain compound I-11(35mg of white solid).
Referring to the preparation method examples of the compounds, the compounds prepared by a series of reactions in a proper solvent and at a proper reaction temperature were subjected to nuclear magnetic and mass spectrometry and HPLC detection, and the test results are shown below.
Biological evaluation
Example 1.1 testing of the Compounds of the invention for IC50 values on XIAP BIR3 and cIAP1BIR3
The BIR3 structural region (10nM) was incubated with Smac polypeptide (10nM) in test buffer (50mM Tris, 120mM NaCl, 0.1% BSA,1mM DTT, 0.05% Triton X100) in the presence of test compound for 1h at room temperature. The mixture was transferred to streptavidin-coated plates and incubated for 1h at room temperature to allow the biotin-linked peptide to bind to the plate with the BIR3 domain. After several washes, Eu-labeled anti-GST antibody (Perkin Elmer DELFIA Eu-N1-anti-GST, # AD0250) was added to each well (1: 5000 dilution with Perkin Elmer DELFIA test buffer 2013-01) and incubated at room temperature for 1 h. After 3 washes in DELFIA Wash buffer (Perkin Elmer DELFIA Wash 2013-05), enhancement solution (Perkin Elmer enhancement solution 2013-02) was added and incubated for 10min, then the intensity of time-resolved fluorescent europium was measured and the IC50 value of compound inhibition was calculated using GraphPad Prizm 5.0 software.
Example 1.2 detection of cytotoxicity IC50 values of the Compound of the present invention against human Breast cancer cell line MDA-MB-231 cells and prostate cancer cell line PC-3 cells
Cells in the logarithmic growth phase were first collected, counted, resuspended in complete medium, adjusted to the appropriate concentration (determined according to the results of the cell density optimization assay), and seeded into 96-well plates, adding 100. mu.l of cell suspension per well. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 24 hours. The test compound was diluted with the medium to the set corresponding effect concentration and the cells were added at 25. mu.l/well. The final concentration of compound was started at 100. mu.M and diluted in 4-fold gradient for 10 concentration points. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2CulturingIncubate in the cabinet for 72 hours. 10. mu.l of CCK-8 was added directly to the cell culture medium and incubated in an incubator at 37 ℃ for 2-4 hours. After gentle shaking, absorbance was measured on a SpectraMax M5Microplate Reader, and the inhibition rate was calculated.
As can be seen from the results of biological evaluation experiments, the compound has strong inhibitory activity on cIAP1 and XIAP, and can strongly inhibit breast cancer cells MDA-MB-231 and prostate cancer cells PC-3.
Claims (9)
1. A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound has the general formula (I):
wherein the content of the first and second substances,
2. The compound of claim 1, wherein X is F, and pharmaceutically acceptable salts thereof.
6. a pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for a disease associated with the overexpression of an IAP protein in a mammal.
8. The use of claim 7, wherein the IAP-associated disease is selected from cancer.
9. The use according to claim 8, wherein the cancer is selected from the group consisting of neuroblastoma, intestinal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, prostate cancer, testicular cancer, breast cancer, urinary system cancer, melanoma, brain tumor hodgkin lymphoma, non-hodgkin lymphoma, burkitt lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, and chorio-cell lymphoma, Seminoma, rhabdomyosarcoma, craniopharyngeal tumor, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma, pancreatic cancer.
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